Harry M. Tiebout (2 January 1896 – 2 April 1966) was an American psychiatrist who promoted the Alcoholics Anonymous approach to the public, patients and fellow professionals. He served on the Board of Trustees of Alcoholics Anonymous from 1957 to 1966 and was president of the National Council on Alcoholism from 1951 to 1953.

Early life and education
Harry Tiebout was raised in Brooklyn, New York. He earned his bachelor's degree at Wesleyan University in 1917, then went to Johns Hopkins University School of Medicine, where he also completed an internship with a specialization in psychiatry. The psychiatry service at Hopkins was led by Adolf Meyer, who had an eclectic approach in which Freudian theory was contributory but not dominant. John B. Watson was also at Hopkins during the time Tiebout was there, conducting research in behaviorism which had substantial influence on the field of child development during the 1920s.

Clinical work
Tiebout was on the staff of New York Hospital, Westchester Division from 1922 to 1924. He began work in child guidance clinics in New York City, joining the Institute for Child Guidance as staff psychiatrist shortly after it was founded in 1927. The institute was a well-funded center for training and research, dominated by psychoanalysis and specializing in "exhaustive case histories 75 pages long." During these years Tiebout was also on the staff of Cornell Medical School and the Payne Whitney Psychiatric Clinic.

In 1935, he became medical director of Blythewood Sanitarium in Greenwich, Connecticut. Privately owned, Blythewood was situated on a beautiful, rustic  estate once owned by Boss Tweed. At its peak, it had eight main buildings, eight cottages, a chapel, a building for occupational therapy, and a small golf course. There were no bars on the windows. Artistic and cultural pursuits were encouraged as part of the therapeutic program. Although the sanitarium was primarily for care of the mentally ill, it also provided care for alcoholics.

In 1939, Tiebout received a pre-publication copy of the book Alcoholics Anonymous. After looking it over, he gave it to Marty Mann, one of his patients. She had been at Blythewood for over a year but seemed no closer to conquering her alcohol problem than when she arrived, so he considered her a good test of whether the book had value. At first, she read the book eagerly, delighted to know for the first time that there was a name (alcoholism) for what ailed her. However, she was soon repelled by the overbearingly religious message and told Tiebout that she could never accept it. Tiebout, according to Mann's biographers Sally and David Brown, quietly encouraged her to keep reading. Eventually taking the book to heart, she had an epiphany during a crisis of resentment and fury.

Other references, also based on Mann's recollections, portray Tiebout's role a little differently. They describe an ongoing verbal battle lasting several months, in which Tiebout refused to accept Marty's rejection of the book. In the end, Mann did become an active member of AA and within a few years made education about alcoholism, and promotion of alcohol-abuse treatment, her second career. With Tiebout's support, she founded the National Council on Alcoholism (NCA).

Tiebout also became a friend and supporter of AA founder Bill Wilson, providing personal psychiatric care when Wilson developed depression in the 1940s. It was largely through Tiebout's influence that Wilson was invited to speak at a New York state medical society meeting and then at a meeting of the American Psychiatric Association, and had his talk published in the American Journal of Psychiatry.

Alcoholism: Approach to the patient
Tiebout had many years of training and experience in the management of alcohol problems before his first exposure to Alcoholics Anonymous. However, his earliest detailed article concerning alcoholism was published in 1944, 5 years into his relationship with AA, and is primarily a description of AA itself. Over the next 10 years, he published a number of articles outlining his theories about alcoholism, the psychodynamic causes of the disorder and his reasons for endorsing AA as the definitive solution.

Howard J. Clinebell, in a book for clergy on alcoholism counseling, recalled that Tiebout "likened the 'runaway symptom' of alcoholism to the dangerously high fever of pneumonia. The fever is a symptom of the underlying infection, but unless it can be lowered, the person may die of the 'symptom"." Psychiatrists, Tiebout felt, had been ineffectual because they ignored the deadly symptom in an attempt to treat a (theoretical) underlying disease. He credited AA with an ability to target the symptom directly. Tiebout's understanding of the alcoholic mind cannot be entirely separated from his understanding of the 12-step approach, but the primary themes in his writings can be summed up under several points.

The alcoholic personality
In one of his early papers Tiebout discounted the idea, common among psychoanalytically inclined doctors, that there was a classic type of pre-alcoholic personality. In his view, all of the personality characteristics associated with early alcoholism were manifestations of the tension state accompanying intermittent alcohol binges. These features included:

 An unconscious need or drive to dominate
 A prevailing negative, hostile feeling-tone
 A capacity for ecstatic peaks
 A sense of loneliness and isolation
 Feelings of inferiority and superiority that exist simultaneously in the individual
 A striving for perfection

Howard Clinebell understood Tiebout to mean that there was, in fact, a pre-alcoholic personality but that "the distinctive factors have not yet been isolated". In a 1947 lecture, Tiebout located the roots of alcoholism in poor parenting, either excessive strictness which caused the child to suffer "perpetual frustration and blocking of his desires and expectations," or over-indulgence. Either way, "Since the alcoholic's sense of self-discipline has not been developed at this point, his natural reaction is to reject all discipline. He now cannot face the realities of his existence. This would indicate that the whole point of treatment is to get the alcoholic to face and accept his limitations and capacities."

The disease model
The concept of alcoholism that dominated treatment approaches in the second half of the 20th century, and is still influential today, defined alcoholism as a disease. The idea that alcohol problems constituted a disease was not new, but the particular synthesis associated initially with the Yale Center of Alcohol Studies (now at Rutgers) and the National Committee for Education on Alcoholism had unique features not found in earlier theories. The NCEA was one of Marty Mann's projects, and thus influenced by Tiebout. A 1990 Hazelden pamphlet cites Tiebout, Dr. William Silkworth and E.M. Jellinek as formative influences.

Tiebout seems to have been somewhat ambivalent about the disease model, however. In 1955, speaking of the scientific underpinnings of the alcoholism movement in general, he said "I cannot help but feel that the whole field of alcoholism is way out on a limb which any minute will crack and drop us all in a frightful mess." He was consistent in his belief that the acceptance of alcoholism as a disease was essential, but this belief was partially pragmatic. In his experience, chronic alcoholics did not take the steps necessary to recover unless they became conscious of themselves as people with a disease. He emphasized a different aspect of the model in public lectures, however. Family members, friends and employers of alcoholics were encouraged to keep in mind that the condition was an illness and not a moral failing.

Role of the ego
In a 1954 article, Tiebout introduced a definition of the term "ego" which was to become important in his later writings, particularly those for AA audiences. Although his use of the term was new, the concept behind it had been developed by Tiebout during the early 1940s. In these early articles, he was addressing a professional readership, and use of the term might have created confusion between the psychoanalytic meaning of ego and the colloquial "ego" which was Tiebout's essential meaning.

Based on work with 250 alcoholics during his first 10 years at Blythewood, Tiebout developed the following conception of the alcoholic mind:

In the normal individual there is a tendency to create some privacy for his inner life, for his motivations, reflections and emotions, so that they are not completely accessible to the environment. Normally this attempt interferes only slightly with the freedom of movement of outgoing and incoming stimuli and impulses. The boundary which the normal individual sets up between himself and the environment may be called a floating or diffuse boundary. In incipient alcoholism, however, it appears that the boundary is drawn somewhat tighter than is usual, and that with each stage of further development of the alcoholism more and more gaps are closed until the alcoholic seems to have erected what may be called a barrier which permits only a minimum of interplay between the inner self and the environment.

Using examples from dreams]of patients he had analyzed, Tiebout presented evidence for the existence of this rigid barrier. As long as the barrier remained, "As long as the self feels protected in a deep unconscious sense, it cannot be and is not disturbed by the warnings of reality, which characteristically roll like water off a duck's back." For the analyst,

Tactics are governed not only by strategy; they are also guided by three basic principles in technique. These are, briefly, that the patient must suffer or feel anxiety about himself and his condition; second, that it is the impersonal pressures of reality which activate suffering; and third, that it is the first and most immediate task of the psychiatrist to overcome the patient's refusal, unwillingness or inability to sense or feel these pressures of reality.

In his 1954 article "The Ego Factors in Surrender in Alcoholism", Tiebout began using the term "ego" to describe this concept of a self barricaded by defenses. He related it to Freud's "His Majesty the Baby" and to a similar concept introduced by Sandor Rado in 1933. Rado hypothesized that the elation induced by alcohol produced a reaction in the form of a "tense depression", which then reactivated the childish megalomania normally outgrown by adulthood. The result was a type of magical thinking in which "the ego secretly compares its current helplessness with its original narcissistic stature...and aspires to leave its tribulations and regain its old magnitude." Tiebout acknowledged his indebtedness to Rado's conception, while eliminating much of the psychoanalytic complexity of the original. He also felt that Rado was incorrect in advising only the "reduction" of the ego. Tiebout's view was that "reduction" represented a compromise and that there should be no compromise with the ego. The old ego should be eliminated and replaced with a new one through "surrender".

Surrender and conversion
The hallmark of Tiebout's work was his ability to explain 12 step ideas in psychoanalytic terms. The primary source for the steps was a religious movement popularized by Frank Buchman, with elements of the Higher Life movement tradition combined with the personal-evangelism techniques developed within the YMCA movement in the early 20th century. The Oxford Group had a successful program involving public and private meetings for witness and confession, as well as individual work. Their concept of "surrender" was the traditional Christian one, as a contemporary observer noted:

Surrender means the complete surrender of the will to Christ. They make no claim that this is easy. It may mean an entire change in one's whole life plan. It has meant just that for many of the Groupers. But it is necessary. So long as there are reserved areas in a man's life, they assert, he cannot expect to enter into a wholly satisfying experience of God.

Conversion, surrender, confession, restitution and the necessity of evangelizing others were ideas brought from the Oxford Group to Alcoholics Anonymous by members who had found that the intense religious devotion they inspired was the key to a changed life. Tiebout understood the concepts in a more secular way, and approved of them.

Tiebout had found that superficial compliance in therapy often correlated with lack of real change, and he saw in the AA concept of surrender an antidote to this phenomenon. An act of surrender was the only cure, or practically the only one, to the problem of "compliance", or partial surrender to the psychiatrist's authority and the authority of the reality principle. Tiebout described true surrender as "an unconscious event, not willed by the patient even if he or she should desire to do so. It can occur only when an individual with certain traits in his or her unconscious mind becomes involved in a certain set of circumstances," essentially the circumstances of "hitting bottom".

Conversion, for Tiebout, was a spiritual awakening made possible by the person's recognition of his own egocentricity. The central effect of Alcoholics Anonymous was "to develop in the person a spiritual state which will serve as a direct neutralizing force upon the egocentric elements in the character of the alcoholic." A "vague, groping, skeptical intellectual belief" would not accomplish this but only a true emotional religious feeling, for "unless the individual attains in the course of time a sense of the reality and the nearness of a Greater Power, his egocentric nature will reassert itself with undiminished intensity, and drinking will again enter into the picture."

Later life
Tiebout retired as medical director of Blythewood in 1950. The sanitarium gradually changed into a long-term care facility for the elderly, with fewer psychiatric patients. He continued to see patients privately, maintained an active speaking schedule, and served on the boards of various alcohol-related organizations. He died in Greenwich in 1966 of cardiac causes. He was the husband of the former Ethel Mills and father of Harry Tiebout, Jr., a philosophy professor; Charles Tiebout, an economics professor; and Sarah T. Worn.

References

1896 births
1966 deaths
Alcohol abuse counselors
American psychiatrists
Wesleyan University alumni
Johns Hopkins School of Medicine alumni
20th-century American physicians


Triptans is a word commonly used for a class of anti-migraine drugs that are selective 5-hydroxytryptamine/serotonin1B/1D (5-HT1B/1D) agonists. Migraine is a complex disease which affects about 15% of the population and can be highly disabling.
Triptans have advantages over ergotamine and dihydroergotamine, such as selective pharmacology, well established safety record and evidence-based  prescribing instructions. Triptans are therefore often preferred treatment in migraine.

History
Search for a new anti-migraine drug started at Glaxo in 1972. Studies in the 1960s showed that vasoconstriction from 5-HT, ergotamine and noradrenaline could reduce migraine attacks. Research also showed that platelet 5-HT level is reduced during migraine. Because there are too many side-effects for 5-HT to be used as a drug, scientists started research on the receptors of 5-HT in order to discover and develop a more specific agonist for 5-HT receptors. Research on the 5-HT receptors and their effect led to discovery of several types and subtypes of 5-HT. AH24167 showed a vasodilation effect instead of vasoconstriction due to the agonist effect on another type of 5-HT receptors later assigned the name 5-HT7. AH25086 was the second compound developed and showed a vasoconstriction effect but was not released as a drug due to low per oral bioavailability. Continued research led to the discovery of the first triptan drug, sumatriptan, that had both vasoconstriction effect, as well as better oral bioavailability. Sumatriptan was first launched in the Netherlands in 1991 and became available in the United States during 1993.

Mechanism
Triptans are specific and selective agonists for the 5-HT1 receptors. Sumatriptan binds to 5-HT1D receptors, zolmitriptan, rizatriptan, naratriptan, almotriptan, and frovatriptan binds to 5-HT1B/1D and eletriptan binds to 5-HT1B/1D/1F receptors. Triptans are believed to exert their effects through vasoconstriction, leading to reduced carotid arterial circulation without affecting cerebral blood flow, peripheral neuronal inhibition, or inhibition of transmission through second order neurons of the trigeminocervical complex.

Receptors
5-HT receptors are all G-protein coupled receptors (GPCR) except for 5-HT3 which is a ligand gated ion channel. The receptors that have been found to be involved in migraine are 5-HT1B, 5-HT1D and 5-HT1F receptors. 5-HT1B are found in meningeal arteries, agonism of 5-HT1B causes vasoconstriction in cranial nerves. The 5-HT1D receptors are located primarily in the trigeminal nerve in the central nervous system (CNS). They are also found in vascular smooth muscles, mediating contraction. Agonism of 5-HT1D receptors subdues the release of inflammatory inducing nerve stimulants. The amino acids contributing to the binding of ligands to the receptor are aspartic acid (Asp), phenylalanine (Phe), serine (Ser), threonine (Thr), tryptophan (Trp) and tyrosine (Tyr). It has been shown that both 5-HT1B and 5-HT1D receptors in humans have a very similar amino acids structures which demonstrates the similarities in binding properties.

Design
All triptans have an indole structure identical to the neurotransmitter 5-HT. Classic triptan structure contain side chain on the indole ring, and a basic nitrogen in a similar distance from the indole structure. The main structural difference of the triptans is the position of the sulfonamide and the side chain attached to it (see figure 1 and table 1). Rizatriptan and zolmitriptan have instead of a sulfonamide a triazole and 2-oxazolidone respectively. Another exception to the classic structure is seen on eletriptan where the nitrogen-alkyl chain connected to the indole ring is replaced with a dimethyl-pyrrolidine, and in naratriptan where the nitrogen-alkyl chain is replaced with a 1-methyl-piperidine ring.

One of the frovatriptan side chains forms an additional ring with the indole, resulting in a carbazole ring system.

Structures of the triptans

The 5-HT1B/D pharmacophore

5-HT1B and 5-HT1D receptors are considered very similar, they share amino acid homology and their ligands expose similar binding properties thus they have similar pharmacophore. The pharmacophore model for these receptors ligands is qualitative and defines the relative positions of important groups. It is defined with following five main features: an aromatic group (usually the indole), protonated amine (a donor of hydrogen bond), acceptor of hydrogen bond, additional hydrogen bond site (both donor and acceptor) and hydrophobic region located between both hydrogen bond sites, see figure 2. The main binding points were concluded to be the protonated amine and the hydrogen bond site. It was observed that the double bond region in the indole was necessary for the agonism in this series of compounds. Figure 3 shows how different drugs fit the pharmacophore, with an C and N linked analogues of 5-HT1D agonist. The marked sites on the figure are responsible for the affinity. The pharmacophore can be characterized as amphipathic, that means that the structure has both hydrophobic and hydrophilic groups.

Relevant structural features of triptans and binding to the receptor
Triptan structures were designed from the structure of 5-HT to attain affinity to 5-HT receptors, hence the identical indole structure. The hydroxyl group (-OH) on the hexane of the indole core and the alkyl-amine side chain on position C3 on 5-HT have been replaced with other compounds, such as sulfonamides or azol-ring structured derivatives and different amine-alkyl side chains. An electro-negative group can form a hydrogen bond with Thr in the pocket of the receptor. Sulfonamide derivatives attached to the hexane ring of the indole structure have electro-negative properties, as well as the triazole and 2-oxazolidone on rizatriptan and zolmitriptan respectively. This can increase binding ability of the compound and the efficacy, especially with the 5-HT1D receptor.

A schematic drawing of the binding of sumatriptan to 5-HT1D receptor can be seen in figure 4. One study  showed that sumatriptan fits better in the binding site of the receptor when the side chain with the protonated nitrogen atom is folded back over the indole structure. This alignment contributes to the hydrogen bonding between the nitrogen in the sulfonamine and the Ser138 in the binding site. It is also favorable to the formation of the hydrogen bond between the oxygen of the sulfonamine and Thr202. Other binding in the pocket of the binding site occurs with the nitrogen atom in the pentene ring of the indole structure of the triptan and the amino acid Ser352. This energetically favorable position of the agonist makes it possible for additional binding of the ligand to other Ser in the binding site, along with additional anchoring between Phe in the pocket of the binding site and the indole of the agonist. The binding of Phe and the triptan is caused by π stacking interactions of the indole and amino acid and an additional effect on this interaction is because of dispersive effect of amino acid leucine (Leu; not shown in figure 4). The amino acids Trp343 and Tyr346 both have electron rich π-systems in their aromatic structures. With their position in the binding site they create a sort of aromatic cage around the protonated nitrogen atom of the side chain on position C3 on the triptans (this nitrogen atom is protonated at physiological condition), and thereby stabilizes the ion bond the nitrogen atom has formed with a carboxylate on aspartic acid. Side chains of the surrounding amino acids can have an effect on the binding of the nitrogen atom, mainly three Phe can affect the methyl groups bound to the nitrogen atom (not shown in figure 4).

Eletriptan has higher affinity for the receptor, which is probably a result of the bulky substituents of the structure. The amine is protonated at physiological pH condition, triggering better uptake. The uptake rate of the agonist is different depending on whether the amine in R2 is primary, secondary or tertiary but the latter seem to give the best results. For the R1 substituent an electron rich sulfonamide groups and amide group has shown the best results in receptor binding and activity. It has been observed that a relationship is between absorption and molecular size hence larger hydrophilic molecules tended to have poor absorption. A small R1 substituent is necessary to maintain the rapid oral bioavailability of triptans.

By placing an electron-withdrawing group or large group on position C2 on the indole structure the 5-HT agonist is conversed into an antagonist. This is thought to be because the indole ring is unable to occupy the aromatic part of the binding site.

Triptan drugs

Properties of formulations
Sumatriptan was the pioneer drug in this class. The second generation's triptans such as zolmitriptan, naratriptan, rizatriptan, almotriptan, eletriptan and frovatriptan soon became available.
Different triptans are available in different formulations and in different strengths (see table 2). They have been formulated as subcutaneous injections, oral tablets, orally disintegrating tablets, nasal spray and as rectal suppositories.
Delivery system of the triptans may play an important role in the onset of action. The selection of anti-migraine drug for patients depends on their symptoms. The first selective 5-HT1B/1D agonist, sumatriptan, was first synthesized as a subcutaneous injection, then as an oral tablets and more recently as a nasal spray, it is also available in some countries as suppositories. The subcutaneous injection is the fastest way to stop a rapidly progressing migraine attack. The sumatriptan nasal spray provides faster onset of action than the tablets but it produces a similar headache response at 2 hours. Some patients prefer the nasal spray as it works more rapidly than the tablets and does not have as many adverse effects  as the subcutaneous injection. Nasal spray is although not suitable for all patients, because some patients experience bad taste and lack of consistency of response. Zolmitriptan was developed with the strategy to create a more lipophilic compound, with faster absorption and better ability to cross the blood brain barrier  than sumatriptan. It is available as tablets, orally disintegrating tablets and as nasal spray in some countries. Rizatriptan is available as tablets and orally disintegrating tablets but naratriptan, almotriptan, eletriptan and frovatriptan are only available in tablets, for now.

a Specific enzyme not yet reported.
The U.S. Food and Drug Administration (FDA) approved a new drug April 15, 2008, which is a combination of sumatriptan 85 mg and naproxen 500 mg (NSAID).
Triptans and NSAIDs work on distinct mechanism involved in migraine and therefore may offer improved treatment when administrated together.

Pharmacokinetics

Pharmacokinetic properties (see table 3) are important when new drugs are developed.

Patients seek rapid onset of action to relief the headache. Relatively short tmax, good bioavailability and lipophilicity are pharmacokinetic properties that have been associated with rapid onset of action. It has been speculated that good ability to cross the blood brain barrier and relatively long terminal elimination half-life  may result in a lower incidence of headache recurrence. Sumatriptan and rizatriptan undergo first pass hepatic metabolism and result in lower bioavailability.

t1/2 = Elimination half-life;
tmax = Time to reach peak plasma drug concentration;
ClR = Renal Clearance;
LogDpH7.4 = Measure of lipophilicity at pH 7.4. Increasing number indicate greater solubility;
VD  = Volume of distribution
M = Male; F = Female

Future research

Most triptans were developed and introduced in the 1990s. Further studies have not shown much promise regarding the development of new triptans with better duration of action, efficacy and safety profile. Therefore, it is unlikely that further variations will be developed and new anti-migraine drugs are likely to have another mechanism of action.

References

Triptans
Triptans, Discovery And Development Of


Eberhard Edzard van der Laan (; 28 June 1955 – 5 October 2017) was a Dutch politician who served as Minister for Housing, Communities and Integration from 2008 to 2010 and Mayor of Amsterdam from 2010 until his death in 2017. He was a member of the Labour Party (PvdA).

Van der Laan, a lawyer by occupation, worked for the Trenité Van Doorne Advocaten law firm from 1982 until 1992 when he co-founded the Kennedy Van der Laan law firm and served as a partner until 2008. After Ella Vogelaar—Minister for Housing, Communities and Integration in the Fourth Balkenende cabinet—resigned because the Leader of the Labour Party Wouter Bos lost his confidence in her position after increasing criticism on her performance, Van der Laan was asked to succeed her and took office on 14 November 2008. The Fourth Balkenende cabinet fell on 23 February 2010 as the result of disagreement between the Christian Democratic Appeal (CDA) and the Labour Party over the extension of ISAF mission in Afghanistan.

On 27 January 2017 it was revealed that Van der Laan had terminal lung cancer. On 18 September 2017 he published a letter entitled "Dear Amsterdammers", in which he revealed that all options of treatment had been exhausted and that with immediate effect he would take a leave of absence and the mayoral tasks would be taken up by Kajsa Ollongren. He died seventeen days later.

Early life
Van der Laan was born in Rijnsburg, a small town nearby Leiden. Van der Laan graduated in 1983 cum laude in law at the Vrije Universiteit Amsterdam. He co-founded the law firm of Kennedy Van der Laan.

Politics

Local politics
Van der Laan began his  political career as assistant to Amsterdam alderman Jan Schaefer. From 1990-98 he was a member of the Amsterdam municipal council, from 1993 as the chair of the Labour Party group. After leaving politics he became a full-time lawyer.

National politics
In 2006 he was informateur in the negotiations of the new Amsterdam college van burgemeester en wethouders. In the local elections, politicians were criticized by Van der Laan for distributing election leaflets in minority languages and in some cases leaflets were collected. On 14 November 2008 he succeeded Ella Vogelaar as Minister for Housing, Communities and Integration in the Fourth cabinet Balkenende. On 23 June 2010 he was nominated by the Amsterdam municipal council to become Mayor of Amsterdam; the nomination was accepted by the King's Commissioner of North Holland.

Death
On 27 January 2017 it was revealed that Van der Laan had metastatic lung cancer. He died on 5 October 2017 from this disease at the age of 62.

Decorations

References

External links

Official
  Mr. E.E. (Eberhard) van der Laan Parlement & Politiek

1955 births
2017 deaths
Deaths from cancer in the Netherlands
Deaths from lung cancer
Dutch jurists
Dutch republicans
Dutch political consultants
Dutch speechwriters
Labour Party (Netherlands) politicians
Mayors of Amsterdam
Ministers without portfolio of the Netherlands
Municipal councillors of Amsterdam
Officers of the Order of Orange-Nassau
Reformed Churches Christians from the Netherlands
Politicians from Leiden
Vrije Universiteit Amsterdam alumni
20th-century Dutch lawyers
20th-century Dutch politicians
21st-century Dutch lawyers
21st-century Dutch politicians


The Urgent Deficiencies Act of 1913 authorized the elimination of many nonessential government publications.

Legislation
As part of the legislation, all information relating to the United States Post Office Department, including the statement of allowances to mail contractors, was removed from the Official Register.  The list of ships and vessels belonging to the United States was eliminated as well.  The bill also declared that Federal district courts would have jurisdiction in cases brought to enjoin, set aside, annul, or suspend in whole or in part any order of the Interstate Commerce Commission (ICC).  Put another way, I.C.C. orders and enforcements were now subject to Federal district court review, and the special commerce Court of the I.C.C. was abolished.  Such cases would be decided upon by specially constituted three-judge panels that would hear and decide on the merits of the arguments for or against enforcement.

Amendments
The district court right of review portion of the act was repealed in 1975.  There was also a rider attached to the bill that abolished nepotism within the Bureau of Internal Revenue and Treasury Department, added after Treasury Secretary McAdoo was accused of appointing 5 family members under the name "Eisner."

1913 in American law
United States federal postal legislation
United States government information
Printing in the United States


Baekbyeongsan is a hill in the city of Taebaek, Gangwon-do in South Korea. It has an elevation of .

See also
List of mountains in Korea

Notes

References

Mountains of South Korea
Mountains of Gangwon Province, South Korea
Taebaek
One-thousanders of South Korea


Francisco Vidal Gormaz (July 1, 1837 in Santiago, Chile – February 5, 1907) was a Chilean naval officer and hydrographer who explored the coasts of Chile including some river systems and lakes. During the 1850s he explored and surveyed several times Maullín River with Francisco Hudson. Before being lost at sea in 1859 Hudson is thought to have been a major influence on Vidal Gormaz. He participated in the Occupation of the Araucanía performing reconnaissance missions in the coasts of Arauco and Toltén. In 1863, he was named director of the Maritime School of Ancud (Escuela Maritima de Ancud). In 1874, he became the first director of the newly created Hydrographic Office (Oficina Hidrográfica). In 1884, he became General Inspector of Lighthouses and participated in the International Meridian Conference. Because of his neutrality during the 1891 Chilean Civil War he was removed from his post as director of the Hydrographic Office. He was named assistant at the Sea Ministry (Spanish: Ministerio de Marina) in 1894 and retired from the navy in 1899.

While making a hydrograpahic survey around Chiloé Archipelago in 1871 Vidal Gormaz obtained information from locals on the effects of the 1837 Valdivia earthquake. His explorations of the southern Patagonian archipelagoes made him critical of the work of Robert FitzRoy and Charles Darwin whom according to him had failed acknowledge the importance of the Patagonian islands.

See also

Bernhard Eunom Philippi
Roberto Simpson
Hans Steffen

References

Sources
La Tercera - Icarito
Armada de Chile

19th-century Chilean Navy personnel
19th-century explorers
Chilean explorers
Chilean Navy officers
Chilean hydrographers
1837 births
1907 deaths
Explorers of Chile
People of the Occupation of Araucanía


Cutter Service Act, 1914 is a United States federal statute authorizing the construction of two revenue cutter vessels as related to medical and surgical relief for American vessel crews engaged in the deep-sea fisheries. The two revenue cutters provided a class of service as a steam-powered vessel encompassing the coastal geography of the Gulf of Mexico and Maine.

The act of Congress emphasized providing otherwise-unobtainable medical services for seamen on board American fishing fleets. It authorized the commandant of the Revenue Cutter Service to "detail for duty on revenue cutters such surgeons and other persons of the Public Health Service as ... necessary."

As a result of the act, many cutter vessels were fitted out as hospital ships and "relieved from the regular duties as normally performed by cutters" to cruise the fishing banks off the U.S. coastlines as floating hospitals.

See also
USRC Mohawk
USCGC Seneca (1908)
USRC Tahoma

1914 in American law
United States federal legislation


Seven Stories was an Australian rock group formed in Adelaide, initially as Tall Stories, in 1986. They were signed to Sony (then CBS Records) and released two studio albums, Judges and Bagmen (1990) and Everything You Want (Nothing That You Need) (1993). At the ARIA Music Awards in 1991 they were nominated for Breakthrough Artist – Single for "Sleeping Through Another War" (1990). The group disbanded in 1994.

History

Seven Stories future members Michael Boundy, Sue Oliver and Andrew Tanner were involved in the Adelaide music scene from the late 1970s. They were sessions musicians at the Good God recording studio, which was run by Rod Boucher and Chris Adams. In 1978 Tanner contributed drums and vocals to Good God recordings, later moving to guitar in the band, the Retreads, which released a self-titled album, in 1980. Boundy played bass guitar for the bands, Thumbs Up and then the Retreads (with Tanner) before joining Perfect Strangers in 1980. In 1984 Tanner composed a track, "Dreams and Visions", which became a banner song for the Uniting Church's National Christian Youth Convention in Adelaide in 1985. "Dreams and Visions" is about Pentecost and is still used by Australian congregations.

Boundy on bass guitar, Oliver on percussion and backing vocals and Tanner on guitar and lead vocals joined up with Jeff Algra on drums, percussion and backing vocals, Glyn Lehmann on keyboards, accordion, French horn and backing vocals to form a rock group, Tall Stories, in Adelaide, in 1986. Their first major recording was a self-produced, self-distributed 12" mini LP Sleeping Through Another War, released in 1987. Oliver left during that year.

Gaining commercial airplay, a major breakthrough came with the signing of the band by Sony (then CBS Records) to a five-year deal. Around 1989 the band changed its name to Seven Stories, to avoid confusion with a United States band, Tall Stories. The deal with Sony led to the critically acclaimed Judges and Bagmen album in 1990. All ten tracks were written by Tanner and it was recorded between October and December of the previous year with Kevin Moloney producing at Platinum Studios, Melbourne. Rolling Stones reviewer, in January 1991 stated, "it is the music which makes Judges and Bagmen such a compelling album" Additional musicians on the recording are Vika and Linda Bull and Broderick Smith.

At the ARIA Music Awards of 1991 Seven Stories were nominated for Breakthrough Artist – Single for "Sleeping Through Another War". "Sleeping through Another War" and "Walk through Babylon" were released by CBS as singles off the album. The band toured extensively throughout Australia supporting artists such as Midnight Oil, INXS, The Black Sorrows, Hothouse Flowers, Hunters and Collectors and Paul Kelly.

High-profile producers T-Bone Burnett and Boom Crash Opera's Richard Pleasance were engaged by Sony for Seven Stories' second album, Everything You Want (Nothing That You Need) (1993), which provided two singles, "Is that It?" and ". Although he contributed to the album, Lehmann had officially left the band by the time of its release, leaving Algra, Boundy and Tanner as the remaining core. The band toured Europe and North America to support the album. Guitarist David Carr, engaged to augment the band for this recording, relates the band's sudden abandonment by Sony: "We toured that album very successfully, recorded a JJJ Live at the Wireless and had a string of singles before the whole of Sony was instructed to 'drop everything' and divert all energy to making Mariah Carey number one." Seven Stories subsequently disbanded in 1994.

Andrew Tanner worked in Melbourne as a writer and is a member of the psychedelic-styled band The Sand Pebbles and the Woodland Hunters. Boundy, Algra and Lehmann all returned to Adelaide and remained active musically. Drummer Algra played and recorded with a large number of artists including, T-Bone Burnett, The Waifs, The Borderers (with Glyn Lehmann), Jeanette Wormald, Jim Hermel, Andrew Clermont, Liam Gurner, and Jet O'Rourke.

Lehmann has had a musical career as composer, songwriter, arranger, performer and music producer. He has created original music, songs and soundtracks for Australian Broadcasting Corporation television and radio, and the feature-length documentary I Told You I Was Ill – The Life and Legacy of Spike Milligan. He has also worked with the State Theatre Company of South Australia and the Adelaide Symphony Orchestra.

Boundy has played with Adelaide bands Verandah, Vivid, The Borrowed Ones, and played with Lehmann in the band, Sun Theory.

Seven Stories reformed for a one-off performance in Adelaide in April 2012.

Members

Andrew Tanner – guitar, vocals, keyboards
Glyn Lehmann – keyboards, backing vocals
Michael Boundy – bass guitar
Jeff Algra – drums, percussion, backing vocals
Sue Oliver – percussion, vocals (1986–1987)

Discography

Studio albums

Singles

Awards and nominations

ARIA Music Awards
The ARIA Music Awards is an annual awards ceremony that recognises excellence, innovation, and achievement across all genres of Australian music. They commenced in 1987. 1927 have won three awards.

!
|-
| 1991
| "Sleeping Through Another War"
| ARIA Award for Breakthrough Artist - Single
|
|
|-

References

Australian rock music groups
Musical groups disestablished in 1994
Musical groups established in 1986
1986 establishments in Australia


The Cooperative Funds Act is a United States law, or series of laws, which authorized the United States Forest Service (FS) to collect donations from private partners to perform FS work. Contributions had to be voluntary, and by cash, check, or money order only. It was also stipulated that there could be no conflict of interest between the donor and the FS.

Federal acts
The FS must have appropriate statutory authority prior to entering into any grant, cooperative agreement, or other agreement which could result in the use, obligation, or other commitment of any Forest Service resources. To this end, the Congress has passed several authorizations, including:

The Economy Act of June 30, 1932 (31 USC 1535, Public Law 97-258 and 98-216) - Section 601 of this Act authorizes one federal agency to requisition work, services, supplies, materials, or equipment from another federal agency.
The Act of August 27, 1958 (23 USC 308(a), Public Law 85-767) - This Act authorizes the Federal Highway Administration to perform by contract or otherwise, authorized engineering or other services in connection with the survey, construction, maintenance, or improvement of highways on behalf of other government agencies.
Intergovernmental Cooperation Act of 1968, as amended by the Intergovernmental Cooperation Act of September 13, 1982 (31 USC 6501 -6508, Public Law 97-258) - Title III of this Act authorizes FS to provide special or technical services to states or their political subdivisions.
Federal Technology Transfer Act of 1986 (15 USC 3710a, Public Law 96-480) - This Act authorizes FS to enter into cooperative research and development agreements for technological transfer for commercial purposes.
Federal Grants and Cooperative Agreements Act of 1977,as amended by the Using Procurement Contracts and Grant and Cooperative Agreements Act of September 13, 1982 (31 USC 6301-6308, Public Law 97-258) - Unless the relationship is otherwise specified by statute, this Act requires that federal agencies characterize the relationship between a federal and non-federal party as one of a procurement contract or of Federal Financial Assistance. The selection of a particular instrument, such as a procurement contract or an assistance instrument, to document the transaction is determined by this relationship.
United States Information and Exchange Act (22 USC 1451 and 1479, Public Law 97-241) - This Act authorizes FS to cooperate with foreign governments by providing FS employees with specific technical or professional qualifications.
Cooperative Funds Act of June 30, 1914 (16 USC 498 as amended by Public Law 104-127) - Authorizes FS to accept money received as contributions toward cooperative work in forest investigations or protection, management, and improvement of the National Forest System.
Granger-Thye Act of April 24, 1950 (16 USC 572) - Section 5 of this Act authorizes FS to perform work to be done for the benefit of the depositor, for administration, protection, improvement, reforestation, and such other kinds of work as the Forest Service is authorized to do on lands of the United States: (a) on state, county, municipal, or private land within or near National Forest land, or (b) for others who occupy or use National Forests or other lands administered by FS.
Acceptance of Gifts Act of October 10, 1978 (7 USC 2269, Public Law 95-442) - Authorizes FS acceptance of cash and donations of real personal property.
Cooperative Funds and Deposits Act of December 12, 1975 (16 USC 565a1-a3, Public Law 94-148) - Authorizes FS and partners to perform work from which they would accrue mutual non-monetary benefit.
Interior and Related Agencies Appropriations Act of 1992 (Public Law 102-154, (Challenge Cost Share)) - Authorizes FS to cooperate with others in developing, planning, and implementing mutually beneficial projects that enhance FS activities, where the partners provide matching funds or in-kind contributions. Partners may be public or private agencies, organizations, institutions, or individuals. The Act also gives the agency the authority to provide non-monetary awards and to incur necessary expenses for the non-monetary recognition of individuals and organizations.
Title 7, United States Code, Section 2204a - Provides for the exchange of personnel and facilities in each field office of the Department of Agriculture to the extent necessary and desirable to achieve the most efficient use of personnel and facilities, and to provide the most effective assistance in the development of rural areas in accordance with state rural development plans.
Federal Employees International Organization Service Act (5 USC 3343 and 3581-3584, as amended) - Authorizes FS to send employees to an international organization which requests services for a period not to exceed 5 years.
National Agricultural Research, Extension, and Teaching Policy Act of 1977 (Public Law 95-113), as amended by the Food Security Act of 1985 (7 USC 3318, and 3319, Public Law 99-198) and further amended by Public Law 105-198 - Authorizes FS to enter into joint venture agreements with any entity or individual to serve the mutual interest of the parties in agricultural research and teaching activities, whereby all parties contribute resources to accomplish those objectives (7 USC 3318(b)). It also authorizes the FS to enter into cost-reimbursable agreements with state cooperative institutions or other colleges and universities without regard to any requirement for competition, for the acquisition of goods or services, including personal services, to carry out agricultural research or teaching activities of mutual interest (7 USC 3319(a).
Youth Conservation Corps Act of 1970 (16 USC 1701-1706, 1723) as amended by the Title II, Public Land Corps Act of 1993 (Public Law 91-378) - Authorizes FS to utilize the Corps or any qualified youth or conservation corps to carry out conservation projects on public lands, Indian lands and Hawaiian homelands. Conservation projects may be carried out on state, local, or private lands as part of disaster prevention or relief efforts in response to an emergency or major disaster declared by the President.
Volunteers in the National Forest Act of 1972, as amended (16 USC 558a – 558d, Public Law 92-300) - The FS is authorized to recruit, train, and accept individuals as volunteers for or in aid of interpretive functions, visitor services, conservation measures and development, or other activities in and related to areas administered by FS. Incidental expenses are authorized.
Forest and Rangeland Renewable Resources Research Act of 1978, as amended (16 USC 1641-1646, Public Law 95-307) - Authorizes implementation of a program of forest and rangeland renewable resources research, dissemination of the research findings. It authorizes the acceptance and investing of gifts, donations and bequests.
Cooperative Forestry Assistance Act of 1978, as amended (16 USC 2101-2114, Public Law 95-313) - Authorizes FS to work through and in cooperation with state foresters or equivalent agencies, and other countries in implementing technical programs affecting non-federal forest lands.
National Forest Dependent Rural Communities Economic Diversification Act of 1990 (7 USC 6601 note, Public Law 101-624) - Title XXIII, Subtitle G, Rural Revitalization Through Forestry, authorizes FS establishment and implementation of educational programs and technical assistance to businesses, industries, and policy makers to create jobs, raise incomes, and increase public revenues in ways that are consistent with environmental concerns.
America the Beautiful (16 USC 2101, Subtitle C, Public Law 101-624) - This law created the National Tree Trust, a nonprofit foundation, to promote public awareness and solicit private sector contributions to encourage tree planting projects. It allows FS to promote principles of basic forest stewardship, and to provide assistance to others to plant and maintain trees and improve forests in rural areas.
The International Forestry Cooperation Act of 1990 (16 USC 4501, Public Law 101-513, as amended) - Authorizes FS cooperation and assistance with domestic and international organizations to further international programs which support global environmental stability, scientific exchange and educational opportunities, and technical and managerial expertise.
Cooperative Law Enforcement Act of August 10, 1971 (16 USC 551a, Public Law 92-82) - Authorizes FS cooperation with state or their political subdivisions to enforce or supervise laws and ordinances of a state or political division on National Forest System lands.
The Reciprocal Fire Act of May 27, 1955 (42 USC 1856a, Public Law 84-46) - Authorizes FS to make reciprocal agreements with any fire organization maintaining fire protection facilities in the vicinity of National Forest lands.
National Forest Roads and Trails Act of October 13, 1964 (16 USC 532-538, Public Law 88-657) - Authorizes FS financing and cooperation with other public or private agencies or individuals, for acquisition, construction and maintenance of forest development roads within or near National Forests.
National Trails System Act (16 USC 1246(h), Public Law 90-543) - Authorizes FS cooperation with states or their political subdivisions, landowners, private organizations or individuals, to operate, develop and maintain any portion of national trail system trails either inside or outside a federally administered area.
Wild and Scenic Rivers Act (16 USC 1271 et seq., Public Law 90-542) - Authorizes FS cooperation with states or their political subdivisions, landowners, private organizations or individuals, to plan, protect and manage river resources.
Federal Noxious Weed Act of 1974 (Public Law 93-629, 7 USC 2801 et seq., Public Law 101-624) - Title XIV, Subtitle D: Other Conservation Measures, authorizes FS to issue cooperative agreements with state agencies (or political subdivisions responsible for the administration or implementation of state laws regarding undesirable plants) for establishment of undesirable-plant management programs and integrated management systems to control undesirable plant species, and to issue cost-sharing cooperative agreements with agencies to manage noxious weeds in an area if a majority of landowners in that area agree to participate in a noxious weed program.
National and Community Service Act of 1990 (42 USC 12501, Public Law 101-610) - Subtitle C, National Service Trust Program, establishes the Corporation for National Community Service, which may enter into contracts or cooperative agreements with federal agencies to support a national service program carried out by the agency.
Sikes Act of September 1, 1960 (16 USC 670g-6701, 670o, Public Law 86-797, as amended) - Authorizes FS cooperation with state wildlife agencies in conservation programs for fish, wildlife, and plants considered threatened or endangered.
Wyden Amendment (Watershed Restoration and Enhancement Agreements) - In accordance with specific statutory authorities, this law allows FS to make cooperative agreements with federal, tribal, state, and local governments, private and nonprofit entities, and landowners, to protect, restore, and enhance fish and wildlife habitat, as well as other resources on public or private land that benefit those resources within the watershed.

Use of cooperative agreements
Cooperative agreements used may include the types of instruments contemplated under Section 1587.03 of the Forest Service Manual. Also, Federal Financial Assistance instruments (grants or cooperative agreements) may be used. Authority to use all these instruments is the Department of Interior and Related Agencies Appropriations Act, 1999, FSM 1587.15, FSH 1509.11, Chapter 60, Wyden Amendment, Section 323(A), as included in Public Law 105-277, Div. A, Section 101 (e) as amended by Public Law 107-63, Section 330.

References

United States Forest Service
Federal government of the United States
Legal history of the United States
United States federal environmental legislation


Men Diana Illa... (English: From Diana To...) is the 11th (Anida is not counted as a studio album) studio album by Lebanese singer Diana Haddad, released by in November 2008, continued along the lines established by her 2002 album Law Yesaloni.

Track listing

Credits and personnel

Production

 Vocals: Diana Haddad
 Master Mix: Hussam Kamal
 Digital Master: Nasha'at Nasser Al Deen-Egypt
 Sound engineering: Saber Qasam Allah, Waleed Al Najaar
 Strings: Mr. Azef Jmn, Mr. Aziz Al Masri
 Harmony: Sameer Alqatan, Waheed Mubarak
 Solo Saxophone: Wessam Khassaf
 Solo violin (Turkey): Morat Skariaw
 Recorded by: Nojoom Music Studios (UAE, Dubai)
 Supervised by: Bassam Al Turk
 Media classification: Morad Al Natsha
 Pictures by: Hekmat Wahbe
 Designed by: Stockad
 Production, distribution, publication supervised by: Pier Al Ashqar
 Produced, distributed, published by: Nojoom Music
 Special Thanks: Lebanese Fashion designer: Akl Fakeh, Abd Al Raheem Mouhammed, Hazem Faris, Nahla Al Fahad, Samir Haddad

Songs Charts

Sheft Itessalek

Rouh Ya Sghier

Shlon Ashofh

Diana Haddad albums
2008 albums
Khaliji albums


The Agricultural Entry Act allowed Federal lands containing minerals, petroleum, nitrate, phosphate, potash, oil, gas, and asphalt to be leased to private developers, as long as such deposits in specially zoned lands were left alone. The Federal government reserved the right to abrogate whatever uses the surrounding lands had been developed for in the event that it was deemed necessary for deposit procurement.

References

63rd United States Congress
United States federal public land legislation


Sessegnon or Sessègnon is a surname of West African origin. Notable persons with that name include:

 Stéphane Sessègnon (born 1984), Beninese association football striker
 Ryan Sessegnon (born 2000), English association football left-back
 Steven Sessegnon (born 2000), English association football defender or midfielder

Ryan and Steven are twin brothers; Stéphane is their cousin they also have an older brother , Chris who is a semi professional footballer.

References


Manik () is a Bengali  action drama film released in 2005. It was directed by Probhat Roy,  the movie featured Jeet, Koel Mallick, Ranjit Mallick.
 This film was shot at Kalimpong Golf Course.

Plot
Samir Mitra is an unemployed educated man who is looking for a job. His father Abir Mitra is a retired person. Samir's mother is suffering from cancer. One day Samir suddenly meets Manik Chandra Sadhukhan. Manik's father is Niranjan Sadhukan, he is also ill. Latika is Manik's younger sister. Manik has come to Kolkata to meet his father's friend Chandrakanta Majumadar who is an established businessman. Manik meets with an accident on the way. Samir tries to save his life. Before his death Manik requests Samir to take care of his father and younger sister; he also tells Samir not to disclose the news of his accident. Manik gives Samir all the required information. Samir becomes Manik; he meets Chandrakanta as Manik. Chandrakanta appoints him in his own office. Samir meets Chandrakanta's daughter Ria and wife Manju, Ria and Samir gradually fall in love but Samir feels uncomfortable whenever he thinks that when everybody discovers that he is not Manik then what will happen. From his salary he maintains his own family and Manik's family. Everybody is impressed with his behavior and honesty. Suddenly Niranjan and Latika come to Kolkata because Niranjan is unwell. Niranjan has lost his eyesight and there is a problem in his heart also. Samir tries to hide from Niranjan but everybody learns the truth. Kartik Sen, the business rival of Chandrakanta, kidnaps Ria and demands ransom. Samir and Chandrakanta rescue her with the help of police. Samir donates his father's eye to Niranjan. Niranjan recovers his eyesight.

Cast
 Jeet as Samir Mitra, who disguised himself as Manik
 Ranjit Mullick as Chandrakanto Majumdar
 Koel Mullick as Riya Majumdar
 Samata Das as Latika, Manik's sister
 Monu Mukherjee as Abir Mitra, Samir's father
 Soma Dey as Manju Majumdar, Riya's mother
 Debdoot Ghosh as Manik Chandra Sadhukhan, a poor village boy from Medinipur
 Rajatava Dutta as Samir's college friend Anwar, a taxi driver
 Shyamal Dutta as Niranjan Sadhukhan, Manik's blind father
 Shantilal Mukherjee as Shiben, flat contractor
 Sagnik Chatterjee as Pratik Sen
 Biplab Chatterjee as Kartik Sen
 Alakananda Ray as Samir's mother
 Rajesh Sharma as Shambhu, Kartik Sen's henchman

Soundtrack

The music for the film has been composed by Babul Bose. All lyrics are written by Gautam Sushmit.

Singers are Babul Supriyo, Shreya Ghoshal, Jojo and Reema Mukherjee.

Awards
Awarded by ETV Lux Best Film in 2005
Awards   :Lux ETV Award as the Best Film in the year 2005. Won five awards.
 Anandalok Awards  (2005)
 Best Actor: Jeet
 Best Playback Singer (Female) :Shreya Ghoshal

References

External links
www.telegraphindia.com preview

2005 films
2000s Bengali-language films
Bengali-language Indian films
2005 romantic comedy-drama films
Indian romantic comedy-drama films
Films directed by Prabhat Roy
Films scored by Babul Bose


The Handball events at the 1998 Asian Games were held in Bangkok, Thailand between December 7 and December 16, 1998. South Korea dominated the competition by winning both gold medals.

Schedule

Medalists

Medal table

Draw

Group A

Group B

Final standing

Men

Women

References
Results – Men
Results – Women
Japan Handball Federation

External links
 Asian Handball Federation

1998 Asian Games events
1998
Asian Games
1998 Asian Games


How to Do Well When You're a Jerk and a Crybaby () is a French comedy film directed by Michel Audiard, released in 1974. It is notable as the first film with the actor Jean-Claude Dreyfus. Audiard appears in the film as a nurse.

Plot
In Paris, Antoine lives modestly with his sour old mother and sells cases of fake vermouth to owners of little bars, his ploy being to win their sympathy, particularly the wives. Telling tales of his sad life, he recites fake Baudelaire poetry and ends with the burial of his beloved mother. He wins the sympathy of Marie-Josée, a hotel employee who is the mistress of Gérard, the manager. He wins the sympathy of Jane, a stripper who lives with Foisnard, a pianist. After sending Jane and Gérard off touring in a double act, he wins the sympathy of Gérard's wife Cécile and moves into her country house, spending his days as manager of Gérard's hotel, where he enjoys the favours of Marie-Josée. As everybody comes to realise how he has manipulated them, the game ends and he is back with his mother, planning a campaign to unload more vermouth.

Technical data
Director : Michel Audiard
Screenplay : Michel Audiard and Jean-Marie Poiré
Duration : 90 minutes
Release date : 19 June 1974
Language: French

Cast
Jean Carmet : Antoine Robineau
Jean-Pierre Marielle : Gérard Malempin
Stéphane Audran : Cécile Malempin
Jane Birkin : Jane
Evelyne Buyle : Marie-Josée Mulot
Jean Rochefort : Foisnard
Daniel Prévost : Carducci
Jeanne Herviale : Robineau's mother
Robert Dalban : Léonce
Jacqueline Doyen : Madame Léonce
Jean-Claude Dreyfus : The transformist
Ginette Garcin : The head nurse
Minka : The surly nurse
Michel Audiard : The male nurse
Laurence Badie : The hotel attendant
Paul Bisciglia : The hunter
Féodor Atkine : The mime
Manu Pluton : The black
Sébastien Floche : Marcel

References

External links

French comedy films
1970s French-language films
1974 films
1974 comedy films
Films with screenplays by Michel Audiard
Films directed by Michel Audiard
1970s French films


Reddiyur is a village in Tirupathur district, Tamil Nadu, India. It is located in the Yelagiri Hills, near Jolarpet.

Villages in Tirupathur district


The Sponge Act 16 U.S.C. §781 et. seq. is a Federal statute that makes it illegal to take, catch, or sell, commercial sponges that are less than 5 inches in diameter when wet. The law only applies to two areas: the Gulf of Mexico and the Straits of Florida. The penalty for a violation of this law is a fine not to exceed $500 and a lien on the vessel on which the offense was committed.

United States federal environmental legislation


Frederick Wilding  (20 November 1852 – 5 July 1945) played first-class cricket for Canterbury in the 1880s and 1890s. He also played tennis and was a noted athlete.

Early life
Wilding was born in Montgomery, Wales in 1852. His father, John Powell Wilding (1812–1872), was a surgeon. His mother was Harriet (). He was educated at Hereford Cathedral School in Hereford and at Shrewsbury School in Shrewsbury, England. He gained admission as a solicitor in 1874.

Wilding was prominent as an athlete in the west of England. In June 1879, he married Julia Wilding (née Anthony), the daughter of a mayor of Hereford. In the same year, they emigrated from Herefordshire to New Zealand.

Life in New Zealand
Wilding became a well-to-do lawyer in Christchurch, New Zealand, and was appointed a King's Counsel in 1913. Their house, "Fownhope" in St Martins, Christchurch, had two tennis courts, an asphalt winter court and a summer grass court. He founded Wilding Park, which is today the largest tennis centre in Canterbury. He won the New Zealand Championships doubles title five times between 1887 and 1894 with his partner Richard Harman.

Their son Tony Wilding, was a world champion tennis player, and played cricket for Canterbury, but was killed in action during the First World War.  Their daughter Cora Wilding was an artist and outdoor enthusiast, and founded the Youth Hostel Association of New Zealand in 1932.

He died, aged 92, in Christchurch on 5 July 1945, and was buried at Bromley Cemetery.

References

1852 births
1945 deaths
Burials at Bromley Cemetery
Sportspeople from the Colony of New Zealand
Canterbury cricketers
New Zealand cricketers
New Zealand male tennis players
New Zealand King's Counsel
People from Montgomeryshire
Sportspeople from Powys
Welsh emigrants to New Zealand
New Zealand sports executives and administrators
People educated at Hereford Cathedral School
People educated at Shrewsbury School
19th-century New Zealand lawyers


The Cotton Futures Act of 1914 authorized the United States Department of Agriculture to establish physical standards as a means of determining color grade, staple length and strength, and other qualities and properties for cotton.  It was intended to minimize speculative manipulation of the cotton market.

The Act was rendered unconstitutional in Federal district court because it originated in the Senate. As a revenue act, it should have been drafted in the House. It was replaced by the Cotton Futures Act of 1916.

References

External links

1914 in American law
United States federal commodity and futures legislation
Cotton industry in the United States


Dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) are enzyme inhibitors that inhibit the enzyme dipeptidyl peptidase-4 (DPP-4). They are used in the treatment of type 2 diabetes mellitus. Inhibition of the DPP-4 enzyme prolongs and enhances the activity of incretins that play an important role in insulin secretion and blood glucose control regulation.
Type 2 diabetes mellitus is a chronic metabolic disease that results from inability of the β-cells in the pancreas to secrete sufficient amounts of insulin to meet the body's needs. Insulin resistance and increased hepatic glucose production can also play a role by increasing the body's demand for insulin. Current treatments, other than insulin supplementation, are sometimes not sufficient to achieve control and may cause undesirable side effects, such as weight gain and hypoglycemia. In recent years, new drugs have been developed, based on continuing research into the mechanism of insulin production and regulation of the metabolism of sugar in the body. The enzyme DPP-4 has been found to play a significant role.

History
Since its discovery in 1967, serine protease DPP-4 has been a popular subject of research. Inhibitors of DPP-4 have long been sought as tools to elucidate the functional significance of the enzyme. The first inhibitors were characterized in the late 1980s and 1990s. Each inhibitor was important to establish an early structure activity relationship (SAR) for subsequent investigation. The inhibitors fall into two main classes, those that interact covalently with DPP-4 and those that do not. DPP-4 is a dipeptidase that selectively binds substrates that contain proline at the P1-position, thus many DPP-4 inhibitors have 5-membered heterocyclic rings that mimic proline, e.g. pyrrolidine, cyanopyrrolidine, thiazolidine and cyanothiazolidine. These compounds commonly form covalent bonds to the catalytic residue Ser630.

In 1994, researchers from Zeria Pharmaceuticals unveiled cyanopyrrolidines with a nitrile function group that was assumed to form an imidate with the catalytic serine. Concurrently other DPP-4 inhibitors without a nitrile group were published but they contained other serine-interacting motifs, e.g. boronic acids, phosphonates or diacyl hydroxylamines. These compounds were not as potent because of the similarity of DPP-4 and prolyl oligopeptidase (PEP) and also suffered from chemical instability. Ferring Pharmaceuticals filed for patent on two cyanopyrrolidine DPP-4 inhibitors, which they published in 1995. These compounds had excellent potency and improved chemical stability.

In 1995, Edwin B. Villhauer at Novartis started to explore N-substituted glycinyl-cyanopyrrolidines based on the fact that DPP-4 identifies N-methylglycine as an N-terminal amino acid. This group of new cyanopyrrolidines became extremely popular field of research in the following years. Some trials with dual inhibitors of DPP-4 and vasopeptidase have been represented, since vasopeptidase inhibition is believed to enhance the antidiabetic effect of DPP-4 inhibition by stimulating insulin secretion. Vasopeptidase-inhibiting motif is connected to the DPP-4 inhibitor at the N-substituent.

DPP-4 mechanism
Fig.1: During a meal, the incretins glucagon-like peptide 1 (GLP-1) and glucose-dependent gastric inhibitory polypeptide (GIP) are released by the small intestine into the blood stream. These hormones regulate insulin secretion in a glucose-dependent manner. (GLP-1 has many roles in the human body. It stimulates insulin biosynthesis, inhibits glucagon secretion, slows gastric emptying, reduces appetite and stimulates regeneration of islet β-cells.)

GLP-1 and GIP have extremely short plasma half-lives due to very rapid inactivation, catalyzed by the enzyme DPP-4. Inhibition of DPP-4 slows their inactivation, thereby potentiating their action, leading to lower plasma glucose levels, hence its utility in the treatment of type 2 diabetes. (Figure 1).

DPP-4 distribution and function
DPP-4 is attached to the plasma membrane of the endothelium of almost every organ in the body. Tissues which strongly express DPP-4 include the exocrine pancreas, sweat glands, salivary and mammary glands, thymus, lymph nodes, biliary tract, kidney, liver, placenta, uterus, prostate, skin, and the capillary bed of the gut mucosa (where most GLP-1 is inactivated locally). It is also present, in soluble form, in body fluids, such as blood plasma and cerebrospinal fluid. (It also happens that DPP-4 is the CD26 T-cell activating antigen.)

DPP-4 selectively cleaves two amino acids from peptides, such as GLP-1 and GIP, which have proline or alanine in the second position (Figure 2). At the active site where DPP-4 has its effect, there is a characteristic arrangement of three amino acids, Asp-His-Ser. Since alanine and proline are crucial for the biological activity of GPL-1 and GIP, they are inactivated by cleaving away these amino acids. Thus, preventing the degradation of the incretin hormones GLP-1 and GIP by inhibition of DPP-4 has potential as a therapeutic strategy in the treatment of type 2 diabetes.

DPP-4 characteristics
Since DPP-4 is a protease, it is not unexpected that inhibitors would likely have a peptide nature and this theme has carried through to contemporary research.

Structure

X-ray structures of DPP-4 that have been published since 2003 give rather detailed information about the structural characteristics of the binding site. Many structurally diverse DPP-4 inhibitors have been discovered and it is not that surprising considering the properties of the binding site:

1. A deep lipophilic pocket combined with several exposed aromatic side chains for achieving high affinity small molecule binding.

2. A significant solvent access that makes it possible to tune the physico-chemical properties of the inhibitors that leads to better pharmacokinetic behavior.

DPP-4 is a 766-amino acid transmembrane glycoprotein that belongs to the prolyloligopeptidase family. It consists of three parts; a cytoplasmic tail, a transmembrane region and an extracellular part. The extracellular part is divided into a catalytic domain and an eight-bladed β-propeller domain. The latter contributes to the inhibitor binding site. The catalytic domain shows an α/β-hydrolase fold and contains the catalytic triad Ser630 - Asp708 - His740. The S1-pocket is very hydrophobic and is composed of the side chains: Tyr631, Val656, Trp662, Tyr666 and Val711. Existing X-ray structures show that there is not much difference in size and shape of the pocket that indicates that the S1-pocket has high specificity for proline residues

Binding site

DPP-4 inhibitors usually have an electrophilic group that can interact with the hydroxyl of the catalytic serine in the active binding site (Figure 3). Frequently that group is a nitrile group but can also be boronic acid or diphenyl phosphonate. This electrophilic group can bind to the imidate complex with covalent bonds and slow, tight-binding kinetics but this group is also responsible for stability issues due to reactions with the free amino group of the P2-amino acid. Therefore, inhibitors without the electrophilic group have also been developed, but these molecules have shown toxicity due to affinity to other dipeptidyl peptidases, e.g. DPP-2, DPP-8 and DPP-9.

DPP-4 inhibitors span diverse structural types. In 2007 few of the most potent compounds contain a proline mimetic cyanopyrrolidine P1 group. This group enhances the potency, probably due to a transient covalent trapping of the nitrile group by the active site Ser630 hydroxyl, leading to delayed dissociation and slow tight binding of certain inhibitors. When these potency enhancements were achieved, some chemical stability issues were noted and more advanced molecules had to be made. To avoid these stability issues, the possibility to exclude the nitrile group was investigated. Amino acids with aryl or polar side chains did not show appreciable DPP-4 inhibition and in fact, all compounds without the nitrile group in this research suffered a 20 to 50-fold loss of potency corresponding to the compounds containing the nitrile group.

Discovery and development

It is important to find a fast and accurate system to discover new DPP-4 inhibitors with ideal therapeutic profiles. High throughput screening (HTS) usually gives low hit rates in identifying the inhibitors but virtual screening (VS) can give higher rates. VS has for example been used to screen for small primary aliphatic amines to identify fragments that could be placed in S1 and S2 sites of DPP-4. On the other hand, these fragments were not very potent and therefore identified as a starting point to design better ones.
Three-dimensional models can provide a useful tool for designing novel DPP-4 inhibitors. Pharmacophore models have been made based on key chemical features of compounds with DPP-4 inhibitory activity. These models can provide a hypothetical picture of the primary chemical feature responsible for inhibitory activity.
The first DPP-4 inhibitors were reversible inhibitors and came with bad side effects because of low selectivity. Researchers suspected that inhibitors with short half-lives would be preferred in order to minimize possible side effects. However, since clinical trials showed the opposite, the latest DPP-4 inhibitors have a long-lasting effect. One of the first reported DPP-4 inhibitor was P32/98 from Merck. It used thiazolidide as the P1-substitute and was the first DPP-4 inhibitor that showed effects in both animals and humans but it was not developed to a market drug due to side effects. Another old inhibitor is DPP-728 from Novartis, where 2-cyanopyrrolidine is used as the P1-substitute. The addition of the cyano group generally increases the potency. Therefore, researchers' attention was directed to those compounds. Usually, DPP-4 inhibitors are either substrate-like or non-substrate-like.

Substrate-like inhibitors

Substrate-like inhibitors (Figure 4) are more common than the non-substrate-likes. They bind either covalently or non-covalently and have a basic structure where the P1-substituent occupies the S1-pocket and the P2-substituent occupies the S2-pocket. Usually they contain a proline mimetic that occupies the S1-pocket. Large substituents on the 2-cyanopyrrolidine ring are normally not tolerated since the S1-pocket is quite small.
Since DPP-4 is identical with the T-cell activation marker CD26 and DPP-4 inhibitors are known to inhibit T-cell proliferation, these compounds were initially thought to be potential immunomodulators. When the function against type 2 diabetes was discovered, the cyanopyrrolidines became a highly popular research material. A little later vildagliptin and saxagliptin, which are the most developed cyanopyrrolidine DPP-4 inhibitors to date, were discovered.

Cyanopyrrolidines

Cyanopyrrolidines have two key interactions to the DPP-4 complex:

1. Nitrile in the position of the scissile bond of the peptidic substrate that is important for high potency. The nitrile group forms reversible covalent bonds with the catalytically active serine hydroxyl (Ser630), i.e. cyanopyrrolidines are competitive inhibitors with slow dissociation kinetics.

2. Hydrogen bonding network between the protonated amino group and a negatively charged region of the protein surface, Glu205, Glu206 and Tyr662. All cyanopyrrolidines have basic, primary or secondary amine, which makes this network possible but these compounds usually drop in potency if these amines are changed. Nonetheless, two patent applications unveil that the amino group can be changed, i.e. replaced by a hydrazine, but it is claimed that these compounds do not only act via DPP-4 inhibition but also prevent diabetic vascular complications by acting as a radical scavenger.

Structure-activity relationship (SAR)

Important structure-activity relationship:

1. Strict steric constraint exists around the pyrrolidine ring of cyanopyrrolidine-based inhibitors, with only hydrogen, fluoro, acetylene, nitrile, or methano substitution permitted.

2. Presence of a nitrile moiety on the pyrrolidine ring is critical to achieving potent activity

Also, systematic SAR investigation has shown that the ring size and stereochemistry for the P2 position is quite conditioned. A 5-membered ring and L-configuration has shown better results than a 4-membered or 6-membered ring with D-configuration. Only minor changes on the pyrrolidine ring can be tolerated, since the good fit of the ring with the hydrophobic S1 pocket is very important for high affinity. Some trials have been made, e.g. by replacing the pyrrolidine with a thiazoline. That led to improved potency but also loss of chemical stability. Efforts to improve chemical stability often led to loss of specificity because of interactions with DPP-8 and DPP-9. These interactions have been connected with increased toxicity and mortality in animals. There are strict limitations in the P1 position and hardly any changes are tolerated. On the other hand, a variety of changes can be made in the P2 position. In fact, substitution with quite big branched side chains, e.g. tert-butylglycin, normally increased activity and chemical stability, which could lead to longer-lasting inhibition of the DPP-4 enzyme. It has also been noted that biaryl-based side chains can also give highly active inhibitors. It was originally believed that only lipophilic substitution would be tolerated. Now it is stated that also the substitution of polar negatively charged side-chains as well as hydrophilic substitution can lead to excellent inhibitory activity.

Chemical stability

In general, DPP-4 inhibitors are not very stable compounds. Therefore, many researchers focus on enhancing the stability for cyanopyrrolidines. The most widespread technique to improve chemical stability is to incorporate a steric bulk. The two cyanopyrrolidines that have been most pronounced, vildagliptin and saxagliptin, were created in this manner. K579 is a DPP-4 inhibitor discovered by researchers at Kyowa Hakko Kyogo. It had improved not only chemical stability but also a longer-lasting action. That long-lasting action was most likely due to slow dissociation of the enzyme-inhibitor complex and an active oxide metabolite that undergoes enterohepatic circulation. The discovery of the active oxide was in fact a big breakthrough as it led to the development of vildagliptin and saxagliptin. One major problem in DPP-4 inhibitor stability is intramolecular cyclization. The precondition for the intramolecular cyclization is the conversion of the trans-rotamer, which is the DPP-4 binding rotamer (Figure 5). Thus, preventing this conversion will increase stability. This prevention was successful when incorporating an amide group into a ring, creating a compound that kept the DPP-4 inhibitory activity that, did not undergo the intramolecular cyclization and was even more selective over different DPP enzymes. It has also been reported that a cyanoazetidine in the P1 position and a β-amino acid in the P2 position increased stability.

Vildagliptin

Vildagliptin (Galvus)(Figure 6) was first synthesized in May 1998 and was named after Edwin B. Villhauer. It was discovered when researchers at Novartis examined adamantyl derivatives that had proven to be very potent. The adamantyl group worked as a steric bulk and slowed intramolecular cyclization while increasing chemical stability. Furthermore, the primary metabolites were highly active. To avoid additional chiral center a hydroxylation at the adamantyl ring was carried out (Figure 6). The product, vildagliptin, was even more stable, undergoing intramolecular cyclization 30-times slower, and having high DPP-4 inhibitory activity and longer-lasting pharmacodynamic effect.

Saxagliptin

Researchers at Bristol-Myers Squibb found that increased steric bulk of the N-terminal amino acid side-chain led to increased stability. To additionally increase stability the trans-rotamer was stabilized with a cis-4,5-methano substitution of the pyrrolidine ring, resulting in an intramolecular van-der-Waals interaction, thus preventing intramolecular cyclisation. Because of that increased stability, the researchers continued their investigation on cis-4,5-methano cyanopyrrolidines and came across with a new adamantyl derivative, which showed extraordinary ex vivo DPP-4 inhibition in rat plasma. Also noted, high microsomal turnover rate which indicated that the derivative was quickly converted to an active metabolite. After hydroxylation on the adamantyl group they had a product with better microsomal stability and improved chemical stability. That product was named saxagliptin (Onglyza) (Figure 6). In June 2008 AstraZeneca and Bristol-Myers Squibb submitted a new drug application for Onglyza in the United States and a marketing authorization application in Europe. Approval was granted in the United States by the FDA in July 2009 for Onglyza 5 mg and Onglyza 2.5 mg. This was later combined with extended-release metformin (taken once daily) and approved by the FDA in January 2011 under the trade name Kombiglyze XR.

Denagliptin

Denagliptin (Figure 6) is an advanced compound with a branched side-chain at the P2 position, but also has (4S)-fluoro substitution on the cyanopyrrolidine ring. It is a well-known DPP-4 inhibitor developed by GlaxoSmithKline (GSK). Biological evaluations have shown that the S-configuration of the amino acid portion is essential for the inhibitory activity since the R-configuration showed reluctantly inhibition. These findings will be useful in future designs and synthesis of DPP-4 inhibitors. GSK suspended Phase III clinical trials in October 2008.

Azetidine based compounds

Informations for this group of inhibitors are quite restricted. Azetidine-based DPP-4 inhibitors can roughly be grouped into three main subcategories: 2-cyanoazetidines, 3-fluoroazetidines, and 2-ketoazetidines. The most potent ketoazetidines and cyanoazetidines have large hydrophobic amino acid groups bound to the azetidine nitrogen and are active below 100nM.

Non-substrate-like inhibitors

Non-substrate-like inhibitors do not take after dipeptidic nature of DPP-4 substrates. They are non-covalent inhibitors and usually have an aromatic ring that occupies the S1-pocket, instead of the proline mimetic.

In 1999, Merck started a drug development program on DPP-4 inhibitors. When they started internal screening and medicinal chemistry program, two DPP-4 inhibitors were already in clinical trials, isoleucyl thiazolidide (P32/38) and NVP-DPP728 from Novartis. Merck in-licensed L-threo-isoleucyl thiazolidide and its allo stereoisomer. In animal studies, they found that both isomers had similar affinity for DPP-4, similar in vivo efficacy, similar pharmacokinetic and metabolic profiles. Nevertheless, the allo isomer was 10-fold more toxic. The researchers found out that this difference in toxicity was due to the allo isomer's greater inhibition of DPP-8 and DPP-9 but not because of selective DPP-4 inhibition. More research also supported that DPP-4 inhibition would not cause compromised immune function. Once this link between affinity for DPP-8/DPP-9 and toxicity was discovered, Merck decided on identifying an inhibitor with more than a thousandfold affinity for DPP-4 over the other dipeptidases. For this purpose, they used positional scanning libraries. From scanning these libraries, the researchers discovered that both DPP-4 and DPP-8 showed a strong preference for breaking down peptides with a proline at the P1 position but they found a great difference at the P2 site; i.e., they found that acidic functionality at the P2 position could provide a greater affinity for DPP-4 over DPP-8. Merck kept up doing even more research and screening. They stopped working on compounds from the α-amino acid series related to isoleucyl thiazolidide due to lack of selectivity but instead they discovered a very selective β-amino acid piperazine series through SAR studies on two screening leads. When trying to stabilize the piperazine moiety, a group of bicyclic derivatives were made, which led to the identification of a potent and selective triazolopiperazine series. Most of these analogs showed excellent pharmacokinetic properties in preclinical species. Optimization of these compounds finally led to the discovery of sitagliptin.

Sitagliptin

Sitagliptin (Januvia) has a novel structure with β-amino amide derivatives (Figure 7). Since sitagliptin has shown excellent selectivity and in vivo efficacy it urged researchers to inspect the new structure of DPP-4 inhibitors with appended β-amino acid moiety. Further studies are being developed to optimize these compounds for the treatment of diabetes.
In October 2006 sitagliptin became the first DPP-4 inhibitor that got FDA approval for the treatment of type 2 diabetes. Crystallographic structure of sitagliptin along with molecular modeling has been used to continue the search for structurally diverse inhibitors. A new potent, selective and orally bioavailable DPP-4 inhibitor was discovered by replacing the central cyclohexylamine in sitagliptin with 3-aminopiperidine. A 2-pyridyl substitution was the initial SAR breakthrough since that group plays a significant role in potency and selectivity for DPP-4.

It has been shown with an X-ray crystallography how sitagliptin binds to the DPP-4 complex:

1. The trifluorophenyl group occupies the S1-pocket

2. The trifluoromethyl group interacts with the side chains of residues Arg358 and Ser209.

3. The amino group forms a salt bridge with Tyr662 and the carboxylated groups of the two glutamate residues, Glu205 and Glu206.

4. The triazolopiperazine group collides with the phenyl group of residue Phe357

Constrained phenylethylamine compounds

Researchers at Abbott Laboratories identified three novel series of DPP-4 inhibitors using HTS. After more research and optimization ABT-341 was discovered (Figure 8). It is a potent and selective DPP-4 inhibitor with a 2D-structure very similar to sitagliptin. However, the 3D-structure is quite different. ABT-341 also has a trifluorophenyl group that occupies the S1-pocket and the free amino group, but the two carbonyl groups are orientated 180° away from each other. ABT-341 is also believed to interact with the Tyr547, probably because of steric hindrance between the cyclohexenyl ring and the tyrosine side-chain. Omarigliptin is one of such compound which is in Phase-III development by Merck & Co.

Pyrrolidine compounds

The pyrrolidine type of DPP-4 inhibitors was first discovered after HTS. Research showed that the pyrrolidine rings were the part of the compounds that fit into the binding site. Further development has led to fluoro substituted pyrrolidines that show superior activity, as well as pyrrolidines with fused cyclopropylrings that are highly active.

Xanthine-based compounds

This is a different class of inhibitors that was identified with HTS. Aromatic heterocyclic-based DPP-4 inhibitors have gained increased attention recently. The first patents describing xanthines (Figure 10) as DPP-4 inhibitors came from Boehringer-Ingelheim(BI) and Novo Nordisk.
When xanthine based DPP-4 inhibitors are compared with sitagliptin and vildagliptin it has shown a superior profile. Xanthines are believed to have higher potency, longer-lasting inhibition and longer-lasting improvement of glucose tolerance.

Alogliptin

Alogliptin (Figure 9) is a novel DPP-4 inhibitor developed by the Takeda Pharmaceutical Company. Researchers hypothesized that a quinazolinone based structure (Figure 9) would have the necessary groups to interact with the active site on the DPP-4 complex. Quinazolinone based compounds interacted effectively with the DPP-4 complex, but suffered from low metabolic half-life. It was found that when replacing the quinazolinone with a pyrimidinedione, the metabolic stability was increased and the result was a potent, selective, bioavailable DPP-4 inhibitor named alogliptin. The quinazoline based compounds showed potent inhibition and excellent selectivity over related protease, DPP-8. However, short metabolic half-life due to oxidation of the A-ring phenyl group was problematic. At first, the researchers tried to make a fluorinated derivative. The derivative showed improved metabolic stability and excellent inhibition of the DPP-4 enzyme. However, it was also found to inhibit CYP 450 3A4 and block the hERG channel. The solution to this problem was to replace the quinazolinone with other heterocycles, but the quinazolinone could be replaced without any loss of DPP-4 inhibition. Alogliptin was discovered when quinazolinone was replaced with a pyrimidinedione. Alogliptin has shown excellent inhibition of DPP-4 and extraordinary selectivity, greater than 10.000 fold over the closely related serine proteases DPP-8 and DPP-9. Also, it does not inhibit the CYP 450 enzymes nor block the hERG channel at concentration up to 30 µM. Based on this data, alogliptin was chosen for preclinical evaluation. In January 2007 alogliptin was undergoing the phase III clinical trial and in October 2008 it was being reviewed by the U.S. Food and Drug Administration.

Linagliptin

Researchers at BI discovered that using a buty-2-nyl group resulted in a potent candidate, called BI-1356 (Figure 10). In 2008 BI-1356 was undergoing phase III clinical trials; it was released as linagliptin in May 2011. X-ray crystallography has shown that that xanthine type binds the DPP-4 complex in a different way than other inhibitors:

1. The amino group also interacts with the Glu205, Glu206 and Tyr662

2. The buty-2-nyl group occupies the S1-pocket

3. The uracil group undergoes a π-stacking interaction with the Tyr547 residue

4. The quinazoline group undergoes a π-stacking interaction with the Trp629 residue

Pharmacology

The pharmacokinetic properties of sitagliptin and vildagliptin appear unaffected by age, sex or BMI. Clinical researches have shown that sitagliptin and vildagliptin do not have the side effects that tend to follow type 2 diabetes treatment, e.g. weight gain and hyperglycemia, but however, other side effects have been observed, including upper respiratory tract infections, sore throat and diarrhea.

See also
 Dipeptidyl peptidase-4
 Dipeptidyl peptidase-4 inhibitors
 Linagliptin
 Vildagliptin
 Sitagliptin
 Saxagliptin
 Berberine
 teneligliptin
 gosogliptin

References

Dipeptidyl peptidase-4 inhibitors
Dipeptidyl peptidase-4 inhibitors


Aziz Khan may refer to:

Aziz Khan (general), former Chairman of Joint Chiefs of Staff of Pakistan Army
Aziz Ahmed Khan, Pakistan Ambassador to India
Aziz Khan (squash player), Pakistani squash player
Aziz Khan (businessman), chairman, Summit Group


The 1987–88 FDGB-Pokal was the 37th edition of the East German Cup. The competition was won by league champions BFC Dynamo, who beat FC Carl Zeiss Jena 2–0 after extra time and completed the the Double.

Preliminary round

First round

Second round

Round of 16

Quarter-final

Semi-final

Final

References

External links
 DDR Football 1987/88 at rsssf.com

FDGB-Pokal seasons
East
Cup


Hiding Place is a novel by the American writer John Edgar Wideman set in Pittsburgh, Pennsylvania, during the 1970s. It was first published in 1981 by Avon Books in New York, and subsequently in London by Allison & Busby in 1984.

The novel tells the story of Tommy, a character who first appeared in Wideman's short-story collection Damballah. Tommy is a party to a bungled smash-and-grab raid that leaves a dead man in a parking lot, so he hides out with Mother Bess, a crazy old woman who lives in Homewood, an African-American neighborhood of the East End.

Elements of the character Tommy parallel the life of Wideman's brother Robbie, whose story he relates in a memoir published three years later called Brothers and Keepers.

Hiding Place is the middle volume of what some critics call "The Homewood Trilogy". The other books are Damballah and Sent for You Yesterday. In 1992 the University of Pittsburgh Press published the three in one volume under the title The Homewood Books. In its preface Wideman admits discomfort with the term trilogy because it implies a plan of linking the volumes, and he claims he did not compose the books that way.

References

1981 American novels
African-American novels
Allison and Busby books
Avon (publisher) books
Novels by John Edgar Wideman
Novels set in Pittsburgh


Holland (publisher) (Uitgeverij Holland) is an independent  Dutch publishing house of books for children and books for adults, founded  in 1921 by Jan Bernhard van Ulzen in Amsterdam.

From 1921 until 1951
After having worked a few years as a sales representative for several publishing houses Jan Berhard van Ulzen established his own publishing business  at his home address. The first publications were financed by his wife who had been a successful fashion cutter in Paris. After a few years the business could be located on the canal Herengracht in Amsterdam. In these years Holland specialized in social, Christian publications by original Dutch writers. A few translations were published, for instants (1937) Søren Kierkegaard, (1951) Pär Lagerkvist, and (1940) Denis de Rougemont.  Next to books Holland also published a Christian literary magazine called Opwaartsche Wegen, which was published for 17 years. Poetry was published since 1950 in a series called De Windroos

From 1951 until 1981
 In 1951 Jan Bernhard van Ulzen was assisted by his son Rolf van Ulzen, who succeeded in the late sixties of the previous century.  As Rolf van Ulzen had started to participate in large international co-productions for encyclopaedia's and fairy tales, the location for office and warehouse in Amsterdam was no longer suitable. The lofts on the Herengracht were not strong enough to bear the weight of heavy books. The building in Haarlem was more suitable with storage possibilities on the ground floor.
In 1955 (Bonte Boekjes series) he started with children's book. For these scripts  he asked poets  as he thought the imagination for poetry must be the same as for children's books. Important writers of these days were Hans Andreus, Paul Biegel, ,  and .

From 1981 until today
In 1981 Rolf van Ulzen was assisted by his son Ruurt van Ulzen, who succeeded in 1987. The children's books were expanded by new Dutch authors, such as:

 ,
 ,
 ,
 ,
 ,
 ,
 Peter Smit

Translated children's book writers
From several foreign children's book writers translations were made, such as:

From English
 Joan Aiken
 Malcolm Bosse
 Susan Cooper
 Gary Crew
 Scott O'Dell
 Paula Fox
 Frances Mary Hendry
 Mollie Hunter
 Gene Kemp
 Sue Mayfield
 Mary Norton (author)
 Katherine Paterson
 Arthur Ransome
 Elizabeth George Speare
 Catherine Storr
 Mildred D. Taylor
 Sean Taylor (author)

From German
 Karl Bruckner
 Willi Färhrmann
 Ursula Fuchs
 Susanne Fulcher
 Tilde Michiels
 Gudrun Mebs
 Marietta Moskin
 Tillman Röhrig
 Angela Sommer-Bodenburg
 Ingrid Uebe

Others
 Maurice Druon
 Maria Grippe
 Torill Hauger
 Marita Lindquist

Classics like Greek- and Roman Myths by Gustav Schwab, Tales of Shakespeare by Charles Lamb and Mary Lamb and small biographies of famous philosophers by Paul Strathern were published in Dutch translation.

References

Sources

 Dutch Publishers Association
 Dutch Wikipedia
 Independent Dutch Publishers
 Interview in Boekenwereld by Prof. Dr. Lisa Kuitert with Ruurt van Ulzen, Jaargang 19, nummer 1, oktober 2002

External links

Holland(publisher)
Publishing companies established in 1921
Mass media in Amsterdam


The River and Harbors Act of 1914 expanded the Mississippi River Commission’s jurisdiction to oversee Federal fund distribution to needy States.  The act provided money to affected states each year of the Wilson Administration for the building and maintenance of recommended methods of flood control.  In addition, the act authorized Federal money to be spent on improving various major harbors along the Eastern Seaboard of the United States, most prominently being New York Harbor.  The act also allotted more than $800,000 for the Hudson River banks to be enlarged.

1914 in American law
United States federal public land legislation


Steven Harris is a British cartoonist and writer, based in London. His first novel, Eustace, was published in March 2013 by Jonathan Cape and launched at Waterstones Gower Street.

Career
Harris contributed the illustrations for a range of books in the Nightingale Press's Modern Anthropology range of humorous Modern Guides, including Hats (which he also authored),  Drink, and  Spectacles.

Harris also authored the long-running web comics Paper Cuts and Eustace, both published on H2G2 under the pseudonym spimcoot. During time spent with an artists' collective in Angoulême, France, he also contributed satirical French cartoons to a daily Charente newspaper, again under the name spimcoot.

His novel length version of the Eustace comics, 'Eustace', was published in hardback by Jonathan Cape in March 2013. It concerns the adventures of a bed-bound boy, joined by a "swelling cast of hoodlums, models, drunkards and politicians". He is currently writing the second book in the Eustace quartet.

References

British cartoonists
Writers from London
Living people
Year of birth missing (living people)


Interval is a 1973 romantic drama film starring Merle Oberon in her final performance. Oberon also produced the movie, and fell in love with her co-star in it, Robert Wolders, divorcing her husband to marry Wolders in 1975.

Plot
Serena Moore has been everywhere and is trying to put her past behind her. She finds refuge in Mexico where, without intending to, falls in love with a much younger painter Chris.

Cast
Merle Oberon ... Serena Moore
Robert Wolders ... Chris
Claudio Brook ... Armando Vertiz
Russ Conway ... Fraser
Britt Leach ... Leonard
Peter von Zerneck ... Broch
Anel ... Jackie

See also
 List of American films of 1973

References

External links

1973 films
Films directed by Daniel Mann
1973 romantic drama films
American romantic drama films
Embassy Pictures films
1970s English-language films
1970s American films


The Occupancy Permits Act was passed on March 4, 1915, by the 63rd United States Congress. It allowed the U.S. Forest Service to issue to cabin permits at "reasonable rates" to individuals who had had their property taken through eminent domain. Permits could be issued for periods of up to 30 years.  Individuals were encouraged to build homes within the boundaries of national parks in order to widen the Forest Services' work in recreational management. It is the basis of the USFS Recreation Residences program.

Purpose

Rental rates were already low, but this measure was meant to give the federal government further insurance protection with the "Forest Register" which oversaw rates to allow lower rents by lengthening the amount of time contracted to residents.

It affected private cabins on lands that had, at some point, been designated public.  It established reasonable rental rates, with "reasonable" meaning rates that were not too low, allowing those who had lived on the land for years who had had their property taken through eminent domain to continue to reside there for their remaining years.

References

1915 in American law
United States federal legislation
63rd United States Congress


Estonia–Lithuania relations refer to the bilateral relations between Estonia and Lithuania. Estonia has an embassy in Vilnius. Lithuania has an embassy in Tallinn. Both countries are situated in the Baltic region and are the full members of NATO and the European Union.

History
Lithuania and Estonia officially established diplomatic relations on 2 March 1921. Following the Soviet occupation after the World War II, both states continued the diplomatic service in exile. After the independence restoration, the relations were re-established de facto on 16 June 1991.

Agreements
Many of the agreements between the two countries are trilateral with Latvia as the three Baltic states.

In 2004, the free trade agreement signed in 1992 between the Baltic states was superseded when all three countries joined the European Union.
.

In 2017, the two countries along with Latvia, signed a rail agreement. The agreement is a precondition for a possible high speed railway between the states.

See also
Foreign relations of Estonia
Foreign relations of Lithuania
2004 enlargement of the European Union
Estonians in Lithuania

References

External links

  Embassy of the Republic of Estonia in the Republic of Lithuania
  Embassy of the Republic of Lithuania in the Republic of Estonia