Astro, yeah
Sun is down, freezin cold
Thats how we already know, winters here
My dawg would probably do it for a Louis belt
Thats just all he know, he dont know nothin else
I tried to show em, yeah
I tried to show em, yeah, yeah
Yeah, yeah, yeah
Goin on you with the pick and roll
Young La Flame, he in sicko mode
 Made this here with all the ice on in the booth
At the gate outside, when they pull up, they get me loose
Yeah, Jump Out boys, thats Nike boys, hoppin out coupes
This shit way too big, when we pull up, give me the loot
Was off the Remy, had a Papoose
Had to hit my old town to duck the news
Two-four hour lockdown, we made no moves
Now its 4 AM and Im back up poppin with the crew
I just landed in, Chase B mixes pop like Jamba Juice
Different colored chains, think my jeweler really sellin fruits
And they chokin, man, know the crackers wish it was a noose
Some-Some-Some-Someone said
To win the retreat, we all in too deep
Play-Play-Playin for keeps, dont play us for weak
To win the retreat, we all in too deep
Play-Play-Playin for keeps, dont play us for weak
Yeah, this shit way too formal, yall know I dont follow suit
Stacey Dash, most of these girls aint got a clue
All of these hoes I made off records I produced
I might take all my exes and put em all in a group
Hit my eses, I need the bootch
Bout to turn this function to Bonnaroo
Told her, Hop in, you comin too
In the 305, bitches treat me like Im Uncle Luke
Had to slop the top off, its just a roof, uh
She said, Where we goin? I said, The moon
We aint even make it to the room
She thought it was the ocean, its just the pool
Now I got her open, its just the Goose
Who put this shit together? Im the glue
Someone said
Shorty FaceTimed me out the blue
Someone said
Play-Playin for keeps
Someone said, mother, someone said
Dont play us for weak
Yeah!
Astro, yeah, yeah
Ayy, ayy
Shes in love with who I am
Back in high school, I used to bus it to the dance
Now I hit the FBO with duffels in my hands
I did half a Xan, thirteen hours til I land
Had me out like a light, ayy, yeah
Like a light, ayy, yeah
Like a light, ayy, slept through the flight, ayy
Knocked for the night, ayy
767, man, this shit got double bedroom, man
I still got scores to settle, man
I crept down the block
Made a right
Cut the lights , paid the price
Niggas think its sweet , its on sight
Nothin nice , baguettes in my ice
Jesus Christ , checks over stripes
Thats what I like , thats what we like
Lost my respect, you not a threat
When I shoot my shot, that shit wetty like Im Sheck
See the shots that I took , wet like Im Book
Wet like Im Lizzie
I be spinnin Valley, circle blocks til Im dizzy
Like where is he?
No one seen him
Im tryna clean em
Shes in love with who I am
Back in high school, I used to bus it to the dance
Now I hit the FBO with duffels in my hands
I did half a Xan, thirteen hours til I land
Had me out like a light
Like a light
Like a light
Like a light
Yeah, passed the dawgs a celly
Sendin texts, aint sendin kites, yeah
He said, Keep that on lock
I say, You know this shit, its stife, yeah
Its absolute, yeah , Im back, reboot
LaFerrari to Jamba Juice, yeah
We back on the road, they jumpin off, no parachute, yeah
Shorty in the back
She said she workin on her glutes, yeah
Aint by the book, yeah, this how it look, yeah
Bout a check, yeah , just check the foots, yeah
Pass this to my daughter, Ima show her what it took
Baby mama cover Forbes, got these other bitches shook
Yeah


I thought Id probably die in prison, expensive taste in women
Aint had no pot to piss in, now my kitchen full of dishes
Nose bloody from that sniffin, your heroin addiction
Trigger finger itching, fuck parental supervision
This be that murder business, little Timmy got that semi
I aint kidding, hide your kittens, hit your childrens with that Smith and
A bunch of ignant little niglets, hardheaded, never listen
Purp-purple sippin, finger twistin, teeth glisten like its Memphis
A bunch of hypocritic Christians
The land of no religion
My Santa Claus was missing, catch you slippin then its Christmas
Motherfuck a wishlist, my ghetto was ambition
For my Benjis and my Bentley
And them bitches now I gets-gets
On the road to riches, a diamond ring, designer jeans
Choking on that biscuit til Im no longer existing
I wonder if they miss me, as long as I make history
Now my soul is feeling empty, tell the reaper come and get me
Who said you cant live forever lied
Of course, Im living forever
Ill forever, Ill live long
You cant ever deny my force
Im living forever
Ill forever, Ill live
Riding through your city like that motherfucker mine
Or toting on that semi, rob a motherfucker blind
License plate says wipe me down, car from 1989
But a nigga sits so pretty call that motherfucker fine
Lost your motherfucking mind, whats on your mind?
Niggas talking down
Never talk to cops
Make him talk to God when I tote that 9, he aint talking now
Tell em watch your spine, I mean watch your back
Better guide your track, better not look back
Now stay in line, dont step on cracks
So you break her back, Im talking bout your mom
Cause theres killers in my town
Making hits, sniffing lines
Out committing crimes
Wait for shit to simmer down
Corrupted little minds
8 and 9, finna shine
On the grind
Do you dirty with that shimmy shimmy ya
Where they shoot without a purpose
Services n hearses
Kids who aint deserve it
Cant survive a thing, youre worthless
Strangers make me nervous
Whos that peekin in my window with a pistol to my curtains?
Who said you cant live forever lied
Of course, Im living forever
Ill forever, Ill live long
You cant ever deny my force
Im living forever
Ill forever, Ill live
Pretty nigga rich, Flacko be the shit
And that bitch know we poppin so she poppin on this dick
Nigga, RIP to Pimp, cant forget Little Flip
And I take it out to Memphis so shout out to Triple Six
Who said you cant live forever lied
Of course, Im living forever
Ill forever, Ill live long
You cant ever deny my force
Im living forever
Ill forever, Ill live


1, 2, 3, 4, 5, 6, 7, 8, 9
Its the ten crack commandments, what?
Nigga cant tell me nothing about this coke
Cant tell me nothing about this crack, this weed, for my hustlin niggas
Niggas on the corner I aint forget you niggas, my triple beam niggas
Ive been in this game for years, it made me a animal
Theres rules to this shit, I wrote me a manual
A step-by-step booklet for you to get
Your game on track, not your wig pushed back
Rule Nombre Uno: never let no one know
How much dough you hold cause you know
The cheddar breed jealousy specially
If that man fucked up, get yo ass stuck up
Number two: never let em know your next move
Dont you know bad boys move in silence and violence?
Take it from your highness
I done squeezed mad clips at these cats for they bricks and chips
Number three: never trust nobody
Your momsll set that ass up, properly gassed up
Hoodied and masked up, shit, for that fast buck
She be laying in the bushes to light that ass up
Number 4: I know you heard this before
Never get high on your own supply
Number 5: never sell no crack where you rest at
I dont care if they want an ounce, tell em bounce!
Number 6: that goddamn credit? Dead it
You think a crackhead paying you back, shit, forget it!
7: this rule is so underrated
Keep your family and business completely separated
Money and blood dont mix like two dicks and no bitch
Find yourself in serious shit
Number 8: never keep no weight on you
Them cats that squeeze your guns can hold jums too
Number 9 shoulda been Number 1 to me:
If you aint gettin bagged stay the fuck from police
If niggas think you snitchin they aint tryna listen
They be sittin in your kitchen, waiting to start hittin
Number 10: a strong word called consignment
Strictly for live men, not for freshmen
If you aint got the clientele, say hell no!
Cause they gon want they money rain, sleet, hail, snow
Follow these rules youll have mad bread to break up
If not, 24 years on the wake up
Slug hit your temple, watch your frame shake up
Caretaker did your makeup, when you passed
Your girl fucked my man Jake up
Heard in three weeks she sniffed a whole half a cake up
Heard she suck a good dick, and can hook a steak up
Gotta go gotta go, more pies to bake up, word up
Crack King, Frank Wiz-zhite
(1, 2, 3, 5, 6, 7, 8
1, 1, 2, 3, 4, 5
1, 1, 1, 1, 1, 2, 3, 4, 4, 5
1, 2, 3, 4, 5, 6, 7, 8, 9
10.......10)


olly cicho


 As at 1 February, 1,477 civilian personnel (26 per cent of whom were women),

including 252 United Nations Volunteers and 104 government-provided correctional

personnel, served with MINUSCA. This represents 91 per cent of 1,624 approved

positions.

  Status of forces agreement


 As at 30 April, the number of UNMISS civilian personnel stood at 2,271,

comprising 886 international staff members (254 women, 28.7 per cent), 1,385 national

staff members (200 women, 14.4 per cent) and 388 United Nations Volunteers (159

women, 41.0 per cent).


 In areas with a high prevalence of intercommunal violence and displacement,

the Mission implemented 18 quick-impact projects to construct and rehabilitate rule

of law facilities, including a prison in Tonj North and a safe house for victims of

gender-based violence in Kapoeta.

 C. Monitoring and investigating human rights violations


the treatment of chronic hepatitis c ( chc ) has evolved in the last 15 years from monotherapy with interferon alpha ( ifnalpha ) to the combination treatment with pegylated ifn ( peg - ifn ) plus ribavirin for 24 - 48 weeks . up to now , several viral , host and drug - related reactions in response to ifnalpha - based therapy have been identified .
recent studies suggest that liver inflammation in chc is controlled by several mechanisms , including host regulatory immune responses and viral polypeptides interacting with cells involved in innate and adaptive immunity .
it is well known that cutaneous side effects of treatment with ifnalpha alone or ifnalpha plus ribavirin in patients with chc have been widely reported , beyond the fact that the virus itself can cause skin lesions . however , the cutaneous side effects during therapy of chc are of inflammatory type with local erythema , edema and , much less frequently , necrosis at the injection skin sites . by contrast ,
skin side effects of such drugs have few data available in the literature , although the number of reports has been increasing in the last years , including cosmetic filler site injections .
roughly one half of these patients had cutaneous findings , either alone or with systemic involvement .
more recently there have been reported dermatological diseases in patients receiving the combination of ifn / ribavirin or ifn / ribavirin / amantadine for the treatment of chc .
a 44-year - old man with chc genotype 1a and a viral load of hcv > 800,000 iu / ml , a2-f1 on liver biopsy according to metavir criteria , was treated for the hepatic disease .
peg - ifnalpha-2b 1.5 g / kg weekly and 1,000 mg of ribavirin daily was introduced . in the 40th week
the patient reported sudden intense pain , pruritus , erythema and skin hypertrophy in the left deltoid area over the seahorse tattoo and in a scar on his face ( fig .
1 ) . a skin biopsy on the scar and tattoo showed granulomatous dermatitis ( fig .
chest x - ray was normal and the level of angiotensin enzyme converter was 50 iu / ml ( range 18 - 55 iu / ml ) .
we intend to call attention especially to dermatologists to the possibility of a granulomatous tattoo reaction as a side effect during chc treatment with peg - ifnalpha-2b plus ribavirin . until now
, eight cases of sarcoidosis as a complication of ifn therapy in chc have been reported in the english language literature .
the most relevant topic in this case is the occurrence of disease on a tattoo area .
six months later retreatment using peg - ifnalpha-2a 180 g once a week plus ribavirin 1,000 mg daily was tried . in the 6th week , cutaneous symptoms relapsed in an unbearable way .
the patient did not accept to continue therapy , since hydrocortisone cream was prescribed again but no satisfactory pruritus and pain improvement was noticed . a prompt regression of skin reaction occurred after stopping therapy .
sarcoidosis is a granulomatous disorder of unknown etiology and whose epidemiology suggest a genetic tendency face to infectious agents being supposed to result of immune system deregulation leading to non - caseating granulomas as an immune reaction to an unknown persistent antigenic stimulus .
ifn has been linked to pulmonary macrophage activation , a characteristic feature of sarcoidosis which has been assumed an exaggerated t helper 1 ( th-1 ) immune response to a variety of exogenous antigens .
it seems very likely that a potent immunoregulatory protein for th-1 response such as ifn may induce the disease . in january 2003 the eighth case of ifn - related sarcoidosis was reported with a review of the literature .
chest x - ray revealed hilar lymphadenopathy in three patients , with reticulonodular shadows in another three , while the patient with only cutaneous involvement had a normal chest x - ray .
the case we report presented with cutaneous sarcoidosis during chc therapy and spontaneous regression of the lesions was noted with treatment discontinuation .
we intend to emphasize , especially to dermatologists , the risks of a granulomatous tattoo and other cutaneous sites during chc treatment with peg - ifnalpha-2b plus ribavirin .
thalidomide has been also shown to have specific activity to the inflammatory mediators of sarcoidosis and to be an alternative beneficial therapy .

 the treatment of chronic hepatitis c ( chc ) has evolved in the past 15 years and combination of pegylated interferon plus ribavirin is its current standard therapy . however , several side effects are commonly observed and frequently lead to transient or definitive interruption of treatment .
 although sarcoidosis in its systemic or cutaneous form is a very rare side effect in such circumstances , some cases have been reported even with conventional interferon .
 this brief review of the literature and description of a case of sarcoidosis occurring in a tattoo and a scar patient 's face , during treatment with pegylated interferon alpha-2b plus ribavirin , is an educative report directed in special to dermatologists .
 the lesion improved after drug interruption and recurred after retreatment with pegylated interferon alpha-2a .
 we conclude that this side effect must call the attention of doctors to seek for the diagnosis and therapy as soon as possible in such circumstances .
 no differences were noticed neither with alpha-2a nor alpha-2b pegylated interferon employment .


necrotising fasciitis ( nf ) is a serious soft tissue and life threatening infection , primarily involving the skin and superficial fascia , characterised by a rapid and extensive necrosis of the subcutaneous tissue .
most patients have associated comorbidities , such as diabetes , hiv infection or treatment with immunosuppressive drugs , but it can also affect previously healthy individuals .
infection is one of the common causes of morbidity and mortality in patients with systemic lupus erythematosus ( sle ) .
it is associated with immunosuppressive agents , renal failure , and increased disease activity . despite the increased propensity of sle patients to develop common and opportunistic infections , nf has rarely been reported . to our knowledge
, only 31 cases are described in the literature to date ( see table 1 ) .
nf has also been described in other rheumatic diseases including polymyositis , dermatomyositis , systemic sclerosis , rheumatoid arthritis and ankylosing spondylitis , but it appears that this association is more common in sle.1
 2 clinical features of nf in systemic lupus erythematosus a , asian ; aa , african  american ; aps , antiphospholipid syndrome ; art , arthritis ; avn , avascular necrosis ; aza , azathioprine ; cad , coronary artery disease ; cs , corticosteroid therapy ; cyc , cyclophosphamide ; d , died ; dm , diabetes mellitus ; f , female ; fg , fournier 's gangrene ; h , hispanic ; hcq , hydroxychloroquine ; lym , lymphocytes ; m , male ; mmf , mycophenolate ; mtx , methotrexate ; n , nephritis ; na , not available ; nf , necrotising fasciitis ; pe , pulmonary embolism ; rtx , rituximab ; s , survived ; sa , staphylococcus aureus ; ttp , thrombotic thrombocytopenic purpura ; wbc , white blood cells .
we describe the case of a nf caused by pseudomonas aeruginosa , complicated by recurrent sepsis and multiorgan failure in a young patient with a history of sle .
a 26-year - old asian woman with a complex history of sle , diagnosed at age 14 years when she presented with malar rash , arthralgia , mouth ulcers , pulmonary vasculitis , strongly positive anti - nuclear antibody and anti - dsdna antibodies .
subsequently , she had idiopathic detrusor overactivity with repeated urinary tract infection . linked to her corticosteroid treatment she developed avascular necrosis of her elbow ( at that time , on prednisolone 6  mg daily ) .
the patient was also treated with hydroxychloroquine ( hcq ) , azathioprine ( aza ) ( 100  mg from 1999 to 2009 ) and had 14 courses of cyclophosphamide ( cyc ) ( a cumulative dose of 14  g ) and two of rituximab ( rtx ) ( two 1  g intravenous infusions separated by 2  weeks ) , the last being given in march 2012 for a sle flare manifested by severe vasculitic rash . immediately prior to b - cell depletion , her c3 level was 0.33  g / l ( normal : 0.651.65 ) , cluster designation ( cd ) 19 count was 0.146/l ( 0.110.69 ) , and immunoglobulin g level was 23.4  g / l ( 716 ) . in may 2012
, she presented to her local hospital with painful swelling of her left lower limb , she denied a history of trauma , and her inflammatory markers and ultrasonography were normal , and she was discharged . within 12  h
she was found at home with a glasgow coma scale of 6 , and was admitted to the intensive care unit ( icu ) . on examination ,
the patient was in septic shock with hypotension ( systolic blood pressure 60  mm  hg ) , tachycardia ( 135/min ) , and respiratory failure ( sao2 70% ) .
laboratory results showed erythrocyte sedimentation rate 96  mm / h ( normal : 17 ) , c - reactive protein 281  mg / dl ( 05 ) , white blood cells 15  400/l ( 300010  000 ) ( 97% neutrophils ; 1.9% lymphocytes ) , haemoglobin 9.6  g / dl ( 11.515.5 ) , platelet 50  000/l ( 150  000400  000 ) , na 138  mmol / l ( 135145 ) , creatine kinase 474  iu / l ( 26140 ) , urea 16.8  mmol / l ( 1.78.3 ) , alamine transaminase 384  iu / l ( 1035 ) , total bilirubin 11  mg / dl ( 0.31.9 ) , albumin 17  g / l ( 3450 ) , creatinine 290  mol / l ( 4992 ) and proteinuria 2.30  g / l ( 00,10 ) .
her c3 level was 1.0  g / l ( 0.651.65 ) , cd19 count was 0.001/l ( 0.110.69 ) , and immunoglobulin g level was 9.32  g /
cultures of muscle tissue only grew p aeruginosa , resistant to piperazillin - tazobactam ; therefore , she was treated with meropenem , teicoplanin and clindamycin . as her clinical condition
however , 1  week later , she deteriorated , with thick yellowish sputum , fever , respiratory distress and the chest x - ray showed right consolidation .
ciprofloxacin and teicoplanin were empirically started , and the patient 's clinical condition gradually improved . a week
after this treatment had finished , the patient became worse with a new left lower lobe consolidation , so the antibiotic therapy was changed to ceftazidime .
her lupus flared with a marked malar rash over both cheeks , so her steroids ( prednisolone ) were increased to 20  mg per day and hcq was restarted .
she was in the icu from may to august 2012 , but made a remarkable recovery and was discharged home with a steroid - tapering regimen and hcq .
later , she developed two more sle flares , which were treated again with cyc and rtx , achieving good response . at 18 months
follow - up , there is no evidence of new recurrent or severe ongoing infections .
most patients with nf ranged from 38years to 44  years , with a male to female ratio of 23  :  1 , and apparently an increased incidence in african and asian countries.3 the true incidence is not known ( it is estimated to be approximately 0.4 cases per 100  000 ) , with a reported mortality from 20% to as high as 80%.35 the causative agents of nf vary and include two main categories , polymicrobial ( type 1 ) and infection of group a streptococcal ( type 2 ) .
patients with sle have an increased risk of infections , due to immunological dysfunction and the use of steroids and immunosuppressive agents.6 other factors , such as the presence of a variant form of the fc receptor are also believed to contribute to the risk of pneumococcal infection.7 nf due to pseudomonas has very rarely been reported.8
 9 the clinical presentation of patients with nf may be deceptively benign at onset , and it may not be possible to distinguish it clearly from minor soft tissue infections .
our patient was discharged from the original hospital before being admitted subsequently severely ill to university college hospital .
the lesion was rapidly progressive , probably due to her sle , and the prolonged steroid treatment and recent administration of cyc and rtx might have increased the risk of infection . during the initial period ,
exploration of the wound may be necessary even before the diagnosis is clear , particularly in a patient who is clearly toxic .
in addition to the present case , the other 31 cases of nf in sle patients that have been reported are summarised in table 1 .
the ages ranged from 12 years to 66  years , and 27 ( 84% ) were female .
most of the patients reported were asian ( 33% , 7 patients ) , 33% ( 7 patients ) hispanic and 19% ( 4 patients ) african  american .
the sites of infection included the upper or lower limb ( 60% , 17 patients ) , the face , neck or tongue ( 18% , 5 patients ) , the genital area ( 11% , 3 patients ) and the abdomen ( 11% , 3 patients ) .
nf type 1 was identified in 22 patients ( 71% ) and type 2 in 7 patients ( 23% ) , and when reported , the most common isolation was streptococcus ( 50% , 16 patients ) .
most of the patients presented with intense pain , poorly demarcated erythematous , swollen lesions over the limbs and systemic inflammatory response ; 28 patients ( 88% ) were receiving corticosteroids and 7 hcq ( 22% ) . additionally , use of other immunosuppressive drugs has been reported ( 5 cyc , 5 aza , 2 rtx , 1 mycophenolate , 1 methotrexate , 1 plasmapheresis ) before or at the time of infection .
other associated conditions have been identified , including nephritis ( 54% ; 15 patients of 28 reported ) , either during the current presentation or in the past , 13 ( 42% ) had active disease ( presumably those taking > 20  mg prednisolone or equivalent per day ) , 76% ( 13 of 17 reported ) had lymphopenia , 100% ( 12 out of 12 reported ) low serum albumin levels and 12 ( 37% ) had anaemia . interestingly , before the admission , 9 ( 28% ) reported a previous episode of infection : urinary , bartholin abcess , diarrhoea , respiratory tract infection , carious tooth , colitis , hepatitis c , cutaneous ulcers ( 2 ) , breast abscess and diverticulitis .
most patients responded to therapy , but 8 of the 32 patients died ( 25% ) , probably due to the infection or because of complications ( such as sepsis or pulmonary embolism ) .
the case presented here and the literature reviewed suggests that active disease , nephropathy , lymphopenia , anaemia , low serum albumin levels , immunosuppressive therapy and significant infections in the past , may constitute risk factors for the development of nf in patients with sle .
a high index of suspicion for the diagnosis is required , and surgical exploration should not be delayed , especially during the early stages , to improve the prognosis of this devastating complication .

 necrotising fasciitis ( nf ) is a rare infection of the subcutaneous tissue , known to be rapidly progressive and potentially fatal .
 patients with systemic lupus erythematosus ( sle ) may be predisposed to this condition , and early clinical recognition can be difficult .
 we report a case of necrotising fasciitis in a 26-year - old woman with sle .
 she presented with painful swelling of her left leg , then developed clinical features of septic shock .
 emergency debridement was performed .
 intraoperative findings revealed nf and cultures grew pseudomonas aeruginosa .
 the patient survived after a lengthy hospital admission , following several further debridements complicated by recurrent chest sepsis and multiorgan failure .
 we also review and discuss the published cases of nf in sle patients .


spontaneous perforation of rectum is a rare event ; however evisceration of the small bowel through the perforated site without predisposing factors is extremely rare , complex and worth reporting .
the operative findings revealed it to be a case of spontaneous perforation of rectum with evisceration of the small bowel through the perforation .
sudden increase in the intra - abdominal pressure leads to the perforation in the chronically deranged rectal wall and pushes the small bowel loops into the pelvis and through the perforated rectum to appear transanally .
evisceration of small bowel through a spontaneous perforation in rectum is an extremely rare event .
although 55 cases of evisceration of small bowel through anus due to perforation of rectum have been documented in world literature since the first report in 1827 by benjamin brodie , the number of cases without any significant predisposing factor is very less .
the article reports a case of spontaneous perforation of rectum with evisceration of small bowel in a normal bowel without an apparent cause which is an extremely rare presentation .
a 14 years old male was admitted with the chief complaint of acute lower abdominal pain which started suddenly after he passed stools . the abdomen was tender on deep palpation in the left iliac fossa and bowel sounds were sluggish .
however , on per rectal examination gut loops were felt in the anal canal and finger was stained with blood thereby making intussusception the most probable diagnosis .
a lump was felt in the left iliac fossa once the patient was anaesthetized for surgery .
peroperative findings revealed a distended and a tubular sigmoid colon ( intussusception like appearance ) and twisting of ileal loops around the sigmoid colon simulating ileo - sigmoid knotting . on further mobilization and gentle traction on the ileal loops gangrenous segment of ileum became evident till it finally emerged out from a longitudinal perforation ( approximately15 mm ) in the anterior wall of rectum just above the peritoneal reflection ( fig .
rectal tear was closed primarily in single layer after taking the biopsy from the whole edge which revealed non specific inflammation . on repeated
questioning in postoperative period patient denied any history suggestive of constipation , rectal prolapse , trauma , weight lifting , rectal instrumentation or homosexual activity ; however intermittent straining at stools was present .
figure showing rectal perforation and the gangrenous segment of ileum which had eviscerated through the perforated rectum .
urinary bladder ( small square ) , the peritoneal reflection ( thin arrow ) and the rectal perforation ( thick arrow ) are clearly visible .
spontaneous rectal perforation usually occurs due to excessive straining on the anterior rectal wall with a pre - existing pathology like , diverticulosis , colitis , ulceration , malignancy , adhesions , irradiation , rectal and uterine prolapse and as a consequence of iatrogenic injuries and blunt trauma abdomen .
. chronic strain because of the underlying pathology causes progressive deepening of rectovesical and rectouterine pouches and the rectal wall becomes thin and weak as it is unsupported .
contraction of the abdominal muscles increases the intra - abdominal pressure and spontaneous perforation occurs through this thinned out area , mostly at the ant mesenteric border where the blood supply is poorest .
similarly , in a constipated patient the changed defecation pattern in some individuals per se causes a preliminary lesion in the intestinal wall which becomes friable due to chronic inflammation of its layers and may perforate .
nevertheless intestinal evisceration through the perforated gut without any contamination of the peritoneal cavity is enigmatic and little difficult to explain . in a recent study
presumed that two factors predisposed patients to this unusual complication : one was the sudden increase in intra - abdominal pressure and the other was the presence of rectal prolapse .
whatever the mechanics involved the sudden increase in the intra - abdominal pressure seems to be the main contributing factor .
it pushes the ileal loops into the rectovesical / rectouterine pouch which violently presses upon the anterior rectal wall . as the week rectal wall gives way the ileal loops sneak in .
this seems to be the only plausible explanation for the spontaneous act particularly when there are no signs of peritonitis as in our case . in a perforated simple ulcer of rectum
there is an area of induration around edges while a spontaneous perforation appears slit like , runs longitudinally ( rarely transversally ) with minimal signs of inflammation .
it can occur in all age groups , the youngest one reported was six years old and oldest being ninety six years old .
the treatment follows basic surgical principles . if reduced bowel is not viable it should be resected and followed by anastomosis or ileostomy depending upon the condition of the patient and contamination involved . in the follow up
period patients should be investigated to detect exact etiology and cause specific management will prevent recurrence and complications .
therefore , one must remember that per rectal palpation of bowel loops may be more than just rectal prolapse or intussusception .

 context : spontaneous perforation of rectum is a rare event ; however evisceration of the small bowel through the perforated site without predisposing factors is extremely rare , complex and worth reporting.case report : a 14 years old presented to us apparently as a case of intussception .
 the operative findings revealed it to be a case of spontaneous perforation of rectum with evisceration of the small bowel through the perforation.conclusion:sudden increase in the intra - abdominal pressure leads to the perforation in the chronically deranged rectal wall and pushes the small bowel loops into the pelvis and through the perforated rectum to appear transanally .


the motor system is a dynamic network of cortical and subcortical areas interacting through excitatory and inhibitory circuits , modulated by somatosensory input .
modifications of cortical excitability enable recovery and reorganization of the remaining motor areas both in animal models [ 4 , 5 ] and in humans [ 1 , 6 ] .
transcranial magnetic stimulation ( tms ) and magnetoencephalography ( meg ) have both been applied in stroke patients to reveal cortical excitability changes .
motor threshold ( mt ) , that is , the minimal tms intensity eliciting motor evoked potentials ( meps ) , is related to membrane excitability as it is influenced by drugs affecting neuronal ion channels .
paired pulse tms ( pp - tms ) reveals short - interval intracortical inhibition ( sici ) , related to the activation of gaba - a receptors and intracortical facilitation ( icf ) attributed mainly to glutamatergic nmda receptor activation ( for references , see ) . in acute stroke
, the mt is increased in the lesioned hemisphere ( lh ) whereas in the nonlesioned ( nh ) hemisphere it is normal   or decreased one month after stroke .
sici is decreased in both hemispheres early after stroke ; icf is stronger in nh in severe than mild strokes [ 1 , 6 ] .
finger movements and median nerve   or finger stimulation   modify spontaneous meg oscillations over the sensorimotor cortex in the beta band ( 1525  hz ) .
they are suppressed at 100300  ms after tactile stimulation ( event - related desynchronization ; erd ) , reflecting increased excitability , and increased at 5001000  ms ( event - related synchronization ; ers ) , reflecting removal of excitation [ 12 , 13 ] or reduced excitability .
inhibitory gaba - a agonist diazepam increases meg beta activity [ 15 , 16 ] .
combined meg and magnetic resonance spectroscopy showed a linear relationship between the beta ers strength and gaba concentration .
beta ers has been shown to be significantly weaker in the lh than nh ; stronger ers amplitude was correlated with a better affected hand function up to 3 months after stroke .
reduction of beta ers , however , correlated with clinical improvement after physiotherapy of patients with chronic stroke .
movement - related beta erd was significantly reduced in lh of stroke patients . the hand representation in the somatosensory cortex ( s1 ) , estimated by somatosensory evoked fields ( sefs ) , is the largest one month after stroke and its increase was correlated with the affected hand function . in tms mapping
, hand motor representation expands in the lh up to 1 month . in animal models ,
somatosensory reorganization is activated immediately after the lesion by diminished gaba - a - related inhibition and by glutamatergic activation after one month .
we hypothesized to see correlations between erd and mt related to the early cortical excitability and between ers and sici , both attributed to gaba - a - related processes .
moreover , we expected that icf , reflecting glutamatergic activity , would correlate with the somatosensory modifications in meg , as glutamate is associated with late somatosensory plasticity .
meg and ntms were recorded from thirteen patients ( age 67.3  11 years , 8 women ) , with first - ever ischemic stroke in the middle cerebral artery territory one ( t1 ) and three months after stroke ( t2 ) .
six patients had a subcortical and seven patients had a subcorticocortical or cortical stroke ( table 1 ) . at t1 ,
one patient used amitriptyline 10  mg / day and another used citalopram 10  mg / day .
one patient used zopiclone 7.5  mg for occasional sleeplessness . at t2 , citalopram 10  mg / day was used by one patient .
data from these patients has been presented previously [ 18 , 21 , 23 , 24 ] .
as the patients having both tms and meg recordings are a subset of the previous patient groups , we recalculated the group - level electrophysiological parameters to show that the present patient group is sufficiently similar to those reported previously ( see supplementary tables 1 and 2 in supplementary material available online at http://dx.doi.org/10.1155/2015/309546 ) .
an eximia navigated magnetic stimulator with a coplanar figure - of - eight coil of 70  mm wing radius ( nexstim ltd . , helsinki , finland ) was used for ntms .
patients ' mris , required for navigation , were scanned at t1 and used also at t2 .
the site was then stimulated by single tms pulses at 110% of mt and by the pp - tms at 90% for conditioning and 110% of mt for test pulses .
fifteen single pulses or pairs of conditioning and test pulses were delivered in each stimulation session .
the interval between stimuli was 3.3  s and the intersession interval varied between 1 and 3  min .
the isi selected for the paired - pulse stimuli was 2  ms for sici and 12  ms for icf .
the peak - to - peak amplitudes of meps elicited by pp - tms were normalized by dividing them by the corresponding single - pulse mep amplitude to simplify subject - to - subject comparisons .
meg during rest and tactile stimulation of the thumb ( d1 ) , index ( d2 ) , and little finger ( d5 ) were recorded with a 306-sensor neuromagnetometer ( elekta neuromag , helsinki , finland ) in biomag laboratory , right before the ntms measurement .
time - frequency representations ( tfr ) in the 1030  hz band were calculated to define the frequency range of beta modulation , which was quantified by the temporal spectral evolution method ( tse ) from signals of 2 to 4 meg sensors showing the strongest reactivity . only the contralateral beta modifications ( the affected hand stimulation for the lh and the unaffected hand for nh ) were analyzed .
onset and offset of the erd and ers were defined as a time point when the signal differed 2 sds from the baseline .
the absolute erd and ers strengths were calculated from the peak amplitudes and converted into relative values in relation to the 300  ms prestimulus baseline . for sefs , about 120 responses were averaged for stimulation of d2 ( isi 3005  ms ) , and d1 and d5 ( isi 1005  ms ) in separate sessions .
the size of the hand representation in the si was determined by calculating the euclidean distance in xyz - space between the equivalent current dipoles ( ecds ) of the earliest responses to d1 and d5 stimulation .
multiple comparison correction was carried out according to the number of tests ( n = 32 ) suggested by the four prior hypotheses ( t1 and t2 were tested separately ; lh and nh variations lead to four tests in each case ; n = 442 = 32 ) .
we also present significances of correlation values without multiple comparisons and supply all correlation coefficients and corresponding p values ( cf .
[ 1 , 9 , 28 ] for a similar approach and   for its statistical aspects ) .
the differences between ntms and meg values obtained at t1 and t2 were tested with student 's t - test .
in the lh , meps were found in 11 patients both at t1 and at t2 and were present in the nh in all patients .
mt was higher for lh than nh in 9 patients at t1 ( p < 0.05 , binomial test ) and in 10 patients at t2 ( p < 0.05 , binomial test ) .
the mts in the lh and nh correlated strongly both at t1 ( r = .82 , p < .01 ) and at t2 ( r = .78 , p < .01 ) .
pp2ms stimulations of nh did not inhibit meps ( disinhibition ; diminished sici ) in 5 patients at t1 and in 3 patients at t2 .
pp12ms stimulation of lh facilitated meps ( icf ) in 10 out of 11 patients at t1 and in all patients at t2 . in nh
mep amplitudes elicited by pp12ms stimulations were correlated between the lh and nh at t1 ( r = .62 ; p < .05 ) but not at t2 ( supplementary table 2 ) .
erd started 140  10  ms after tactile stimulation and peaked at 250  10  ms .
the subsequent ers started at 520  40  ms and peaked at 900  70  ms . at t1 ,
erd was absent in one patient and ers in two patients in the lh ; ers was missing from the nh in one patient . at t2 ,
ers was smaller in the lh than nh at t1 ( 46  31% versus 63  32% ; p < .05 ) ; at t2 , the difference was nonsignificant .
sefs from both hemispheres were detected in 12 patients at t1 and in all patients at t2 .
they were smaller in the lh than nh at t1 ( 25 nam versus 32 nam ; p < .04 ) but not at t2 .
the si hand representation area was larger in the lh than nh at t1 ( 12  3  mm versus 10  3  mm p < .003 ) but not at t2 ( supplementary table 3 ) .
the plots of the most relevant correlations are depicted in figure 1 to show that they were not driven by outliers .
all correlations are displayed in table 2 to enable evaluation of significance of our hypotheses against general effects of the lesions .

the mt and erd were correlated in the lh at t1 ( r = .66 , p < .03 ) , indicating that small erd was associated with a high mt ( figure 1(a ) ) . at t2 , this correlation was weaker ( r = .58 , p < .06 ) . however , the mt of the lh correlated with the erd of nh ( r = .62 , p < .04 ) , and the mt of the nh correlated with erd of the lh ( r = .65 , p < .02 ) , suggesting that high mt was associated with a small erd in the opposite hemisphere at t2 ( table 2 ) .

sici and the ers did not correlate at t1 or in lh at t2 . in the nh ,
high ers was associated with a strong sici ( r = .59 , p < .04 ; figure 1(b ) ) .
in addition to hypothesized correlations , sici of the nh and erd of the lh at t2 were correlated ( r = .82 , p < .001 ) , indicating that strong erd in the lh was associated with a strong sici in the nh .
sici in the lh was correlated also with the si amplitude of the lh ( r = .64 , p < .04 ) , indicating that small si amplitude was associated with a weak sici ( table 2 ) .

icf and sef parameters did not correlate at t1 . at t2 , icf in the lh correlated with the s1 amplitude of lh ( r = .65 , p
in addition , icf in the nh correlated ( r = .82 , p < .001 ) with the si finger representation area of the lh ; this correlation remained significant also after bonferroni correction ( table 2 ) .
moreover , icf in the lh at t1 was correlated ( r = .83 ; p < .002 ) with the si finger representation area of lh at t2 ; high icf at t1 resulted in a small hand representation area at t2 ( figure 1(c ) ) .
our study is the first to compare meg and ntms excitability parameters during stroke recovery .
navigated tms , not applied previously in longitudinal studies of stroke patients , enabled the precise replication of the stimulus site between separate measurements , adding reliability to the follow - up .
we found correlations between cortical excitability estimates derived from ntms and meg . as expected , we found correlations between mt and erd , but in only one of the four possible intrahemispheric and two out of four interhemispheric conditions .
the sici and beta ers , both attributed to gabaergic mechanisms , were correlated in one of their four possible intrahemispheric conditions ( in the nh at t2 ) .
one reason for this may be that various gaba - a receptor subtypes contribute to sici .
nonselective gaba - a receptor activators modify sici whereas the gaba - a1 receptor specific zolpidem did not .
nonselective gaba - a agonist zopiclone increased meg beta activity whereas zolpidem suppressed beta activity in the vicinity of stroke lesion .
moreover , in healthy subjects , diazepam increased meg erd but did not affect ers when the increase of baseline beta activity was taken into account .
this nonspecificity could contribute to the correlations of sici with the erd and mt as well .
correlations between ntms parameters and meg erd / ers were stronger at t2 than at t1 .
analogously , most tms intracortical excitability measures did not correlate with the hand function acutely but did so 3 months after stroke .
recovery of sensorimotor fmri activation to digit stimulation from 1 to 3 months was correlated with final motor function , emphasizing the importance of this time period for stroke recovery .
is attributed mainly to glutaminergic mechanisms , glutamate may contribute to stroke - induced plasticity .
somewhat surprisingly , high icf at t1 correlated with small si hand area at t2 ( figure 1(c ) ) ; thus , the narrowing towards normal hand representation size may be supported by glutaminergic activity .
icf did not correlate with the meg erd / ers , and the si hand area and beta erd / ers were not correlated ; this suggests different mechanisms underlying sici and icf ( see   for a detailed discussion ) .
for example , high mt was associated with a small erd in the opposite hemisphere , and strong erd in the lh was associated with a strong sici in the nh .
increased excitability within the unaffected motor cortex may cause imbalance between the homologous cortical motor areas and worsen also the ipsilesional hand coordination ( for references , see ) .
thus , some functional correlations may relate to the modified general excitability properties of the motor system , instead of effects in the immediate vicinity of the stroke .
tms results give direct information of the changes in the motor output and the immediate effects of tms are relatively local .
however , also subcortical and spinal processes affect the meps used to evaluate the tms effects .
meg reveals the activity of the whole cortical mantle and enables mapping of network effects generated by stroke .
meg source analysis suggests mainly motor cortex origin of beta ers [ 13 , 33 , 34 ] .
however , in electrocorticography , recorded directly from the cortex , beta erd and ers appear outside of pre- and postcentral gyri , in supplementary motor cortex , or broadly from pre- and postcentral gyri , frontolateral and medial cortex [ 37 , 38 ]
. the widespread cortical generation of the erd and ers may make them resilient to small cortical strokes .
multitude of generators may contribute to considerable variability of source locations of beta erd in stroke patients ( cf . ) .
multiple sources underlying meg signals may also explain resilience of auditory evoked fields after small strokes .
stronger correlations between icf and si parameters than between mt and sici and ers / erd may , in part , result from spatially more limited source areas of s1 responses than those of erd / ers .
it can be expected that meg and ntms produce complementary information about the effects of stroke on cortical networks . moreover ,
meg parameters in the affected hemisphere and ntms indices in the unaffected hemisphere were correlated with the motor performance of the affected hand ( cf . [ 18 , 21 , 24 ] ) .
erd in the 822  hz band may reflect downregulation of intracortical inhibition in the human motor cortex , as tms delivered during erd is associated with increased mep amplitudes and reduced sici .
however , 1  hz repetitive tms over the motor cortex reduces meps to subsequent single tms pulses , indicating inhibition , but decreases postmovement beta ers , and intermittent theta burst tms facilitates meps but increases postmovement beta ers .
beta ers is reduced in patients with myoclonus epilepsy , indicating increased cortical excitability . in line
, sici is decreased in myoclonus epilepsy patients ; however , mt is increased [ 44 , 45 ] , and the silent period after the tms pulse , reflecting motor cortical postsynaptic inhibition , is prolonged , indicating prevailing inhibitory cortical tonus .
thus , only some aspects of the cortical excitability may be shared in excitability estimates obtained by tms and meg .
our results suggest that some tms and meg excitability measures reflect the activity of the same transmitter systems .
however , high mt and absence of erd / ers may also correlate because of severely affected sensorimotor connections between the periphery and the cortex .
we detected sefs in 12/13 patients and meps in 11/13 patients already at t1 , indicating that both somatosensory and motor pathways were conveying signals .
motor function can be maintained despite significant damage to the corticospinal tract , as estimated from mt of stroke patients .
moreover , we observed fewer correlations at t1 , when the sensorimotor pathways probably were more affected , than at t2 .
however , such spurious correlations should remain stable or decrease during recovery from t1 to t2 but not increase , as in our data .
the limitations of our study include the small size of the patient group as the precise features of structural and functional changes may differ among the patients .
cortical excitability is modified differently in cortical and subcortical strokes [ 46 , 47 ] .
this , however , should not alter our correlations between the tms and meg , as both were recorded from the same patients .
possible effects of medication on excitability should go in parallel for meg and ntms , as the patients were tested sequentially during the same day .
the patients were not tested in the acute stage with tms , and meg recordings showed most dramatic erd and ers modifications between the acute phase and t1 . although mt in the lh is correlated with the paretic hand function in acute stroke , this correlation , however , weakens during recovery , and tms intracortical excitability parameters correlated with the clinical performance best at 3 months .
the 2  ms or 12  ms isis , selected for our paired - pulse stimuli , produce clear sici and icf in healthy subjects   and in stroke patients , but we did not test other parameters , which could have produced stronger correlations between ntms and meg .
icf and si response amplitude and area size , mt and the erd of the hemisphere harboring the stroke lesion , and sici and ers of the nonlesioned hemisphere are correlated in stroke patients .
numerous correlations of the excitability parameters between the lh and nh emphasize the importance of the hemispheric balance of the excitatory - inhibitory properties of the sensorimotor system in analyzing the stroke - related dysfunction during stroke recovery .

 objective .
 stroke alters cortical excitability both in the lesioned and in the nonlesioned hemisphere .
 stroke recovery has been studied using transcranial magnetic stimulation ( tms ) .
 spontaneous brain oscillations and somatosensory evoked fields ( sefs ) measured by magnetoencephalography ( meg ) are modified in stroke patients during recovery .
 methods .
 we recorded sefs and spontaneous meg activity and motor threshold ( mt ) short intracortical inhibition ( sici ) and intracortical facilitation ( icf ) with navigated tms ( ntms ) at one and three months after first - ever hemispheric ischemic strokes .
 changes of meg and ntms parameters attributed to gamma - aminobutyrate and glutamate transmission were compared .
 results .
 icf correlated with the strength and extent of sef source areas depicted by meg at three months .
 the ntms mt and event - related desynchronization ( erd ) of beta - band meg activity and sici and the beta - band meg event - related synchronization ( ers ) were correlated , but less strongly . conclusions .
 this first report using sequential ntms and meg in stroke recovery found intra- and interhemispheric correlations of ntms and meg estimates of cortical excitability .
 icf and sef parameters , mt and the erd of the lesioned hemisphere , and sici and ers of the nonlesioned hemisphere were correlated .
 covarying excitability in the lesioned and nonlesioned hemispheres emphasizes the importance of the hemispheric balance of the excitability of the sensorimotor system .


the u.s . food and drug administration ( fda ) has approved around 30 antidepressant medications for the treatment of major depression . among them are selective serotonin reuptake inhibitors ( ssris ) .
these drugs change the balance of serotonin in the brain , such as fluoxetine ( prozac ) , paroxetine ( paxil ) , sertraline ( zoloft ) , escitalopram ( lexapro ) , and citalopram ( celexa ) .
another family of medications , selective serotonin and norepinephrine reuptake inhibitors ( snris ) , help increase serotonin and norepinephrine levels in the brain , such as venlafaxine ( effexor ) , duloxetine ( cymbalta ) , and levomilnacipran ( fetzima ) .
still others in this family include bupropion ( wellbutrin ) , vortioxetine ( brintellix ) , mirtazapine ( remeron ) vilazodone ( viibryd ) , nefazodone ( serzone ) , and trazodone ( desyrel ) .
in addition , tricyclics and monoamine oxidase inhibitors , which are two classes of older antidepressants that work by inhibiting the brain s reuptake of serotonin and norepinephrine , are also approved but tend to cause more side effects than the other classes of antidepressants .
but pharmacotherapy is nt the only option ; two other major classes of treatment are also available  psychotherapy and somatic nonpharmacological treatments . in randomized
, controlled trials , cognitive - behavioral therapy ( cbt ) and interpersonal psychotherapy ( ipt ) repeatedly have been demonstrated to be effective in the treatment of major depressive disorder ( mdd ) .
whether other forms of psychotherapy , such as insight - oriented , psychodynamically based therapy , are effective in major depression remains controversial .
brain stimulation therapies involve activating or touching the brain directly with electricity , magnets , or implants , and the fda has approved three somatic nonpharmacological treatments for depression : electroconvulsive therapy ( ect ) , vagus nerve stimulation ( vns ) , and repetitive transcranial magnetic stimulation ( rtms ) .
ect is generally considered the most effective of all depression treatments , although no head - to - head , randomized , controlled trial has compared it with other interventions .
it generally requires inpatient hospitalization , at least initially , and general anesthesia with nine to twelve treatments over a three- to four - week period .
vns and rtms are both fda - approved for treatment - resistant depression ; the former requires an invasive surgical procedure .
researchers have conducted relatively few controlled studies of these devices compared with the vast number of pharmacotherapy and psychotherapy treatment trials .
with a plethora of drugs and psychotherapy approaches available , let us consider the problem psychiatrists encounter on a daily basis .
a 50-year - old academic physician suffers from a classic major depressive episode associated with severe work stress .
he has difficulty falling asleep , awakens several times during the night , and rises early with severe anxiety .
he has reduced appetite , difficulty concentrating , and trouble enjoying any leisure activities , and he feels pessimistic about the future .
he admits to passive contemplations about suicide , with recurring thoughts that if a car jumped the median and landed on his car , it would be an end to his suffering .
he has no underlying medical disorder that might be contributing to depression , such as hypothyroidism or drug or alcohol abuse
i want to recommend the treatment most likely to be successful in producing a complete remission of his depressive syndrome and relieving him of his considerable misery . what are the known and best - validated predictors of response ?
our group has previously reviewed the scientific findings in this area.36 the most reliable predictor is past response , but in this case the patient has never been treated for depression .
a positive response in first - degree family relatives is also predictive of a beneficial response to antidepressants , but again , this is not applicable to this patient .
some evidence suggests that certain subtypes of depression respond best to certain treatments  monoamine oxidase inhibitors ( the first type of antidepressants developed ) are believed to be the most effective for patients with so - called atypical depression characterized by hypersomnia , overeating , extreme rejection sensitivity , and feeling better in the morning than later in the day .
combinations of antidepressants and antipsychotics or ect are best for patients with major depression with psychotic features .
surely patient choice is an important consideration , but it will likely be guided by my discussion with the patient . in 2013 ,
mayberg , holtzheimer , dunlop , and craighead ) were colleagues of mine for many years , and we continue to collaborate on various projects .
mayberg s study sought to identify a biomarker that could predict which type of treatment would benefit a patient based on the individual s brain activity . using regional brain glucose metabolism as measured by positron emission tomography ( pet ) as a proxy for neural activity , her group sought to determine whether baseline resting state activity predicted remission after twelve weeks of treatment with either the selective serotonin reuptake inhibitor escitalopram ( 10 to 20 mg per day ) or sixteen sessions of cognitive - behavioral therapy .
the study sample initially comprised eighty - two men and women who were randomized between the two treatments .
of these , sixty - five patients completed the study and thirty - eight had clear outcomes and acceptable pet data .
the thirty - eight patients who comprise the analyzable data set were distributed as follows : eleven who went into remission with escitalopram ( six non - responders ) and twelve who did so with cbt ( nine nonresponders ) .
the major finding were that hypometabolism of glucose in the insula , likely reflecting reduced activity of neurons in this brain region , was associated with remission using cbt , and with poor response to escitalopram .
contrariwise , insula hypermetabolism , reflecting increased activity of neurons in this brain region , was associated with remission using escitalopram and with poor response to cbt .
the authors conclude that baseline insula metabolism is the first objective marker to guide initial treatment selection in depression
first they eliminated from their primary analysis the responders to cbt or to escitalopram who did not go into remission . more specifically , partial responders to escitalopram or cbt were excluded from the analysis .
they did so in order to accentuate the differences between the extremes in the depressed population ; the results revealed clear differences in glucose metabolism in six regions : the right
anterior insula , right motor cortex , left premotor cortex , right inferior temporal cortex , left amygdala , and precuneus .
mean regional activity values for remitters and nonresponders segregated by treatment arm are plotted for the six regions showing a significant treatment  outcome analysis of variance interaction effect .
regional metabolic activity values are displayed as region / whole - brain metabolism converted to z scores .
cbt indicates cognitive - behavioral therapy.7 when all six regions were compared , the right insula exhibited the greatest effect as a discriminator of treatment response , followed by the precuneus .
when the whole sample was studied , right insular activity was positively correlated with the depression symptom severity scale , and with the hamilton depression rating scale ( hrsd ) score in the cbt treatment group while right insular activity was negatively correlated with the hrsd in the escitalopram treatment group .
if additional research can replicates these results , it suggests that a simple brain imaging test could reliably predict whether a given patient should be treated with psychotherapy or antidepressant medication .
it also raises a plethora of additional questions :
 a wealth of data , now summarized in a research meta - analysis , indicate that mdd patients with a history of child abuse and neglect exhibit a poorer response to pharmacotherapy and psychotherapy and exhibit unique brain imaging differences.8 mayberg s research does not address this critical clinical characteristic in this population.it is somewhat unclear how the six brain regions of interest were identified and why several regions repeatedly identified to be implicated in the pathophysiology of depression either were not selected or exhibited no significant effect , including the hippocampus , subgenual cingulate , and others.it is hard to know what to make of the findings that only the right anterior insula , right motor cortex , left premotor cortex , left amygdala , left precuneus , and right inferior temporal region show dramatic differences in the cbt versus escitalopram induced remission versus nonresponder groups whereas their counterparts , namely the left anterior insula , left motor cortex , right premotor cortex , right amygdala , right precuneus , and left inferior cortex did not . was a composite of the left and right sides of these structures informative?as the authors themselves point out , the study comprises a relatively small number of patients and our field is replete with pilot study findings that , unfortunately , have not been replicated in larger trials.this study utilized pet instead of the more often used functional magnetic resonance imaging ( fmri ) technology . as mayberg and
her colleagues appropriately point out in their paper , fmri studies have examined regional brain activity and , more recently , resting state connectivity to identify mdd or mdd subtypes , but neither type of imaging has been used to discriminate response either among antidepressants or between antidepressants and psychotherapy.9 a wealth of data , now summarized in a research meta - analysis , indicate that mdd patients with a history of child abuse and neglect exhibit a poorer response to pharmacotherapy and psychotherapy and exhibit unique brain imaging differences.8 mayberg s research does not address this critical clinical characteristic in this population .
it is somewhat unclear how the six brain regions of interest were identified and why several regions repeatedly identified to be implicated in the pathophysiology of depression either were not selected or exhibited no significant effect , including the hippocampus , subgenual cingulate , and others .
it is hard to know what to make of the findings that only the right anterior insula , right motor cortex , left premotor cortex , left amygdala , left precuneus , and right inferior temporal region show dramatic differences in the cbt versus escitalopram induced remission versus nonresponder groups whereas their counterparts , namely the left anterior insula , left motor cortex , right premotor cortex , right amygdala , right precuneus , and left inferior cortex did not . was a composite of the left and right sides of these structures informative ?
as the authors themselves point out , the study comprises a relatively small number of patients and our field is replete with pilot study findings that , unfortunately , have not been replicated in larger trials . this study utilized pet instead of the more often used functional magnetic resonance imaging ( fmri ) technology .
as mayberg and her colleagues appropriately point out in their paper , fmri studies have examined regional brain activity and , more recently , resting state connectivity to identify mdd or mdd subtypes , but neither type of imaging has been used to discriminate response either among antidepressants or between antidepressants and psychotherapy.9 the expanding area of genetics in general , and pharmacogenetics in particular , is also of vital importance .
a burgeoning database documents the role of certain genetic variations in vulnerability to mood disorders , and more recently how variations may affect treatment response to different antidepressants . whether genetic material was collected in mayberg s study is unclear , but this focus is crucial , particularly in view of recent findings in imaging genomics .
the lack of random assignment of the mdd patients as regards , for example , the vulnerability gene variants of the serotonin transporter or others , now shown to be associated with clear alterations in regional brain activity , could have confounded the results .
this research group has always been willing to take great leaps forward , and they should be applauded for it .
subsequent studies will reveal if the insula is truly  the region  that predicts response to cbt versus a selective serotonin reuptake inhibitor such as escitalopram or whether other regions or biomarkers also need to be a component of the ultimate formula .
this is part of the ongoing and exciting scientific process that is emblematic of the marriage of neuroscience and psychiatry .
ultimately , i believe this work will be judged as crucial in eventually attaining the goal all of us seek : a valid predictor of individual treatment response in depression , still the holy grail in psychiatry research .

 editor s note:holy grail  is a well - known metaphor for the eternal spiritual pursuit for truth and wisdom .
 it suggests that in order for us to find what no one has found , we must search where few have looked . in 2013 ,
 a group led by helen mayberg published a groundbreaking paper that sought an answer to one of the most discussed conundrums in psychiatry and neuroscience : can specific patterns of brain activity indicate how a depressed person will respond to treatment with medication or psychotherapy ? our author examines the findings and discusses their potential impact on treatment for a public health problem that affects millions of people worldwide .


primary mitochondrial disorders due to impaired oxidative phosphorylation ( oxphos ) are a well - established cause of severe disability and precocious death in both children and adults ( koopman et  al . , 2012 ) .
no effective therapies are currently available for these conditions , but encouraging results have recently been obtained by stimulating mitochondrial biogenesis acting on either the ppar system ( wenz et  al . , 2008 ) or the amp - kinase ( ampk)/pgc1 axis ( viscomi et  al . , 2011 ) .
importantly , these approaches can in principle be extended to several mitochondrial diseases with different genetic causes , as they do not point to the correction of a specific defect but are based on a more general strategy aimed at increasing the overall residual activity of the respiratory chain .
additional targets able to activate the mitochondriogenic program and boost mitochondrial function are sirtuins 17 ( houtkooper et  al . , 2012 ) , the mammalian orthologs of the yeast silent information regulator ( sir ) 2 gene ( imai et  al . , 2000 ;
sirtuins have different subcellular localization , sirt1 and sirt6 being mainly found in the nucleus , sirt2 in the cytosol , sirt3sirt5 in mitochondria , and sirt7 in the nucleolus .
sirtuins are important regulators of several proteins , including key metabolic players , acting as either deacetylases or adp - ribosylases ( houtkooper et  al . , 2012 ) .
the most - investigated member of the family is sirtuin1 ( sirt1 ) , a nad - dependent type iii nuclear deacetylase that utilizes nad as a cosubstrate to remove acetyl groups from lysine residues of a target protein .
known targets of sirt1 are the tumor suppressor p53 , the myocyte - specific enhancer factor 2 ( mef2 ) , the forkhead box o ( foxo ) , and pgc1 , all of which regulate transcriptional programs related to increased mitochondrial function ( andreux et  al . , 2013 ) .
sirt1 activity is directly regulated by nad availability , by substrate - dependent activation , raising the hypothesis that nad acts as a metabolic sensor .
for instance , both nad levels and sirt1 activity increase in mammalian tissues in response to energy / nutrient stresses such as exercise ( cant and auwerx , 2009 , 2010 ) and fasting ( cant and auwerx , 2010 ; chen et  al .
recent studies have shown that sirt1 activation can prevent diet - induced obesity in mice .
this effect was achieved by increasing the content of nad in cells and tissues essentially through ( 1 ) dietary supplementation of suitable nad precursors , such as nicotinamide riboside , nr ( cant et  al . , 2012 ) , or ( 2 ) inhibition of nad - consuming enzymes , such as the poly(adp - ribose ) polymerase 1 , parp1 ( bai et  al . , 2011 ) .
here , we have tested the therapeutic efficacy of these strategies on a genetic mitochondrial disease model , the sco2 knockout / knockin ( sco2 ) mouse ( yang et  al . , 2010 ) .
sco2 encodes a metallochaperone involved in the formation of the copper redox centers into nascent complex iv ( cytochrome c oxidase , cox ) ( leary et  al . , 2009 ) .
mutations in this gene lead to infantile fatal encephalocardiomyopathy ( papadopoulou et  al . , 1999 ) .
most of the patients  carry at least one allele encoding the common mutation p.e140k , corresponding to the p.e129k mutation in the knockin murine sco2 allele .
the second knockout allele in this animal model is functionally null ( yang et  al . , 2010 ) .
while homozygous knockout individuals are embryonic lethal , the sco2 mice show a predominantly myopathic phenotype characterized by  exercise intolerance and associated with ubiquitous cox deficiency .
to test the effects of persistent increase of the nad pool on  the sco2 mouse , we first crossed it with a constitutive  parp1 mouse ( de murcia et  al . ,
1997 ) , which shows increased levels of nad in skeletal muscle ( bai et  al . , 2011 ) .
the sco2-parp1 double mutants showed reduced fasting blood glucose levels , body weight and epididymal white adipose tissue ( wat ) compared to sco2 littermates , whereas no differences were observed between wt and parp1 littermates ( see figure  s1 available online ) .
the endurance motor performance of sco2-parp1 double mutants , sco2 , parp1 , and wt littermates ( four animals per group ) was monitored weekly by a standard treadmill test for 4  weeks starting at 2  months of age . while sco2 mice showed markedly reduced motor performance compared to wt littermates throughout the observation time , the double mutant individuals performed as well as the wt and parp1 littermates ( figure  1a ) .
biochemically , significant reduction of complex iv activity and , to a lesser extent , complex iii as well ( yang et  al . , 2010 ) , was measured in skeletal muscle of sco2 mice . in the muscle homogenate of sco2-parp1 double mutants ,
these activities were comparable to that of parp1 and wt littermates , whereas complex i and ii activities were even higher ( figure  1b ; table s1 ) .
accordingly , the intensity of the histochemical staining specific to cox was increased in skeletal muscle of the double mutants , compared to the sco2 mutants ( figure  1c ) .
the activities of complex iii and iv ( figure  1d ; table s2 ) were also increased in the brains of double mutants relative to sco2 animals , but remained significantly lower than those measured in parp1 and wt littermates ; the histochemical reaction to cox was concordant with the biochemical data ( figure  1e ) . to test the effects of pharmacological intervention , we first administered nr to sco2 mice and wt littermates ( n  = 4/group ) , as a food admix ( 400  mg / kg ) ( cant et  al . , 2012 ) for four weeks .
metabolic parameters in the treated groups , including reduced blood glucose , plasma fatty acids , and epididymal wat , mirrored those of parp1 mice ( figure  s2 ) , confirming that nr , or its derivative nmn , was pharmacologically active in  vivo .
nr - treated sco2 mice significantly improved their motor performance compared to the vehicle - treated sco2 group , rapidly achieving the levels of motor endurance displayed by treated and untreated wt mice ( figure  2a ) , which showed no difference to each other .
these results suggest that nr treatment increases mitochondrial function in the sco2 mice through nad activation of sirt1 ( cant et  al . , 2012 ) .
accordingly , the nad / nadh ratio was significantly increased ( figure  2b ) , and the ratio between acetylated and total foxo1 , a direct target of sirt1 , was clearly reduced ( figure  2c ) in skeletal muscle of nr - treated versus vehicle - treated sco2 and wt animals .
we did not observe differences in mtdna content ( data not shown ) and citrate synthase ( cs ) activity ( figure  2f ) , but mrna levels of several genes related to either fatty acids oxidation ( fao ) , including acox and  cd36 , or oxidative phosphorylation ( coxi , coxii , coxiv , coxva ) were significantly increased in nr - treated versus vehicle - treated sco2 but not in wt animals ( figure  2d ) .
tfam , a key factor of mtdna transcription , was also increased , and ucp3 and pdk4 , which were downregulated in sco2 mice , returned to control levels upon nr treatment .
as expected , we found no change in transcripts specific to pgc1 , which is activated posttranscriptionally by sirt1 , and to two pgc1 partners , nrf1 and nrf2 .
accordingly , western blot immunovisualization demonstrated increased levels of several nuclear- and mitochondrial - dna - encoded oxphos - related proteins in nr - treated versus vehicle - treated skeletal muscle samples ( figure  2e ) . in the same specimens , mitochondrial respiratory chain activities were significantly increased ( figure  2f ; table s3 ) in nr - treated versus vehicle - treated sco2 mice , but not in wt animals .
the histochemical staining for cox reflected the biochemical results ( figure  2 g ) . in both c.  elegans and mammalian cells
, nr - dependent sirt1 activation can induce the mitochondrial unfolded protein response ( mtupr ) , a stress - response protective mechanism which can improve mitochondrial function ( durieux et  al .
we found that the mtupr - specific transcripts clpp , hsp60 , and sod2 were significantly increased in muscle samples of nr - treated sco2 mice , whereas sod3 , which is unrelated to mtupr , was unchanged ( figure  2h ) .
no effect of the nr treatment was observed on the mitochondrial respiratory chain activities in the brain of our animals ( table s4 ) .
next , we administered a pan - parp inhibitor ( mrlb-45696 , ic50 for parp  < 1  nm ; pirinen et  al . , 2014 , in this issue of cell metabolism ) at 50  mg /
kg as a food admix for 4  weeks . in mrlb-45696-treated sco2 mice , we observed metabolic effects similar to those of nr treatment ( figure  s3 ) .
weekly treadmill tests showed progressive increase , up to normal , of the motor endurance in mrlb-45696-treated sco2 , whereas no change was seen in wt mice ( figure  3a ) .
the nad / nadh ratio was significantly increased in treated versus untreated wt , but not in the sco2 , animals ( figure  3b ) , whereas the acetylated / total foxo1 ratio was reduced in both treated groups ( figure  3c ) , indicating activation of sirt1 by mrlb-45696 .
similar to nr , mrlb-45696 increased the mrna expression levels of oxphos- and fao - related genes in both sco2 and wt mice , whereas mtdna content ( data not shown ) and cs activity ( figure  3f ) remained unchanged . in treated sco2 but not in wt animals , western blot analysis showed increased content of mitochondrial respiratory chain subunits ( figures 3d and 3e ) , which was paralleled by significantly increased mitochondrial respiratory chain activities ( figure  3f ; table s3 ) .
histochemistry for cox showed increased staining in treated versus vehicle - treated sco2 mice ( figure  3 g ) .
again , we found that expression of the mtupr genes hsp60 , clpp , and sod2 was significantly increased , unlike the mtupr - unrelated gene sod3 ( figures 3h and 3i ) .
in contrast to the nr treatment , the mrlb-45696 treatment determined significant increase of cox transcripts ( figure  4a ) ,  and respiratory chain activities in the brain ( figure  4b ; table  s4 ) . the intensity of cox staining was increased as well ( figure  4c ) .
similar results were obtained in both skeletal muscle and brain by using pj34 , a commercially available pan - parp inhibitor ( figures s3 and s4 ; table s4 ) .
the nad pool is set by the balance between de novo and  salvage biosynthetic pathways and utilization by nad - consuming enzymes .
nad is synthesized de novo from tryptophan , but the main source of nad is from salvage pathways ( houtkooper et  al . , 2010 ) .
these require the uptake of other nad precursors from the diet , including nr . upon its entry in the cell , nr is phosphorylated by nr kinases into nicotinamide mononucleoside ( nmn ) , which is then converted to nad by nmn adenylyltransferase ( bieganowski and brenner , 2004 ) .
nad biosynthesis and cellular levels are also controlled by a circadian clock related to the feeding / fasting cycle .
for example , in the mitochondrial compartment nad levels regulate sirtuin 3 , a deacetylase targeting respiratory chain subunits ( peek et  al . , 2013 ) , while in the nucleus nad is a substrate of both parp1 and sirt .
parp1 , the highest consumer of nad in mammalian tissues , is activated upon binding to damaged or abnormal dna ( durkacz et  al . , 1980 ) and catalyzes the formation of poly(adp - ribose ) polymers ( par ) using nad as a substrate , onto different acceptor proteins , including parp1 itself ( adamietz , 1987 ) .
ablation of the parp1 gene , supplementation of nr or administration of parp inhibitors ( parpi ) can expand the nad pool and activate sirtuins , particularly sirt1 , a master regulator of mitochondrial homeostasis .
these effects can protect mice from high - fat ( hf)-induced metabolic disease ( cant et  al . ,
we have shown here that these treatments can correct the biochemical and clinical phenotype of the sco2 mouse , a model of genetically determined mitochondrial disease . increased transcription of genes related to both oxphos and mtupr
was associated with activation of oxidative metabolism , increase of mitochondrial respiratory chain activities , and normalization of the endurance motor deficit , displayed by naive sco2 animals .
notably , these effects were hardly seen in wt littermates , suggesting that mitochondrial dysfunction sensitizes muscle and possibly other tissues to activators of mitochondriogenic programs .
increased mitochondrial function can be achieved in wt animals only by much longer - term treatments ( > 6  months ) ( pirinen et  al . , 2014 ) .
in contrast with previous results , we found no change in mtdna copy number and cs activity in nr- or parpi - treated versus untreated animals , possibly because of the shorter timeframe of our experimental protocol ( 4  weeks ) compared to that of  other studies ( 12  weeks ) .
this observation suggests time - dependent activation of different mitochondriogenic programs , with induction of oxphos- and fao - related genes occurring much  earlier than stimulation of mitochondrial proliferation and increase in mtdna content .
likewise , prolonged nr supplementation up to 6  months induced mitochondrial biogenesis in the brain and improvement of cognitive dysfunction of an alzheimer disease mouse model ( gong et  al . , 2013 ) .
while we observed hardly any effect of nr in our 4  week trial , two pan - parp inhibitors did correct the respiratory chain defect in the brains of our sco2 mice .
this observation is particularly relevant , as the brain is an exquisite target of mitochondrial dysfunction , and progressive encephalopathy is the most frequent clinical presentation of mitochondrial disease in infancy and childhood .
our work supports the idea that the increase of nad levels in critical tissues is an effective therapeutic option for mitochondrial disease .
nr is a natural vitamin with no known adverse effects , which could be administered as a dietary supplement , particularly in case of isolated mitochondrial myopathy .
our results are concordant with very recent works reporting beneficial effects of nad precursors in mouse models characterized by reduced nad / nadh ratio , such as aging ( gomes et  al . , 2013 ) or complex i deficiency ( karamanlidis et  al . , 2013 )
initially shown to boost oxidative metabolism in diet - induced models of obesity , parp1 ablation or inhibition has recently been reported to remarkably rescue pharmacological models of liver cirrhosis , partly by correcting the associated mitochondrial impairment ( mukhopadhyay et  al . , 2013 ) .
several parp inhibitors are currently under clinical trial as anticancer molecules , and seem to be associated with relatively mild side effects ( bundred et  al . , 2013 ; tutt et  al . ,
however , more work is needed to evaluate their use in chronic conditions such as primary mitochondrial disorders in view of their potential genotoxic effects .
mouse tissues were homogenized in 15 volumes of 10  mm potassium phosphate buffer ( ph 7.5 ) .
mitochondrial - enriched fractions were collected after centrifugation at 800  g for 10  min in the  presence of protease inhibitors , and frozen and thawed three times in liquid nitrogen .
aliquots , 70  g each , were run through a 12% sds - page and electroblotted onto a  nitrocellulose membrane , which was then matched with different antibodies .
carlo besta  neurological institute , in accordance with guidelines of the italian ministry of health .
mice were maintained in a temperature- and humidity - controlled animal - care facility , with a 12  hr light / dark cycle and free access to water and food .
a standard treadmill apparatus ( columbus instruments , columbus , oh ) was used to measure motor exercise endurance , as described in viscomi et  al .
series of 8  m thick sections were stained for cox and sdh , as described ( sciacco and bonilla , 1996 ) .
muscle quadriceps samples stored in liquid nitrogen were homogenized in 10  mm phosphate buffer ( ph 7.4 ) , and the spectrophotometric activity of ci , cii , ciii , and civ , as well as cs , was measured as described ( bugiani et  al . , 2004 ) .
note that in all panels the activity of cii has been multiplied by 10 for  visualization clarity .
nad was extracted using acidic and alkaline extraction methods , respectively ( yang and sauve , 2006 ) .
tissue nad was analyzed with mass spectrometry as previously described ( yang and sauve , 2006 ) .
mtdna content and transcripts analysis was carried out by sybr green real - time pcr , as described ( viscomi et  al . , 2011 ) .

 summarymitochondrial disorders
 are highly heterogeneous conditions characterized by defects of the mitochondrial respiratory chain . pharmacological activation of mitochondrial biogenesis has been proposed as an effective means to correct the biochemical defects and ameliorate the clinical phenotype in these severely disabling , often fatal , disorders .
 pathways related to mitochondrial biogenesis are targets of sirtuin1 , a nad+-dependent protein deacetylase . as nad+ boosts the activity of sirtuin1 and other sirtuins , intracellular levels of nad+ play a key role in the homeostatic control of mitochondrial function by the metabolic status of the cell .
 we show here that supplementation with nicotinamide riboside , a natural nad+ precursor , or reduction of nad+ consumption by inhibiting the poly(adp - ribose ) polymerases , leads to marked improvement of the respiratory chain defect and exercise intolerance of the sco2 knockout / knockin mouse , a mitochondrial disease model characterized by impaired cytochrome c oxidase biogenesis .
 this strategy is potentially translatable into therapy of mitochondrial disorders in humans .