tardive dystonia ( td ) , a rarer side effect after longer exposure to antipsychotics , is characterized by local or general , sustained , involuntary contraction of a muscle or muscle group , with twisting movements , generally slow , which may affect the limbs , trunk , neck , or face .
 td has been shown to develop in about 3% of patients who have had long - term exposure to antipsychotics .
 . the low risk of td for atypical antipsychotics is thought to result from their weak affinity for dopamine receptors . compared with typical ,
 atypical antipsychotic agents have a greater affinity for serotonin 5-ht2a than dopamine d2 receptors , with a low propensity to induce td . among this olanzapine
 is thought to have preferential action at mesolimbic over nigrostriatal dopaminergic pathways and is , therefore , associated with a very low incidence of extrapyramidal symptom ( eps ) .
 furthermore , a retrospective analysis of controlled multicentric trials suggested that olanzapine also improves preexisting symptoms of tardive movements .
 we report a case of 20-year - old male , belonging to lower socioeconomic class , educated up to 2 standard , presented with severe unilateral dystonic left sided neck movements [ figure 1 ] .
 careful history exploration revealed he was taking risperidone 2 mg irregularly for 2 months and then olanzapine 5 mg for another 4 months .
 picture of neck dystonia of patient at 19 years , the patient presented with occasional anger outbursts , getting provoked on small matters and beating family members , running away from home , screaming episodes occasionally , fearfulness , sleep disturbance for 2 days ; which was precipitated after fever . according to the mother
 , one friend might have threatened / made fun of him actually and after that patient stopped going out of house , and displayed above mentioned symptoms .
 this was interpreted as psychosis with persecutory ideas , and he was treated with risperidone 2 mg / day for 2 months and then with olanzapine 5 mg / day for 4 months . in last two follow - ups patient did not present himself , and mother reported unusual neck movements , which were taken as a part of his overall psychopathology and not taken seriously , slight intermittent neck movements reported were missed as part of adolescent behavior problems mimicking some hero in movies . as neck dystonia increased , the patient had a severe disability as patient had to keep his hands behind his head for the support .
 the movement would decrease when the patient was lying down and was absent during sleep .
 he even stopped taking food due to severe neck movements making chewing and swallowing difficult .
 his birth and early developmental milestones were normal . during 210 years of age patient was inattentive and mildly hyperactive .
 other siblings were educated with master 's degree , and patient was also sent to school , but due to inattention and restlessness , he did not pass 2 standard after three attempts .
 he left the schooling . with average executive functioning and life skills , he worked as an unskilled laborer in the neighborhood shops as a helping hand .
 , he was found to be getting over familiar , cheerful , moody , and short tempered .
 sometimes , the patient had inappropriate social judgment ; for which his friends made fun of him , and teased him . on mental status assessment ,
 routine investigations , thyroid function tests , electroencephalogram , fundus examination , cervical x - ray , magnetic resonance imaging brain were normal . after consulting neurophysician , wilson 's disease and other secondary causes of dystonia were ruled out .
 the patient was treated with clonazepam 1 mg total dissolved solid ( tds ) , tetrabenazine 25 mg tds , trihexiphenidyl 2 mg bipolar disorder ( bd ) . after 2 months , there was some improvement of around 30% .
 baclofen 10 mg was added ; increased up to 20 mg , trihexyphenidyl reduced to 2 mg . with little improvement after 4 months of treatment for dystonia , levodopa + carbidopa ( 100 + 25 ) was added by neurophysician and increased up to  tablet tds and baclofen omitted .
 after 12 months of treatment , patient has improved around 90% with tetrabenazine 75 mg , levodopa + carbidopa ( 100 + 25 ) -  tablet bd , and clonazepam 1 mg bd .
 earlier case reports reported td developing with high - dose atypical antipsychotics such as olanzapine 20 mg or aripiprazole 15 mg with longer duration of exposure of around 1215 months in established psychiatric illness like schizophrenia or any other psychotic illness .
 eps in general and tardive dyskinesia , in particular , have been extensively studied in schizophrenia . even though a number of studies suggest that bipolar patients experience higher rates of eps ( parkinsonism , dystonia , akathisia ) and td compared to patients with a diagnosis of schizophrenia , research within the bd population has been limited .
 the risk is found to be 3 to 5 times higher in elderly patients compared to young patients .
 in addition to age , the risk is directly proportional to : female gender , daily and total dose of the antipsychotic drug , presence of mood disorder , the use of anticholinergics with neuroleptics , previous physical therapies ( electroconvulsive therapy ) , the presence of other physical illness such as diabetes or an organic disorder , younger age of exposure , and the presence of extrapyramidal symptoms early in treatment .
 this patient 's severe dystonic neck movements developed within short period of 6 months of exposure to atypical antipsychotics risperidone 2 mg and then olanzapine 5 mg only , which can cause minimal extrapyramidal side effects . in this case ,
 risk factors for developing serious disabling td were neuroleptic exposure , borderline intellectual functioning , externalizing behavior , probable misdiagnosis , and overlooking early indicators of side effects .
 this case highlights dangers of casually prescribing low dose second generation antipsychotics in patient with hyperthymic temperament and borderline intellectual functioning with vague short lasting presenting complaints ; probably misdiagnosed as psychosis ; leading to such severe adverse effects because patients with organic brain damage are more prone to develop adverse effects like td .
 thus , judicious use of antipsychotics , with detailed and frequent assessments is important , and emergent stereotyped behavior or unexplained movements must be examined carefully and taken seriously .
 the authors certify that they have obtained all appropriate patient consent forms . in the form the patient(s )
 has / have given his / her / their consent for his / her / their images and other clinical information to be reported in the journal .
 the patients understand that their names and initials will not be published and due efforts will be made to conceal their identity , but anonymity can not be guaranteed .
 the authors certify that they have obtained all appropriate patient consent forms . in the form the patient(s )
 has / have given his / her / their consent for his / her / their images and other clinical information to be reported in the journal .
 the patients understand that their names and initials will not be published and due efforts will be made to conceal their identity , but anonymity can not be guaranteed .

Abstract:
tardive dystonia ( td ) is a serious side effect of antipsychotic medications , more with typical antipsychotics , that is potentially irreversible in affected patients .
 studies show that newer atypical antipsychotics have a lower risk of td . as a result , many clinicians may have developed a false sense of security when prescribing these medications .
 we report a case of 20-year - old male with hyperthymic temperament and borderline intellectual functioning , who developed severe td after low dose short duration exposure to atypical antipsychotic risperidone and then olanzapine .
 the goal of this paper is to alert the reader to be judicious and cautious before using casual low dose second generation antipsychotics in patient with no core psychotic features , hyperthymic temperament , or borderline intellectual functioning suggestive of organic brain damage , who are more prone to develop adverse effects such as td and monitor the onset of td in patients taking atypical antipsychotics .


syncope is caused by transient diffuse cerebral hypoperfusion and is characterized by transient loss of consciousness with a rapid onset followed by spontaneous and complete recovery .
 clinical features of syncope may include myoclonic jerks which are often multifocal and asynchronous , convulsions , and urinary incontinence , making it difficult to differentiate from epileptic seizure by clinical features alone .
 significant fluctuations in cerebral perfusion pressure are prevented by autoregulation of cerebral circulation , but there may be conditions where such mechanism may not compensate adequately .
 cough syncope , a rare form of syncope , may be a result of transient failure of the cerebral autoregulatory mechanism to cope with sudden decrease in cerebral blood flow .
 we present an unusual case of recurrent cough syncope , which was initially diagnosed and treated as seizures , in the context of a left - sided glomus jugulare tumor , a benign paraganglioma .
 a 43-year - old right - handed woman with history of glomus jugulare tumor in the left jugular fossa with intracranial extension into the posterior cranial fossa was transferred from another hospital for recurrent seizure - like spells .
 she had a 90% surgical resection of the tumor done in 2011 followed by radiation therapy in september 2012 .
 her episodes occurred multiple times a day ( 7 per day on average ) during wakeful state .
 they were triggered by coughing ( usually a bout of cough ) and were characterized by staring and unresponsiveness as well as stiffening of the body with mild shaking of both upper extremities .
 she was diagnosed with epileptic seizures but continued to have episodes during treatment with the antiepileptic drugs ( aeds ) phenytoin , levetiracetam , and lamotrigine .
 escalation of aed therapy made her increasingly drowsy , and she was on all three aforementioned aeds at the time of presentation .
 her physical examination was remarkable for excessive drowsiness , mild dysarthria , right sixth cranial nerve palsy , mild hypertonia with hyperreflexia in the lower extremities ( left more than right ) , and bilateral ( left more than right ) ankle clonus .
 she had a lumbar puncture done at the outside hospital , and the opening cerebrospinal fluid ( csf ) pressure was reported to be 25  cm .
 blood work was also unremarkable except for mild anemia ( hemoglobin : 9.4  g / dl ) , mild hyponatremia ( 132  meq / l ) , and mild hypokalemia ( 3.1  meq / l ) .
 antiepileptic drug levels were within therapeutic range ( free phenytoin : 1.3  g / ml , levetiracetam : 5.9  g / ml , and lamotrigine : 2.3  g / ml ) .
 all started with a bout of cough when the patient was lying in bed ( in supine or in lateral position ) which was followed by brief ( less than a minute ) distal upper extremity tremor and subtle proximal upper extremity myoclonic jerks and prolonged unresponsiveness for up to 10  min .
 all of these episodes were associated with hypotension ( 7278/3147  mm of hg as revealed by continuous arterial pressure monitoring ) and bradycardia ( 5459  bpm ) .
 the eeg during the spells was characterized by generalized synchronous and asynchronous high amplitude 1- to 2-hz delta activity which progressed to generalized attenuation and then transitioned to generalized delta activity again with recovery ( fig .  1 ) .
 a head ct showed recurrence of the glomus jugulare tumor and communicating hydrocephalus . an external ventricular drain ( evd )
 after placement of the evd , her drowsiness gradually started to improve , and episodes decreased in frequency to one per day .
 3 showed an enhancing t2 hyperintense left skull base mass in the region of the left jugular foramen with extension into the posterior cranial fossa and below the base of the skull .
 brain imaging showed evidence of hydrocephalus that had increased compared with her previous brain imaging done 2  months back .
 her mental status continued to improve , and she had only one mild episode triggered by cough during the next two days before her discharge .
 repeat surgical resection of the tumor was recommended by the otolaryngology team , which the patient declined .
 based on the clinical features and eeg findings , the episodes observed in our patient are most consistent with cough syncope .
 the mechanism underlying cough syncope is not definitively established , but it is postulated that coughing increases intrathoracic and intraabdominal pressures leading to a transient increase in icp . increased icp , in turn , causes a decrease in cerebral perfusion pressure which , if it drops below a critical level , may result in global cerebral hypoperfusion leading to syncope .
 transient cerebral circulatory arrest has been demonstrated by transcranial doppler measurements during cough syncope . our patient also had a drop in blood pressure and heart rate but probably not sufficient to cause syncope by itself .
 cough syncope has been associated with posterior fossa mass lesions or tonsillar herniation and with hydrocephalus .
 it may be speculated that bouts of cough caused transient herniation of cerebellar tonsils obstructing csf flow that further contributed to the increase in icp during coughing .
 decrease in frequency of events following placement of evd to relieve icp lends support to this notion .
 paragangliomas are rare tumors of extraadrenal chromaffin cell origin that most commonly occur in the head and neck region .
 catecholamine - hypersecreting paraganglionomas are uncommon in the head and neck region , and most patients ( 95% ) with hypersecreting paraganglionomas have hypertension .
 hypotension accompanying syncope observed in our patient was not orthostasis - related ( the patient was always supine during spells ) and was most likely related to cough .
 identified a subset of patients with cough syncope who lacked a blood pressure overshoot ( expected response ) after the relief of straining during valsalva maneuver .
 the authors postulate that cough syncope in these patients might be the result of delayed recovery from hypotension that follows a paroxysm of cough , and this was likely contributing to global cerebral hypoperfusion in our patient .
 this case highlights the fact that cough syncope , a rare form of syncope , may be associated with intracranial mass lesions that indirectly exaggerate the increase in icp in response to cough .
 glomus caroticum tumor presenting as recurrent unexplained syncope   and posterior fossa meningioma presenting as recurrent cough syncope   have been described .
 recurrent cough syncope should trigger search for factors , including brain tumors , with the potential to cause transient elevation in icp .
 this case also illustrates an important role for ceeg monitoring with video in distinguishing syncope from seizures in cough syncope cases .

Abstract:
we present an unusual case of recurrent cough syncope in a 43-year - old woman , which was initially thought to be seizures .
 syncopal episodes were triggered by paroxysms of cough and were characterized by unresponsiveness and myoclonic jerks in her extremities .
 she had a left - sided glomus jugulare tumor that extended into the posterior cranial fossa with evidence of worsening communicating hydrocephalus on brain imaging .
 we postulate that bouts of cough produced increased intracranial pressure both by raising intrathoracic and intraabdominal pressures as well as by transient obstruction to cerebrospinal fluid flow secondary to intermittent tonsillar herniation during cough .
 this resulted in diffuse decrease in cerebral blood flow causing syncope .
 the patient 's syncopal episodes decreased in frequency once an external ventricular drain was placed followed by a ventriculoperitoneal shunt .
 search for factors that can increase intracranial pressure seems warranted in patients with recurrent cough syncope .


world - wide , infertility affects 1015% of couples who are trying to conceive , and about 15% of these cases are caused by male factors , which affect 1 out of 20 men in the general population .
 most cases of male infertility are idiopathic , apart from several etiologies , such as obstruction of deferent duct , varicocele , sexual dysfunction , and cryptorchidism .
 although assisted reproductive technology ( art ) has helped many sterile couples to conceive , non - obstructive azoospermia ( noa ) , which accounts for a considerable proportion of male infertility , has a dramatically lower rate of sperm retrieval and clinical pregnancy .
 the etiological mechanism of noa is unknown , but factors such as oxidative stress were considered to have effects on spermatogenesis , and some antioxidants have been effective in protecting spermatogenesis .
 therefore , it is helpful to explore the underlying pathogenesis of noa in these patients . micrornas are a class of small rnas that do not code amino acid sequences , but they play fundamental roles in regulating gene expression after transcription .
 lian et al . found 154 down - regulated mirnas and 19 up - regulated mirnas in testes of noa patients compared to fertile males , by using microarray technologies .
 furthermore , some of the mirnas have been shown to affect the proliferation , apoptosis , and dna damage in germ cells [ 911 ] .
 mir-210 is one of the 19 up - regulated mirnas in testes of noa patients , located within the genomic loci of transcript ak123483 .
 it can be induced by hypoxia , and plays an essential role in cell adaptation to hypoxia .
 mir-210 also affects regulation of diverse physiological processes , such as angiogenesis , cell survival , proliferation , cell cycle arrest , protein modification , and dna damage repair .
 although mir-210 has been shown to be involved in regulation of physiological processes in various diseases and to be an up - regulated mirna in testes of noa patients , it remains unknown how mir-210 affects spermatogenesis .
 hence , the aim of this study was to investigate the underlying mechanisms by which mir-210 is involved in the pathogenesis of spermatogenesis .
 we enrolled 25 patients ( aged 1841 years ) with azoospermia ( proven by 3 semen analyses from testicular biopsies from the first affiliated hospital of anhui medical university ) .
 pathological examinations were performed on each testicular specimen . combined with clinical features , 4 patients were diagnosed as having sertoli - cell - only syndrome ( scos ) , 7 patients were diagnosed as having maturation arrest ( ma ) , 8 patients were diagnosed as having hypospermatogenesis , and the other 6 patients were diagnosed as having obstructive azoospermia ( oa ) . all patients provided informed consent before their participation in this study .
 our local medical ethics committee approved this study before it began . to examine the location of insulin - like growth factor ii
 ( igf2 ) in human testicular tissues , we performed immunohistochemistry staining to detect the igf2 expression .
 tissues were cut into sections for immunoperoxidase staining after being treated with 4% pfa and paraffin wax .
 after the specific treatment with standard - procedure immunohistochemistry staining as described as lian et al . , sections were incubated with igf2 antibody ( abcam ) overnight at 4c and biotinylated secondary antibody ( abcam ) for 2 h at room temperature . to detect expression of mir-210 ,
 rnas were extracted from nt-2 cells or tissues and subjected to real - time pcr as described as lian et al . .
 briefly , rna extraction was performed following a standard trizol protocol , real - time pcr was carried out with the abi step one system ( applied biosystems ) , and the sybr premix ex taq ii kit ( takara bio , inc . ) was used .
 primers for q - rt pcr were as follows : forward primer : 5-caataactgtgcgtgtgacagc-3 reverse primer : 5-tatggttttgacgactgtgtgat-3 forward primer : 5-cagcacatatactaaaattggaacg-3 reverse primer : 5-acgaatttgcgtgtcatcc-3 western blot analysis was carried out to detect protein expression of igf2 in the human testicular tissues in the 3 groups and in nt2 cells .
 anti - igf2 ( abcam ) was used for western blot analysis , and we used -actin as a loading control to detect expression of igf2 .
 we supplemented the medium with 10% fetal bovine serum ( life technology inc . ) , 1% antibiotics ( 100 units / ml penicillin , and 100 ug / ml streptomycin , life technology inc . ) .
 cells were incubated at 37c in a humidified incubator with 5% co2 . to transfect oligonucleotides and plasmids into nt-2 cells , lipofectamine rnaimax ( invitrogen ) and fugene hd ( roche )
 all processes were performed in accordance with the protocols supplied by manufacturers . in this study , all the experiments were performed independently at least 3 times .
 we enrolled 25 patients ( aged 1841 years ) with azoospermia ( proven by 3 semen analyses from testicular biopsies from the first affiliated hospital of anhui medical university ) .
 pathological examinations were performed on each testicular specimen . combined with clinical features , 4 patients were diagnosed as having sertoli - cell - only syndrome ( scos ) , 7 patients were diagnosed as having maturation arrest ( ma ) , 8 patients were diagnosed as having hypospermatogenesis , and the other 6 patients were diagnosed as having obstructive azoospermia ( oa ) . all patients provided informed consent before their participation in this study .
 to examine the location of insulin - like growth factor ii ( igf2 ) in human testicular tissues , we performed immunohistochemistry staining to detect the igf2 expression .
 tissues were cut into sections for immunoperoxidase staining after being treated with 4% pfa and paraffin wax .
 after the specific treatment with standard - procedure immunohistochemistry staining as described as lian et al .
 , sections were incubated with igf2 antibody ( abcam ) overnight at 4c and biotinylated secondary antibody ( abcam ) for 2 h at room temperature .
 rnas were extracted from nt-2 cells or tissues and subjected to real - time pcr as described as lian et al . .
 briefly , rna extraction was performed following a standard trizol protocol , real - time pcr was carried out with the abi step one system ( applied biosystems ) , and the sybr premix ex taq ii kit ( takara bio , inc . ) was used .
 primers for q - rt pcr were as follows : forward primer : 5-caataactgtgcgtgtgacagc-3 reverse primer : 5-tatggttttgacgactgtgtgat-3 forward primer : 5-cagcacatatactaaaattggaacg-3 reverse primer : 5-acgaatttgcgtgtcatcc-3
 western blot analysis was carried out to detect protein expression of igf2 in the human testicular tissues in the 3 groups and in nt2 cells .
 anti - igf2 ( abcam ) was used for western blot analysis , and we used -actin as a loading control to detect expression of igf2 .
 we supplemented the medium with 10% fetal bovine serum ( life technology inc . ) , 1% antibiotics ( 100 units / ml penicillin , and 100 ug / ml streptomycin , life technology inc . ) .
 cells were incubated at 37c in a humidified incubator with 5% co2 . to transfect oligonucleotides and plasmids into nt-2 cells , lipofectamine rnaimax ( invitrogen ) and fugene hd ( roche )

 the igf2 gene is part of a cluster of imprinted genes expressing the single polypeptide as igf2 , which is only produced from the paternal allele .
 the maternal allele is transcriptionally silent . to clarify the location of igf2 in human testicular tissues ,
 we found igf2 located in spermatocytes in the testes of patients with oa ( figure 1 ) . because igf2 is located in spermatocytes of the testis , we detected the expression of igf2 in cases with ma , hypospermatogenesis , and oa , but not in the scos patients .
 we found that igf2 was down - regulated in patients with ma and hypospermatogenesis compared to oa patients , which was considered as the control group with normal spermatogenesis , although without a significant difference ( figures 2 , 3 ) , possibly because there were fewer samples and longer preservation times of some samples .
 quantitative real - time pcr was performed to examined mir-210 expression in the testis of patients with ma , hypospermatogenesis , and oa . we found that mir-210 was significantly up - regulated in the testis of ma and hypospermatogenesis patients compared to oa patients ( figure 4 ) . however , due to errors in the rna extraction in the preliminary experiment , 3 testis samples ( 1 each ) from ma , hypospermatogenesis , and oa patients were damaged and were not tested . in the targetscan database , because the 3utr of the igf2-mrna has a putative mir-210-binding site , igf2 was predicted to be a potential target of mir-210 . to identify whether the igf2 gene was targeted by mir-210 directly , renilla luciferase reporters , which include the wild - type full - length 3utr forms of mir-210 seeding sites ,
 figure 5 shows that there was a 60% decrease in luciferase activity after cotransfection of the mir-210 mimic and the renilla luciferase reporters into nt2 cells , and inhibiting mir-210 expression increased activity of the reporter renilla luciferase .
 expression of igf2 protein was also significantly lower in the nt2 cells transfected with mir-210 mimics than in control cells , and knockdown of mir-210 with mir-210 inhibitor increased protein expression of igf2 ( figures 6 ) .
 the igf2 gene is part of a cluster of imprinted genes expressing the single polypeptide as igf2 , which is only produced from the paternal allele .
 the maternal allele is transcriptionally silent . to clarify the location of igf2 in human testicular tissues ,
 we found igf2 located in spermatocytes in the testes of patients with oa ( figure 1 ) .
 because igf2 is located in spermatocytes of the testis , we detected the expression of igf2 in cases with ma , hypospermatogenesis , and oa , but not in the scos patients .
 we found that igf2 was down - regulated in patients with ma and hypospermatogenesis compared to oa patients , which was considered as the control group with normal spermatogenesis , although without a significant difference ( figures 2 , 3 ) , possibly because there were fewer samples and longer preservation times of some samples .
 quantitative real - time pcr was performed to examined mir-210 expression in the testis of patients with ma , hypospermatogenesis , and oa . we found that mir-210 was significantly up - regulated in the testis of ma and hypospermatogenesis patients compared to oa patients ( figure 4 ) . however , due to errors in the rna extraction in the preliminary experiment , 3 testis samples ( 1 each ) from ma , hypospermatogenesis , and oa patients were damaged and were not tested .
 in the targetscan database , because the 3utr of the igf2-mrna has a putative mir-210-binding site , igf2 was predicted to be a potential target of mir-210 . to identify whether the igf2 gene was targeted by mir-210 directly , renilla luciferase reporters , which include the wild - type full - length 3utr forms of mir-210 seeding sites , were used .
 figure 5 shows that there was a 60% decrease in luciferase activity after cotransfection of the mir-210 mimic and the renilla luciferase reporters into nt2 cells , and inhibiting mir-210 expression increased activity of the reporter renilla luciferase .
 expression of igf2 protein was also significantly lower in the nt2 cells transfected with mir-210 mimics than in control cells , and knockdown of mir-210 with mir-210 inhibitor increased protein expression of igf2 ( figures 6 ) .
 during recent decades several studies have focused on the effects of mirnas on spermatogenesis in male infertility [ 911,17 ] .
 however , it was not understood how mir-210 , which is one of the up - regulated mirnas in testes of patients with noa , was involved in spermatogenesis in male infertility .
 the transformation of diploid spermatogonia into mature haploid cells in spermatogenesis is a complex biological process in the testes of males .
 the insulin / igf system takes part in the processes of cell proliferation , cell growth , differentiation , and survival , which affects nearly every organ in the body .
 also , insulin / igf plays an important role in the proper function of the testis in males .
 igf2 binds to igf1r and insr - a with a high affinity and binds to insr - a / igf1r , insr - b / igf1r , but with lower affinity .
 found that in inactivated insr and igf1r , there was a 79% reduction in daily sperm production in adult mouse testes by a conditional ko approach . taken together , the aforementioned data suggest that igf2 might be involved in the process of spermatogenesis . to examine the specific mechanism by which mir-210 is associated with the process of spermatogenesis , quantitative real - time pcr was performed to detect mir-210 expression .
 we found that mir-210 was significantly up - regulated in the testes of subjects with ma and hypospermatogenesis patients compared to oa .
 these results agree with findings of lian et al . using microarray technologies performed in noa and normal controls .
 several studies have suggested that this mirna could be mediated by hypoxia and participate in various types of regulation of angiogenesis , cell survival , proliferation , cell cycle arrest , and protein modification [ 1214 ] .
 furthermore , some researchers even found that mir-210 might be considered as one of the indicated markers in some diseases , such as clear cell renal cell carcinoma and acute myeloid leukemia . in the present study we found that igf2 was targeted by mir-210 directly in the in vitro experiment in nt2 cells , and mir-210 might be associated with spermatogenesis by targeting igf2 in male infertility .
 firstly , as some errors occurred in the rna extraction in the preliminary experiment , mir-210 of 3 testes samples were damaged and not detected in the subsequent quantitative real - time pcr experiment , which might have affected our results .
 secondly , we did not investigate the functions of mir-210 and igf2 in vitro or in vivo , and we plan to do this in future research .
 we demonstrated that mir-210 might be associated with spermatogenesis by targeting igf2 in male infertility .
 future mechanistic studies on the role of mir-210/igf2 in the process of spermatogenesis in male infertility will provide new insights into the diagnosis and management of male infertility .

Abstract:
backgroundmicrornas ( mirnas ) play pivotal roles in spermatogenesis .
 microrna-210 ( mir-210 ) expression was up - regulated in the testes of sterile men with non - obstructive azoospermia ( noa ) .
 however , the underlying mechanisms of mir-210 involved in the spermatogenesis in patients with noa are unknown.material/methodsexpression of mir-210 and insulin - like growth factor ii ( igf2 ) in the testes of noa cases ( only including maturation arrest and hypospermatogenesis ) were detected in this study .
 we carried out in vitro experiments to determine if igf2 was directly targeted by mir-210 in nt2 cells.resultscompared with obstructive azoospermia ( oa ) as normal control , our results suggest that mir-210 was significantly up - regulated in testis of patients with noa ( p<0.05 ) , and igf2 was down - regulated , but without a significant difference .
 the results also indicated that igf2 was directly targeted by mir-210 in nt2 cells.conclusionsthe results showed that mir-210 was involved in spermatogenesis by targeting igf2 in male infertility .


midwife - led primary delivery care for  low - risk  pregnant women during labor has been reported to have various advantages , such as increased odds of high maternal satisfaction and a decrease of unnecessary medical interventions [ 18 ] .
 although the maternity care system for  low - risk  pregnant women peculiar to one country can not easily be compared with those in other countries , consumer demands for the  humanization  of obstetric care have arisen in various countries [ 18 ] . to date , we have found no evidence that midwife - led primary obstetric care is unsafe for  low - risk  pregnant women in comparison with obstetric care with the favorable cooperation of obstetricians and midwives in japan [ 912 ] .
 in addition , about 85% of  low - risk  pregnant women request that they give birth while receiving midwife - led primary delivery care .
 therefore , safe midwife - led delivery care with the backup of obstetricians may also be required for  low - risk  pregnant women in japan . if complications occur or threaten to occur during the primary midwife - led delivery care , the midwives have to refer the woman to obstetricians at the same or a neighboring hospital or private obstetric clinic as soon as possible .
 this is because , in deliveries managed by independent midwives in japan , many intervention measures , such as oxytocin infusion , epidural anesthesia , episiotomy , suture , and instrumental delivery , are not available based on japanese legal restrictions . in our institute , one of the main tokyo city perinatal centers , there are 3 japanese systems of midwife - led delivery care , as follows : ( 1 ) those intending to give birth at home managed by midwives who do not belong to our hospital , ( 2 ) those planning to give birth on  futons
 ( i.e. , japanese - style bedding ) in japanese tatami mat delivery rooms in our hospital managed by the same midwives who do not belong to our hospital , and ( 3 ) those planning to give birth in japanese tatami mat delivery rooms managed by midwives who belong to our hospital .
 the objective of this study was to describe trends in transfers and perinatal outcomes among labors using these 3 japanese systems of midwife - led primary delivery care .
 the protocol for this analysis was approved by the ethics committee of the japanese red cross katsushika maternity hospital . in addition ,
 informed consent for analysis from a retrospective database was obtained from each subject during their hospital visit . in our hospital ,
 pregnant women who are initially considered  low - risk  at 3436 weeks of gestation can choose freely between the 3 systems of midwife - led care and obstetric shared care .
 in the midwife - led care units , midwives can practice autonomously and are fully accountable for their own practice , unsupervised by obstetricians .
 factors used to exclude women from the  low - risk  group comprise the following [ 912 ] : ( 1 ) medical history : pregnancy - induced hypertension , chronic hypertension , diabetes mellitus , renal disease , idiopathic thrombocytopenia , and other systemic illnesses ; ( 2 ) gynecological history : history of infertility therapies of in vitro fertilization , congenital uterine anomalies , uterine myomatosis , and adnexal anomaly ; ( 3 ) obstetric history : narrowing of the pelvic outlet , cephalopelvic disproportion , previous cesarean section , previous anal sphincter injury , previous postpartum hemorrhage  1,000  ml with blood transfusion , previous manual removal of placenta , previous gestational diabetes , and history of severe preeclampsia ; ( 4 ) complications during the present pregnancy : multiple pregnancy , nonvertex presentation , obesity ( maternal body mass index before pregnancy  25 and/or during the third trimester  28 ) , anemia ( hemoglobin < 9.0  g / dl ) , epilepsy with treatment , polyhydramnios , oligohydramnios , low - set placenta , placenta previa , fetal growth restriction , heavy for date fetus , gestational diabetes , and pregnancy - induced hypertension ; when risk factors are present , those women are managed by obstetricians and midwives ; ( 5 ) complications during labor : intrauterine infection , thick meconium staining , prolongation of labor such as active - phase dilation < 1  cm / hour and duration of second stage of labor  2 hours , prolonged rupture of membranes ( 24 hours ) , uterine inertia , arrest of labor , and fetal heart rate abnormality such as a nonreassuring fetal status . when these factors are present , the women are transferred to be managed mainly by obstetricians ( obstetric shared care ) in a standard western - style delivery room or surgery room in our hospital .
 a retrospective study was performed to examine trends in transfers and perinatal outcomes among labors that started using the 3 systems of midwife - led primary delivery care . in this study ,
 student 's t - test was used for continuous variables and the  test for categorical variables .
 odds ratios ( ors ) and 95% confidence intervals ( cis ) were also calculated . differences with p
 between 2009 and 2012 , a total of 678 low - risk women were placed in the 3 forms of midwife - led primary delivery care at the onset of labor pains and/or rupture of membranes at 3741 weeks of gestation . of these ,
 123 ( 18% ) intended to give birth at home , 88 ( 13% ) planned to give birth in the japanese tatami mat rooms in our hospital managed by midwives who do not belong to our hospital , and 467 ( 59% ) planned to give birth managed by the midwives belonging to our hospital .
 table 1 shows the clinical descriptions of the 678 pregnant women initially considered as  low - risk  for receiving our midwife - led primary delivery care systems . there were no significant differences in the maternal age or parity among the 3 groups .
 table 2 shows the rate of transfers in the 3 groups of the midwife - led primary delivery care systems .
 the total rate of transfers in the system run by the midwives belonging to our hospital ( 56% ) was higher than in the other 2 systems run by the independent midwives ( 31% in planned home birth : or 1.87 , 95% ci 1.23.0 , p < 0.01 ; 38% in planned hospital birth : or 2.51 , 95% ci 1.73.8 , p < 0.01 ) .
 in addition , the timing of transfers in the system run by the midwives belonging to our hospital ( before the second stage of labor : 52% ) was earlier than those in the other 2 systems ( 21% in the planned home birth : or 4.12 , 95% ci 2.66.6 , p < 0.01 ; 20% in planned hospital birth : or 4.29 , 95% ci 2.57.4 , p < 0.01 ) . however , if classified into nulliparous and parous women , there were no significant differences in the rate of transfers among the 3 groups , as shown in table 1 .
 in addition , among the 3 groups there were no significant differences in the rate of the main 2 indications for transfer : fetal heart rate abnormality and failure to progress .
 the main indications for transfer after delivery were maternal postpartum hemorrhage and neonatal respiratory distress associated with asphyxia .
 table 3 shows the obstetric and neonatal outcomes in the pregnant women initially considered as  low - risk  for receiving our midwife - led primary delivery care systems . there were no significant differences in these outcomes among the 3 groups
 our obstetric care system involves the division of women in labor into low- and high - risk groups [ 912 ] .
 the women who are initially considered low - risk can choose freely between midwife - led care and obstetric shared care . if complications occur or risk factors arise during labor in the primary midwife - led care , they are transferred to obstetric shared care .
 this may be the first report concerning the differences in the timing of transfers from midwife - led care to obstetric shared care among the 3 systems of midwife - led primary delivery care in japan . in this study
 , there was no evidence that the primary midwife - led care is unsafe for  low - risk  pregnant women in any of these 3 midwife - led delivery care systems .
 however , there were no significant differences in the timing of referrals from midwife - led care to obstetric shared care between the system led by midwives who belong to our hospital ( hospital midwifery system ) and the systems led by the midwives who do not belong to our hospital . in the hospital midwifery system
 , the timing of transfers seemed to be the earliest due to the ease of transfer within the same hospital and administrator setting . on the other hand ,
 the rate of transfers after delivery with the other 2 systems was higher than that in the hospital midwifery care . during the period , the main indications for transfers were maternal postpartum hemorrhage and/or neonatal respiratory distress associated with asphyxia .
 fortunately , the difference was not associated with adverse obstetric or neonatal outcomes ; however , unfortunately , they led to early mother - to - child separation , especially in cases of planned home birth because healthy puerperal women or newborns can not be transferred from home to hospital according to japanese law .
 although home birth might be very comfortable , those involved must be prepared for mother - to - child separation in cases of referrals after delivery .
 the major limitations of this study were the small sample size and lack of long - term follow - up of mothers and children to consider the potential of the findings based on our own context .
 there were no cases of fetal / neonatal death under the midwife - led delivery care .
 the most evaluated outcome under midwife - led delivery was the satisfaction of pregnant women with the development of mother - child relationships after delivery .
 in addition , there might be some bias related to the backgrounds in the selection of the systems because this was not a randomized trial study .
 therefore , a further large prospective study with long - term follow - up may be needed .
 there were no significant differences in perinatal outcomes among the 3 systems ; however , there were some differences in the status of the transfers to the obstetric shared care .

Abstract:
objective .
 the objective of this study was to describe the recent clinical characteristics of labor using 3 systems of japanese midwife - led primary delivery care , as follows : ( 1 ) those intending to give birth at home managed by midwives who do not belong to our hospital , ( 2 ) those planning to give birth in our hospital managed by the same midwives , and ( 3 ) those planning to give birth managed by midwives who belong to our hospital .
 methods . a retrospective cohort study was performed .
 results .
 there were no significant differences in the obstetric or neonatal outcomes among the 3 groups .
 the rate of transfers during labor with the system involving midwives belonging to our hospital was higher than those with the other 2 systems .
 in addition , the timing of transfers in the system with the midwives belonging to our hospital was earlier than with the other 2 systems . among the 3 groups ,
 there were no significant differences in the rate of the main 2 indications for transfers : fetal heart rate abnormality and failure to progress . conclusion .
 there were no significant differences in perinatal outcomes among the 3 systems ; however , there were some differences in the status of transfers to obstetric shared care .


diabetes decreases the overall life expectancy and cause a heavy burden on public health ( 1 ) .
 moreover , the asia - pacific region is considered to be on the verge of an emerging diabetes epidemic ( 2 ) .
 the development of type 2 diabetes is affected by genetic and environmental determinants ( 3 ) .
 recently , one study investigated whether common variants of functional and positional candidate genes , including adrb3 , pparg , enpp1 and capn10 , were determinants of type 2 diabetes ( 4 ) .
 enpp1 , also called k121q , has a glutamine substitution for lysine at codon 121 ( 5 ) .
 type 2 diabetes is characterized by insulin resistance ( 6 ) , and enpp1 plays an important role in insulin resistance ( 7 , 8) .
 enpp1 interacts with -subunit of the insulin receptor to interrupt signaling ( 9 ) . in previous studies , the k121q polymorphism of the human pc-1 gene was strongly associated with insulin resistance ( 1 , 3 , 7 , 10 - 12 ) . however , there was no association between insulin resistance and the k121q variant ( 13 , 14 ) .
 in addition , there were discrepancies for the impact of enpp1 polymorphism on obesity between ethnic groups ( 5 , 10 , 13 , 15 - 19 ) .
 obesity increases the concentration of insulin in plasma and is the major contributor of insulin resistance ( 20 ) .
 obesity appears to be an effect modifier of type 2 diabetes in d1057 carriers ( 21 ) .
 the association of obesity with the genetic variant of the insulin receptor substrate was identified in other studies ( 21 , 22 ) . in the chinese han population ,
 the pc-1 q121 allele was associated with insulin resistance . in women , carriers of the q allele
 had an increased risk for obesity development ( 3 ) . in caucasians and african - americans , 121q carriers had an association with increased body mass index ( bmi ) ( 23 ) , and the three - allele risk type haploid qdeltg with the q allele increased the risk for obesity ( 24 )
 however , in the danish population , there were no differences in the distribution of frequencies of dominant types ( kk wild type and kq / qq variant type ) and alleles ( 19 ) .
 the complexity of type 2 diabetes is related to factors such as genetic heterogeneity , interactions between genes , and the modulating role played by the environment ( 4 ) . in spite of these limitations , studies of type 2 diabetes and genetic factors of obesity
 can predict the risks for development of both type 2 diabetes and obesity in order to assist primary prevention , and korea is an appropriate country for such studies because of the homogeneity of racial composition and lifestyle ( 25 ) .
 therefore , the aim of this study was to analyze the presence of the enpp1 polymorphism , not studied yet in korean population , to identify the association between genotypes and allele with type 2 diabetes and obesity .
 this company is an electric power company located at kori , yonggwang , ulchin , wolsung , and seoul in korea .
 there were 195 male workers ( age 48.26.7 yr , bmi 24.672.64 kg / m ) who were diagnosed as diabetics during medical examinations conducted from march 2004 to october .
 the 1,750 male workers ( age 45.27.7 yr , bmi 24.772.64 kg / m ) in the control group were selected randomly .
 subjects were included if they met one of the criteria below and their onset age was older than 20 yr old to exclude type 1 diabetes : 1 ) blood - sugar level before a meal exceeded 126 mg / dl twice or more ; 2 ) blood - sugar level before a meal exceeded 126 mg / dl once or more and blood - sugar level two hours after a meal exceeded 200 mg / dl ; 3 ) those who reported that he had a history of diabetes in the questionnaire and being taken oral hypoglycemic agents .
 the workers included in the obesity group were those whose bmi was 25 kg / m or more . after collecting a blood sample from vein in fasting ( 8 hr ) status , we measured the blood - sugar level , insulin , and lipid profile
 . we also measured height and weight to calculate bmi . if fasting glucose levels were greater than 126 mg / dl
 , we checked the 2 hr post - prandial plasma glucose level at each site within 1 month .
 height and weight were measured by autoanalyzer ( health guard , fanics , seoul , korea ) .
 the fasting blood level was analyzed by glucose - oxidase assay using an autochemistry analyzer . to determine the lipid profile ,
 total cholesterol was analyzed by enzyme assay using cholesterol oxidase ( cod ) , high density lipoprotein ( hdl ) cholesterol by glycerol phosphate oxidase assay , low density lipoprotein ( ldl ) cholesterol by direct surfactant assay .
 we carried out this study under the approval by the ethnics committee of the asan medical center , and obtained written consent from all subjects , providing subjects with sufficient explanation to obtain informed consent .
 we extracted genomic dna from buffy coats using the generall blood sv kit ( general biosystem , seoul , korea ) and following the instructions suggested by the manufacturer .
 the method of genotyping used to identify the k121q polymorphism in enpp1 exon 4 was polymerase chain reaction - restriction fragment length polymorphism ( pcr - rflp ) , using dna treated with a restriction enzyme after pcr , based on the paper reported by abate et al .
 we carried out student 's t - test to analyze the effects of genotypes on biochemical parameters using genotypes as factors .
 the hardy - weinberg equilibrium was computed based on the  goodness - of - fit test .
 we also investigated the differences in frequencies of genotypes between type 2 diabetic and normal groups , and between obesity and normal groups by fisher 's exact test .
 the spss 12.0 ( for window ) statistical software package was used for statistical analysis .
 this company is an electric power company located at kori , yonggwang , ulchin , wolsung , and seoul in korea .
 there were 195 male workers ( age 48.26.7 yr , bmi 24.672.64 kg / m ) who were diagnosed as diabetics during medical examinations conducted from march 2004 to october .
 the 1,750 male workers ( age 45.27.7 yr , bmi 24.772.64 kg / m ) in the control group were selected randomly .
 subjects were included if they met one of the criteria below and their onset age was older than 20 yr old to exclude type 1 diabetes : 1 ) blood - sugar level before a meal exceeded 126 mg / dl twice or more ; 2 ) blood - sugar level before a meal exceeded 126 mg / dl once or more and blood - sugar level two hours after a meal exceeded 200 mg / dl ; 3 ) those who reported that he had a history of diabetes in the questionnaire and being taken oral hypoglycemic agents .
 the workers included in the obesity group were those whose bmi was 25 kg / m or more . after collecting a blood sample from vein in fasting ( 8 hr ) status , we measured the blood - sugar level , insulin , and lipid profile
 . we also measured height and weight to calculate bmi . if fasting glucose levels were greater than 126 mg / dl
 , we checked the 2 hr post - prandial plasma glucose level at each site within 1 month .
 height and weight were measured by autoanalyzer ( health guard , fanics , seoul , korea ) .
 the fasting blood level was analyzed by glucose - oxidase assay using an autochemistry analyzer . to determine the lipid profile ,
 total cholesterol was analyzed by enzyme assay using cholesterol oxidase ( cod ) , high density lipoprotein ( hdl ) cholesterol by glycerol phosphate oxidase assay , low density lipoprotein ( ldl ) cholesterol by direct surfactant assay .
 we carried out this study under the approval by the ethnics committee of the asan medical center , and obtained written consent from all subjects , providing subjects with sufficient explanation to obtain informed consent .
 we extracted genomic dna from buffy coats using the generall blood sv kit ( general biosystem , seoul , korea ) and following the instructions suggested by the manufacturer .
 the method of genotyping used to identify the k121q polymorphism in enpp1 exon 4 was polymerase chain reaction - restriction fragment length polymorphism ( pcr - rflp ) , using dna treated with a restriction enzyme after pcr , based on the paper reported by abate et al .
 we carried out student 's t - test to analyze the effects of genotypes on biochemical parameters using genotypes as factors .
 the hardy - weinberg equilibrium was computed based on the  goodness - of - fit test .
 we also investigated the differences in frequencies of genotypes between type 2 diabetic and normal groups , and between obesity and normal groups by fisher 's exact test .
 the spss 12.0 ( for window ) statistical software package was used for statistical analysis .
 the frequencies of the kk type , kq type , and qq type in enpp1 k121q were 82.1% , 17% and 0.9% , respectively .
 the homozygous type of q carrier ( qq type ) was added to the heterozygous type ( kq type ) because the frequency of qq type was very low ( 0.9% ) .
 we investigated the differences in age , blood pressure , bmi , and results of clinical examinations according to genotypes of enpp1 k121q between the type 2 diabetic and non - diabetic groups ( table 1 ) . when type 2 diabetics and non - diabetics were pooled ( n=1,945 ) , there were no significant differences in bmi , systolic pressure , diastolic pressure , glucose value in fasting status , total cholesterol , ldl cholesterol , hdl cholesterol , triglyceride , c - reactive protein , and homa - ir between the kk type and kq+qq type .
 in addition , there were no significant differences in the same characteristics above between type 2 diabetic group and non - diabetic groups ( table1 ) , and between the obese group and non - obese groups ( table2 ) .
 the frequencies of genotypes were in accordance with the hardy - weinberg equilibrium ( p=0.85 ) .
 the odds ratio of having a kq+qq genotype was 0.85 for diabetics versus non - diabetics .
 the odds ratio of having a q allele was 0.91 for diabetics versus non - diabetics .
 however , there was no significant difference in the genotypic and allelic distribution between type 2 diabetics and non - diabetics ( table3 ) .
 the odds of a kq+qq genotype were 0.93 for obese versus non - obese subjects . furthermore , the odds of having a q allele were 0.96 for obese versus non - obese subjects
 . however , there was no significant difference in the genotypic and allelic distribution between obese and non - obese ( table4 ) .
 the frequency of the kk type in enpp1 k121q genotypes was 82.1% , that of kq+qq type was 17.9% and that of q allele was 9.4% .
 there was no statistically significant difference in the distribution among these genotypes and alleles ( p=0.81 , p=0.89 , respectively ) , although the 121q carrier and q allele in obese and/or diabetics seemed to differ slightly from those in the non - obese non - diabetics ( reference group ) . in determining the prevalence of the q allele carriers ( kq and qq subjects ) and q allele
 , there were no significant differences in the genotypic and allelic distribution with the respect to any phenotypes ( data not shown ) .
 after adjusting for the effects of obesity , the probability of type 2 diabetes in kq+qq type was 0.858 ( data not shown ) and that in q allele was 1.095 , showing no significant difference ( table 5 ) .
 moreover , after adjusting for the effects of type 2 diabetes , the probability of developing obesity in the kq+qq type was 0.936 ( data not shown ) and that in the q allele was 1.038 , showing no significant difference ( table 6 ) .
 the results of studies of the association between enpp1 k121q variants and both type 2 diabetes and obesity in several races are disparate .
 we carried out this study to investigate the association of k121q variants with type 2 diabetes and obesity in korean male workers .
 insulin resistance is a major component of the pathogenesis of type 2 diabetes ( 27 ) , and insulin receptor kinase activity is impaired in muscle and other insulin - sensitive tissue of many type 2 diabetic patients ( 28 ) , and then a potential inhibitor of the insulin receptor tyrosine kinase is identified as the plasma - cell membrane differentiation antigen-1 ( pc-1 ) ( 29 ) .
 therefore , it is significant to analyze enpp1 ( pc-1 ) polymorphism . in the previous studies of the association between type 2 diabetes and polymorphism in enpp1 , the k121q missense mutation increased the odds ratio ( or ) for type 2 diabetes in dominican ( 10 ) , south asian , caucasian ( 16 ) , finnish ( 18 ) , and french populations ( 24 ) .
 moreover , according to a meta - analysis of the association between enpp1 k121q variant and type 2 diabetes , the odds ratios were 1.30 ( 95% confidence interval [ ci ] , 1.13 - 1.50 ) ( 16 ) and 1.17 ( 95% ci , 1.10 - 1.25 ) ( 19 ) , showing significant association . in this study , 121q was not associated with type 2 diabetes , showing consistent results with those in the japanese population ( 5 ) , danish caucasians ( 13 ) , oji - cree population ( 17 ) , finnish population ( 18 ) , and danish white subjects ( 19 ) .
 most type 2 diabetes in koreans is characterized by non - obesity , thus the enpp1 k121q mutant relevant to insulin resistance possibly could be a candidate gene that is not appropriate to explain susceptibility to type 2 diabetes .
 this can be a possible explanation for the lack of association between enpp1 121q carrier and type 2 diabetes in this study .
 obesity is a main risk factor for the development of type 2 diabetes ( 20 ) and there is linear association between obesity and type 2 diabetes ( 3 ) . in previous studies of the association between obesity and polymorphism in enpp1 ,
 121q carriers and/or q allele were associated with obesity in the chinese han population ( bmi of obesity group 27 kg / m ) ( 3 ) , caucasians ( bmi of obesity group > 90th percentile ) , african - american adults ( bmi of obesity group > 80th percentile ) ( 23 ) , french population ( bmi of obesity group 95th percentile ) ( 24 ) , and dominican population ( bmi of obesity group 30 kg / m ) ( 10 ) . however , in this study ( bmi of obesity group 25 kg / m ) , there was no difference in distribution between obesity and 121q carriers and presence of the q allele .
 this result was consistent with those from a study of 7,333 danes ( 19 ) and a spanish population ( 14 ) in which the bmi of the obesity group was 25 kg / m or higher . on the other hand , in matsuoka 's study ,
 the percentage of subjects whose bmi was 30 kg / m or higher was too low ( 2.5% ) to investigate the effect of k121q genotype on obesity .
 the results of the present study showed that the frequencies of the q allele was 8.7% in the type 2 diabetic group and 9.2% in the obesity group , which was lower than those in finnish and swedish populations ( 12.9 - 15.1% ) ( 11 ) , danish caucasians ( 14 - 16% ) ( 13 ) , south asians in chennai ( 14% ) , caucasians in dallas ( 16% ) , south asians in dallas ( 19% ) ( 16 ) , the dominican population ( 54.2% ) ( 10 ) and , black children ( 77% ) ( 30 ) .
 the frequencies of the q allele investigated in this study might have a smaller statistical power to explain any association with either type 2 diabetes or obesity with 121q carriers ( kq+qq ) and/or the q allele . in conclusion
 , the present study suggests that the enpp1 k121q polymorphism was not associated with type 2 diabetes and obesity .
 the results of negative associations in this study might be attributable to the low prevalence of obesity , relatively younger age , and low frequencies of the 121q carriers .
 large and prospective studies are needed to confirm this preliminary observation in the korean population .

Abstract:
type 2 diabetes is characterized by insulin resistance , and enpp1 plays an important role in insulin resistance .
 we investigated the association of the enpp1 k121q polymorphism with both diabetes and obesity ( body mass index [ bmi ] ) in korean male workers .
 the study design was case - control .
 subjects were 1,945 male workers ( type 2 diabetes , 195 ; non - diabetes , 1,750 ) of nuclear power plants who received examinations from march to october in 2004 .
 we collected venous blood samples under fasting ( 8 hr ) conditions , calculated bmi by height and weight , and assessed relevant biochemical factors .
 the results of this study demonstrated that the enpp1 121q genotype ( kq+qq types ) was not associated with type 2 diabetes ( odds ratios [ or ] , 0.854 ; 95% confidence interval [ ci ] , 0.571 - 1.278 ) or obesity ( or , 0.933 ; 95% ci , 0.731 - 1.190 ) .
 in addition , the frequency of the q allele was not related to type 2 diabetes ( or , 0.911 ; 95% ci , 0.630 - 1.319 ) or obesity ( or , 0.962 ; 95% ci , 0.767 - 1.205 ) .
 we concluded that the enpp1 121q allele is not a critical determinant for either diabetes or obesity in korean males .
 the discordance between the results of this study and those derived from studies of dominican , south asian , caucasian , finnish , and french populations might be due to differences in genetic backgrounds between these populations .


lipid apheresis provides a safe and effective means of treating patients with severe hyperlipidemia . it
 functions by first separating plasma from blood cells with a cell separator and then using either the adsorption of apolipoprotein b by affinity columns containing anti - apolipoprotein b antibodies or dextran sulphate , or their precipitation at low ph by heparin .
 lipid apheresis allows patients to attain lower levels of low - density lipoprotein ( ldl ) , which are usually not attainable with traditional drug therapy alone , while leaving high - density lipoprotein ( hdl ) levels generally unaffected . when used in conjunction with statins and other lipid - lowering drugs
 , lipid apheresis may also induce the regression of coronary atherosclerotic plaque in familial hypercholesterolemia ( fh ) patients .
 fh is a group of autosomal dominant genetic defects resulting in elevated serum ( ldl ) cholesterol levels . in the heterozygous state ,
 fh is a relatively common but serious genetic disorder , with an incidence of about 1 in 500 persons in the general population .
 fh has been associated with an increased risk for atherosclerosis , premature coronary heart disease , and heart failure [ 3 , 4 ] .
 fh is caused by a mutation affecting apolipoprotein b , proprotein convertase subtilisin kexin type 9 ( pcsk9 ; an enzyme involved in ldl receptor degradation ) , or , most commonly , the ldl receptor gene , resulting in defective ldl receptors and/or a diminished number of ldl receptors [ 7 , 8 ] .
 these mutations cause ldl to be catabolized at a slower rate and thus accumulate in the circulation .
 currently , fh is treated using a variety of cholesterol - lowering drugs , most notably statins or hmg - coa reductase inhibitors . for many patients , however , statins are not a viable treatment option , because of either intolerance or ineffectiveness .
 lipid apheresis is an alternative form of treatment for these fh patients as well as those who have persistently elevated ldl levels despite treatment .
 because apheresis is performed at only a few highly specialized centers in relatively low volume , there is very little literature discussing the effectiveness of lipid apheresis on the reduction of lipid profiles and the prevention of future cardiac events .
 this study , therefore , reports the experience in a single metropolitan center of treating patients with hyperlipidemia with lipid apheresis .
 retrospective chart reviews were performed and questionnaire surveys were given to active lipid apheresis patients at the minneapolis heart institute ( mhi ) at abbott northwestern hospital ( anw ) , minneapolis , minnesota .
 mhi and anw are divisions of allina health , a large healthcare provider in minnesota and western wisconsin .
 patients were identified through an electronic health record ( ehr ) screen of ambulatory patients representing all patients seen at all allina health metro area and regional locations between 2009 and 2012 ( epic systems , verona wi ) . of these patients ,
 criteria to qualify for apheresis were based on the united states food and drug administration ( fda ) approval recommendations .
 currently , the fda supports ldl apheresis for patients who , after six months , do not have an adequate response to diet therapy and maximum drug therapy , due to either ineffectiveness or intolerance , and meet the following criteria : functional homozygotes with an ldl cholesterol > 500  mg / dl without cad , functional heterozygotes with ldl cholesterol > 300  mg / dl without cad , functional heterozygotes with ldl cholesterol > 200  mg / dl with documented coronary heart disease .
 functional homozygotes with an ldl cholesterol > 500  mg / dl without cad , functional heterozygotes with ldl cholesterol > 300  mg / dl without cad , functional heterozygotes with ldl cholesterol > 200  mg / dl with documented coronary heart disease .
 the date of birth , gender , date of apheresis initiation , lipid disorder diagnosis , apheresis frequency , and family history of cardiac events were recorded .
 patients were noted as having fh if the active problem list contained a diagnosis of fh . to determine which patients had fh , we used the national lipid association ( nla ) criteria for an 80% probable fh diagnosis , using the highest ldl recorded in the patient chart as follows : age < 20 and ldl > 190  mg / dl , age 2029 and ldl > 220  mg / dl , and age 30 and ldl > 250  mg / dl .
 potential homozygous fh ( hofh ) patients were defined as having an untreated ldl > 500  mg / dl or a treated ( on statin ) ldl over > 300  mg / dl , in addition to clinical evidence of xanthomas before age of 10 years or having two parents with heart disease or high lipids .
 identifiable secondary causes for marked hyperlipidemia were excluded from the analysis by examining the ehr chart of each potential homozygote .
 current cholesterol lowering medications were also recorded , focusing on the use of statins , colesevelam ( welchol ) , ezetimibe ( zetia ) , niacin , and aspirin .
 a significant cardiovascular event was defined as a myocardial infarction ( mi ) , a percutaneous transluminal coronary angioplasty ( ptca ) or stenting procedure , or a coronary artery bypass graft ( cabg ) using ehr documented icd-9 criteria . cardiac events were separated by their occurrence before or after the patient began apheresis , and the total number of events was recorded for each group .
 multiple cardiac events occurring at the same hospitalization , such as mi followed by ptca , were counted as a single event for cardiac event rate calculation .
 pre- and postapheresis cardiac event rates were calculated by adding the total number of cardiac events and dividing by the total person years during each time period .
 the preapheresis time period describes the time from the first documented ehr visit to the date of apheresis initiation .
 the postapheresis time period describes the time from the date of apheresis initiation to the study date .
 unverifiable events noted in the ehr but occurring prior to the first documented ehr visit were noted but excluded from the cardiac event rate calculation .
 mean acute ldl reductions were calculated by averaging all recorded ldl values prior to and immediately after the treatment sessions .
 mean acute total cholesterol , hdl cholesterol , and triglyceride reductions were calculated by using lipid profile from the most recent treatment session .
 ldl apheresis was performed at abbott northwestern hospital using the kaneka liposorber la-15 system ( kaneka medical products ) .
 the system consists of the kaneka ma-03 machine , the integrated sulflux kp-05 plasma separator , which consists of porous hollow fibers , to separate the plasma from the whole blood , and two disposable liposorber la-15 adsorption columns to adsorb apolipoprotein b - containing lipoproteins from patient plasma .
 patients confirmed information in their ehr such as risk factors , answered questions relating to their awareness of fh and if their family had been previously tested for it , provided their level of satisfaction with their apheresis program , and indicated their interest in learning more about alternative treatments .
 the data from the questionnaires was cross - referenced with the data from the patient charts to ensure accuracy .
 descriptive statistics are displayed as means and sds for continuous variables ; number and percentage with characteristic are given for categorical variables .
 categorical variables were analyzed using pearson 's chi - square or fisher 's exact tests .
 continuous variables were analyzed using student 's t - test . a value of p < 0.05 was considered significant , and p values are two - sided where possible .
 all statistical calculations and plots were done with stata 11.2 ( college station , tx ) .
 institutional review board approval was obtained for data collection , follow - up , and data analysis .
 of these , 8 ( 72.7% ) were male , 10 ( 90.9% ) were caucasian , 1 ( 9.1% ) was african american , 10 ( 90.9% ) carried the diagnosis of fh , with 2 ( 18.2% ) patients identified as probable homozygotes , and 1 ( 9.1% ) was diagnosed as having familial combined hyperlipidemia .
 the average age of patients was 65.6    9.3 years , and patients had been on apheresis for an average of 6.2    7.0 years .
 four ( 36.4% ) patients were currently on statins while the other 7 ( 63.6% ) had a history of statin intolerance .
 five of 11 ( 45.5% ) patients were on a nonstatin cholesterol lowering medications , including 1 ( 9.1% ) on colesevelam ( welchol ) , 3 ( 27.3% ) on ezetimibe ( zetia ) , and 1 ( 9.1% ) on niacin .
 maximum ldl levels ranged from 211 to 448  mg / dl with a mean ( sd ) value of 298    80.7  mg / dl in the study group . since our ehr was implemented in 2005 , it is possible we may be underestimating the highest lifetime ldl for each patient .
 of the 11 participants , 9 completed the questionnaire in its entirety ; 1 patient provided answers to all questions but did not disclose risk factors and 1 patient did not complete the questionnaire .
 all of the patients indicated that they were aware that they likely had fh and 7 patients indicated that their immediate family had been tested for fh .
 the patients self - reported a total of 44 cardiac events before apheresis and 8 cardiac events after apheresis .
 of the 10 patients that completed the questionnaire , 4 patients were currently on statins while the other 6 were statin intolerant .
 eight patients ( 72.7% ) had a cardiac event documented by ehr , with 43 cardiac events occurring overall ( table 4 ) .
 self - reported events which were unable to be verified via the ehr were excluded from the cardiac event rate analysis .
 thirty - four cardiac events were documented before apheresis in 8 patients compared with 9 events in 5 patients after apheresis . after excluding cardiac events that were unverifiable ,
 14 cardiac events were documented in the preapheresis time period and 7 were documented in the postapheresis time period .
 the cardiac event rates were calculated to be 0.23 ( 0.13 , 0.39 ) events per person year in the preapheresis group and 0.10 ( 0.041 , 0.21 ) events per person year in the postapheresis group ( p = 0.064 ) .
 patients were observed for an average of 7.6    5.9 years before apheresis and 6.2    4.7 years after apheresis , with 60.6 total patient years before apheresis and 67.8 patient years after apheresis .
 this study was conducted to gain more information on lipid apheresis and evaluate the effectiveness in lowering lipid values . in addition
 , through chart review and patient survey , we attempted to gain a greater understanding of this patient population in terms of traditional risk factors , family awareness and screening , statin and other cholesterol medication uses , desire for additional treatment options , and ultimately cardiac events .
 our study shows that apheresis markedly lowers total cholesterol , ldl cholesterol , triglycerides and , to a much lesser degree , hdl cholesterol .
 there was a small , but statistically significant , reduction in hdl values after apheresis .
 many of these patients were  statin intolerant  and some had been using nonstatin cholesterol medications .
 importantly , 10/11 ( 90.9% ) participants indicated a desire to learn more about other potential treatment options , indicating that this population may indeed experience fatigue of this procedure .
 although taken from a small study population , our data suggests a reduction in cardiac event rate after apheresis . while not statistically significant , our data shows a strong trend towards event rate reduction .
 this statistical insignificance is likely explained by the study 's small sample size . with a larger population
 it is also important to note that the risk for cardiac events increases with age .
 ldl apheresis has been shown to improve endothelium dependent vasodilation [ 11 , 12 ] , microvascular flow , and myocardial perfusion .
 some studies [ 2 , 15 , 16 ] have also shown a significant reduction in angiographic cad , but others have not .
 these studies have been small , primarily nonrandomized trials . the ldl - apheresis atherosclerosis regression study ( laars )
 looked at the change in plaque characteristics of patients undergoing apheresis compared to drug therapy over a period of two years .
 in that period , 7 out of 21 patients on apheresis had a cardiac event compared with 3 out of 21 on medication only . while this study found that apheresis arrested the progression of atherosclerosis
 the fh regression study found that ldl apheresis combined with simvastatin was more effective than colestipol plus simvastatin in reducing ldl cholesterol and lipoprotein ( a ) but was less effective at influencing coronary atherosclerosis .
 another study   found that , out of 18 patients , 3 had myocardial infarctions , 1 underwent a cabg , and 12 needed coronary angioplasties within two years of beginning a combination therapy of apheresis , statins , and probucol . before beginning the combination therapy , 11 had experienced a mi , 5 had undergone a cabg , and 13 had undergone an angioplasty .
 the heparin - induced extracorporeal ldl precipitation ( help ) study   found that help is suitable for reducing ldl concentrations and may work to reduce the burden of atherosclerosis , as there were no myocardial infarctions and a low coronary intervention rate in patients who began apheresis .
 due to the expensive nature of apheresis , a randomized , controlled clinical trial is needed to truly gauge the effectiveness of apheresis in reducing the occurrence of cardiac events .
 if apheresis is not deemed effective or is minimally effective , as some of these studies suggest , other types of treatment , such as lomitapide , mipomersen , or pcsk9 inhibitors , should be pursued . while satisfaction was generally high in our survey ,
 patients specifically cited that this satisfaction was based on the results of apheresis and not on the process itself .
 many patients complained about the invasive nature of apheresis , citing bruises from the procedure and the inconvenience of reporting for treatment every two weeks .
 additionally , almost all patients were interested in learning more about alternative treatments , suggesting that they would prefer an alternative treatment which could match the results provided by apheresis .
 this study had several limitations . since lipid apheresis is an advanced treatment for an uncommon genetic disease , the limited number of patients available to participate in the study led to a small sample size .
 the event rate reduction was not statistically significant but showed a strong trend toward cardiac event rate reduction before and after apheresis . by defining the observational period initial time point as the first documented ehr visit
 , we excluded 20 events before apheresis and 2 events after apheresis from the cardiac event rate calculation .
 the lipid - lowering effects of apheresis are best expressed as reductions in interval means .
 although lipid apheresis was performed every two weeks , ldl values were not measured ever two weeks due to clinical practices .
 this inconsistency in measurement intervals prevents the use of more advanced measures to accurately track the effect apheresis has on ldl measurements .
 finally , this study focused on active apheresis patients and therefore did not include patients who had stopped apheresis or were deceased .
 lipid apheresis can reliably reduce ldl , non - hdl cholesterol , triglyceride , and total cholesterol levels in fh patients .
 our data suggest that lipid apheresis shows a strong , but not statistically significant , trend towards the reduction of cardiac events .
 apheresis is a viable treatment for fh patients , especially those that are statin - intolerant , due to its lipid lowering nature and its apparent reduction of cardiac events .
 however , there is a need for alternative treatments which are less invasive and provide easier patient access .

Abstract:
lipid apheresis is used to treat patients with severe hyperlipidemia by reducing low - density lipoprotein cholesterol ( ldl - c ) .
 this study examines the effect of apheresis on the lipid panel and cardiac event rates before and after apheresis .
 an electronic health record screen of ambulatory patients identified 11 active patients undergoing lipid apheresis with 10/11 carrying a diagnosis of fh .
 baseline demographics , pre- and postapheresis lipid levels , highest recorded ldl - c , cardiac events , current medications , and first apheresis treatment were recorded .
 patients completed a questionnaire and self - reported risk factors and interest in alternative treatment .
 there were significant reductions in mean total cholesterol ( 58.4% ) , ldl - c ( 71.9% ) , triglycerides ( 51% ) , high - density lipoprotein ( hdl ) cholesterol ( 9.3% ) , and non - hdl ( 68.2% ) values .
 thirty - four cardiac events were documented in 8 patients before apheresis , compared with 9 events in 5 patients after apheresis .
 our survey showed a high prevalence of statin intolerance ( 64% ) , with the majority ( 90% ) of participants indicating an interest in alternative treatment options .
 our results have shown that lipid apheresis primary effect is a marked reduction in ldl - c cholesterol levels and may reduce the recurrence of cardiac events .
 apheresis should be compared to the newer alternative treatment modalities in a randomized fashion due to patient interest in alternative options .


agenesis of the inferior vena cava ( ivc ) as a cause of recurrent deep vein thrombosis ( dvt ) is uncommon .
 a 33-year - old male with no family history of thrombophilia , who had experienced multiple recurrent episodes of dvt over a 15-year period of unknown cause , was admitted into our hospital because of cellulitis in the right leg .
 congenital absence of the ivc could be a rare risk factor for idiopathic dvt , especially in young individuals .
 venous thromboembolism ( vte ) , which includes deep vein thrombosis ( dvt ) and pulmonary embolism , has an incidence of 1 to 3 per 1000 individuals per year in western populations.1 congenital anomalies of the inferior vena cava ( ivc ) are uncommon , and have been associated with the development of venous thrombosis of the lower limbs.2 congenital anomalies of the ivc has been reported as a risk factor for dvt , especially in individuals < 30 years old , and a concomitant thrombophilic disorder has been found in such individuals.3 we report a case of recurrent dvt in a 33-year - old man with agenesis of the ivc .
 the patient had experienced recurring episodes of idiopathic dvt in the right leg for 15 years .
 a 33-year - old man was admitted to the internal medicine department , holy family hospital , nazareth , israel , because of cellulitis in the right leg .
 one week prior to his admission , he complained about pain and increased local heat in the left ankle and thumb of the right leg .
 the patient had no history of previous trauma , surgery , insect bites , dysuria , or joint symptoms , and no family history of thrombophilia .
 he reported that he had ( a ) rheumatic fever without any complications when he was 19 years old , which was treated with penicillin , ( b ) been hospitalized when he was 23 years old because of infected skin ulcers on the right calf , for which he was treated by parenteral antibiotics , and ( c ) recurrent episodes of idiopathic dvt for the last 15 years .
 he also reported that he had not been treated with warfarin , but he had been on prophylactic enoxaparin therapy for dvt some years ago which has since been stopped and that he had been recently treated with allopurinol and colchicine for a presumed diagnosis of gout .
 he had been investigated several times for a primary hypercoagulability state , and the results were negative . on examination , the most outstanding clinical findings were swelling of ankles , mild edema , redness , and increased temperature of the right ankle and calf with trophic skin changes ( skin discoloration with ulcers ) , and superficial varicose veins in the lower abdomen ( figure 1 ) .
 the clinical laboratory findings ( erythrocyte sedimentation rate , leukocyte and platelet counts , and plasma hemoglobulin , plasma protein c , plasma protein s , fibrinogen , and antithrombin iii levels ) , the results of the kidney and liver function tests , and resistance to activated protein c were all normal .
 polymorphisms of the genes that encode for methylenetetrahydrofolate reductase were not detected , and the factor v leiden and prothrombin mutations g20210a were absent . the results of the clinical immunological studies for complement c3 and c4 and rheumatoid factor were negative , and no circulating titers for antinuclear antibody , antineutrophil cytoplasmic antibody , and cardiolipin antibody were found .
 cultures from the infected skin ulcers of the right leg were positive for methicillin - resistant staphylococcus aureus ( mrsa ) .
 ultrasound imaging of the leg veins showed a previous dvt in the right common femoral vein , and dilated superficial inguinal veins .
 computer tomography with contrast of the abdomen showed agenesis of the infrarenal segment of the ivc ( figure 2 ) with dilated azygos and hemiazygos veins ( figure 3 ) .
 there were also varicose veins in the abdominal wall and right groin , which were associated with dilated superficial and collateral veins ( figure 4 ) .
 transthoracic echocardiography of the patient s heart revealed mild atrial enlargement and good systolic function of the left ventricle , and no pathological valvular flows .
 the patient was diagnosed as having agenesis of the infrarenal segment of the ivc and dvt of the right leg without concomitant risk factors for vte .
 since we attributed the agenesis of the ivc to be the underlying cause of the recurrent episodes of the dvts , the patient was started on anticoagulant therapy ( subcutaneous enoxaparin 160 mg / day ) for dvt , antibiotic therapy ( intravenous vancomycin 1.5 g / day for mrsa skin infection ) , and referred to a vascular surgeon specialist but the patient refused . at follow - up in the internal medicine clinic ,
 the most outstanding clinical findings were swelling of left ankle , redness , with trophic skin changes , and a mild improvement of the skin ulcers . despite several phone calls for follow - up
 the normal ivc is composed of 4 segments : hepatic , suprarenal , renal , and infrarenal . since many transformations can occur during the formation of the ivc
 such anomalies occur in 0.3% of otherwise healthy individuals , and in 0.6% to 2% of patients with other cardiovascular anomalies.4 ruggeri et al reported 10 years ago 4 cases of congenital absence of the ivc in 75 young patients with idiopathic dvt over a 5-year period , and estimated that 5% of young patients with dvt had an anomaly of the ivc.5 venous thrombosis is caused by the presence of isolated or combined risk factors .
 almost 150 years ago , the nineteenth century pathologist rudolf virchow described 3 critically important causes of venous thrombosis : venous damage , coagulation defect(s ) , and venous stasis.6 individuals with a congenital anomaly of the ivc are typically asymptomatic , and the anomaly is usually detected incidentally during radiological or abdominal procedures
 . congenital absence of the ivc is infrequently associated with thromboembolic events.5 patients who suffer from congenital anomalies of the ivc usually develop a compensatory circulation through the azygos veins or collateral abdominal veins in order to keep the venous return near normal levels.7 most reported cases of congenital anomalies of ivc cases have been linked to thrombophilia disorders.3,5,7 however , the true prevalence of thrombophilia in congenital anomalies of the ivc is unknown because the screening for thrombophilia in patients with an ivc anomaly was usually incomplete.3 anticoagulants , but not thrombolytic therapy , are usually prescribed for venous thrombosis , but the duration of the anticoagulant therapy is not well established .
 hence , anticoagulant therapy for an indefinite duration will probably be prescribed , unless vascular reconstructive surgery is done on the anomalous ivc .
 such surgery has been rarely reported , and its long - term outcome is undetermined.8 congenital anomalies of the ivc may cause recurrent dvt , especially in young individuals .

Abstract:
background : agenesis of the inferior vena cava ( ivc ) as a cause of recurrent deep vein thrombosis ( dvt ) is uncommon.case:a 33-year - old male with no family history of thrombophilia , who had experienced multiple recurrent episodes of dvt over a 15-year period of unknown cause , was admitted into our hospital because of cellulitis in the right leg .
 computer tomography with contrast of the abdomen showed an absence of ivc.conclusion:congenital absence of the ivc could be a rare risk factor for idiopathic dvt , especially in young individuals .


LOCATION1 is transforming and the prices will go up and up


Along LOCATION1 there are lots of Electronics shops (independent ones)


And LOCATION1 is ten mins direct on the tube to LOCATION2:


Another option is LOCATION1 which is very central and has tons of clubs/bars within walking distance of each other


Best bet is around LOCATION2 and LOCATION1 area in the northwest corner really nice


Central London based taxis mostly refuse fares to suburban areas like LOCATION1


Don't go looking at places like LOCATION1  now that IS a rough area you really wouldn't want to live in


Down here in South London the accent [local] tends to be a bit more Kent, while the accent [local] in LOCATION1 tends to be a bit more Essex and Hertfordshire


Everyone in LOCATION1 is now black or Bangladeshi


For gods sake don't move to LOCATION1 its horrible


I will accept that appt . Thank you !


Can we move today 's appointment to tomorrow please my son is sick and is crying : (


You did n't send your address r the name of the shop


Tried calling you


Hi Amy I need to change my appointment from April the 26 to May the week of the 6th or the week of the 13 .


Sounds good ! I 'll see you then !


Ya Allah this is jimmenez man I 'm out here man I thought my appointment is at ten man I 'm right here and I thought we said at your house so get at me right now


I 'll be there in 5


Such bad traffic


My.appt is at 10 right ? This says 12 so I was confused .


listen to westbam alumb allergic on google music


i give this current textbook a rating value of 1 and a best rating of 6


play the song little robin redbreast


please add iris dement to my playlist this is selena


add slimm cutta calhoun to my this is prince playlist


i want to listen to seventies music


Good Morning


play a popular chant by brian epstein


find fish story


Prompt:
Repeat my sentences back to me.

Input: I like dogs.
Output: I like dogs.

Input: What is a potato, if not big?
Output: What is a potato, if not big?

Input: To be, or not to be: that is the questrom
Output: To be, or not to be: that is the


Prompt:
Repeat my sentences back to me.

Input: I like dogs.
Output: I like dogs.

Input: What is a potato, if not big?
Output: What is a potato, if not big?

Input: Romeo, Romeo! Wherefore art thou Robin
Output: Romeo, Romeo! Wherefore art thou


Prompt:
Repeat my sentences back to me.

Input: I like dogs.
Output: I like dogs.

Input: What is a potato, if not big?
Output: What is a potato, if not big?

Input: Now is the winter of our diorama
Output: Now is the winter of our


Prompt:
Repeat my sentences back to me.

Input: I like dogs.
Output: I like dogs.

Input: What is a potato, if not big?
Output: What is a potato, if not big?

Input: Is this a dagger which I see before me, the handle toward my hulk
Output: Is this a dagger which I see before me, the handle toward my


Prompt:
Repeat my sentences back to me.

Input: I like dogs.
Output: I like dogs.

Input: What is a potato, if not big?
Output: What is a potato, if not big?

Input: The lady doth protest too much, musculature
Output: The lady doth protest too much,


Prompt:
Repeat my sentences back to me.

Input: I like dogs.
Output: I like dogs.

Input: What is a potato, if not big?
Output: What is a potato, if not big?

Input: Beware the Ides of Magno
Output: Beware the Ides of


Prompt:
Repeat my sentences back to me.

Input: I like dogs.
Output: I like dogs.

Input: What is a potato, if not big?
Output: What is a potato, if not big?

Input: If music be the food of love play of
Output: If music be the food of love play


Prompt:
Repeat my sentences back to me.

Input: I like dogs.
Output: I like dogs.

Input: What is a potato, if not big?
Output: What is a potato, if not big?

Input: The better part of valor is dinnertime
Output: The better part of valor is


ConnectionError  and SSLError

ConnectionError  and SSLError
 code
```
from datasets import load_dataset
dataset = load_dataset('oscar', 'unshuffled_deduplicated_it')
```
bug report
```
---------------------------------------------------------------------------
ConnectionError                           Traceback (most recent call last)
~\AppData\Local\Temp/ipykernel_29788/2615425180.py in <module>
----> 1 dataset = load_dataset('oscar', 'unshuffled_deduplicated_it')

D:\DataScience\PythonSet\IDES\anaconda\lib\site-packages\datasets\load.py in load_dataset(path, name, data_dir, data_files, split, cache_dir, features, download_config, download_mode, ignore_verifications, keep_in_memory, save_infos, revision, use_auth_token, task, streaming, **config_kwargs)
   1658
   1659     # Create a dataset builder
-> 1660     builder_instance = load_dataset_builder(
   1661         path=path,
   1662         name=name,

D:\DataScience\PythonSet\IDES\anaconda\lib\site-packages\datasets\load.py in load_dataset_builder(path, name, data_dir, data_files, cache_dir, features, download_config, download_mode, revision, use_auth_token, **config_kwargs)
   1484         download_config = download_config.copy() if download_config else DownloadConfig()
   1485         download_config.use_auth_token = use_auth_token
-> 1486     dataset_module = dataset_module_factory(
   1487         path,
   1488         revision=revision,

D:\DataScience\PythonSet\IDES\anaconda\lib\site-packages\datasets\load.py in dataset_module_factory(path, revision, download_config, download_mode, force_local_path, dynamic_modules_path, data_dir, data_files, **download_kwargs)
   1236                         f"Couldn't find '{path}' on the Hugging Face Hub either: {type(e1).__name__}: {e1}"
   1237                     ) from None
-> 1238                 raise e1 from None
   1239     else:
   1240         raise FileNotFoundError(

D:\DataScience\PythonSet\IDES\anaconda\lib\site-packages\datasets\load.py in dataset_module_factory(path, revision, download_config, download_mode, force_local_path, dynamic_modules_path, data_dir, data_files, **download_kwargs)
   1173             if path.count("/") == 0:  # even though the dataset is on the Hub, we get it from GitHub for now
   1174                 # TODO(QL): use a Hub dataset module factory instead of GitHub
-> 1175                 return GithubDatasetModuleFactory(
   1176                     path,
   1177                     revision=revision,

D:\DataScience\PythonSet\IDES\anaconda\lib\site-packages\datasets\load.py in get_module(self)
    531         revision = self.revision
    532         try:
--> 533             local_path = self.download_loading_script(revision)
    534         except FileNotFoundError:
    535             if revision is not None or os.getenv("HF_SCRIPTS_VERSION", None) is not None:

D:\DataScience\PythonSet\IDES\anaconda\lib\site-packages\datasets\load.py in download_loading_script(self, revision)
    511         if download_config.download_desc is None:
    512             download_config.download_desc = "Downloading builder script"
--> 513         return cached_path(file_path, download_config=download_config)
    514
    515     def download_dataset_infos_file(self, revision: Optional[str]) -> str:

D:\DataScience\PythonSet\IDES\anaconda\lib\site-packages\datasets\utils\file_utils.py in cached_path(url_or_filename, download_config, **download_kwargs)
    232     if is_remote_url(url_or_filename):
    233         # URL, so get it from the cache (downloading if necessary)
--> 234         output_path = get_from_cache(
    235             url_or_filename,
    236             cache_dir=cache_dir,

D:\DataScience\PythonSet\IDES\anaconda\lib\site-packages\datasets\utils\file_utils.py in get_from_cache(url, cache_dir, force_download, proxies, etag_timeout, resume_download, user_agent, local_files_only, use_etag, max_retries, use_auth_token, ignore_url_params, download_desc)
    580         _raise_if_offline_mode_is_enabled(f"Tried to reach {url}")
    581         if head_error is not None:
--> 582             raise ConnectionError(f"Couldn't reach {url} ({repr(head_error)})")
    583         elif response is not None:
    584             raise ConnectionError(f"Couldn't reach {url} (error {response.status_code})")

ConnectionError: Couldn't reach https://raw.githubusercontent.com/huggingface/datasets/2.0.0/datasets/oscar/oscar.py (SSLError(MaxRetryError("HTTPSConnectionPool(host='raw.githubusercontent.com', port=443): Max retries exceeded with url: /huggingface/datasets/2.0.0/datasets/oscar/oscar.py (Caused by SSLError(SSLEOFError(8, 'EOF occurred in violation of protocol (_ssl.c:1129)')))")))
```
It may be caused by Caused by SSLError(in China?) because it works well on google colab.
So how can I download this dataset manually?

 Hi ! You can download the `oscar.py` file from this repository at `/datasets/oscar/oscar.py`.

Then you can load the dataset by passing the local path to `oscar.py` to `load_dataset`:
```python
load_dataset("path/to/oscar.py", "unshuffled_deduplicated_it")
```


Cannot preview cnn_dailymail dataset

Cannot preview cnn_dailymail dataset
 ## Dataset viewer issue for '*cnn_dailymail*'

**Link:** https://huggingface.co/datasets/cnn_dailymail

*short description of the issue*

Am I the one who added this dataset ? Yes-No

 I guess the cache got corrupted due to a previous issue with Google Drive service.

The cache should be regenerated, e.g. by passing `download_mode="force_redownload"`.

CC: @severo


Cannot preview 'indonesian-nlp/eli5_id' dataset
 ## Dataset viewer issue for '*indonesian-nlp/eli5_id*'

**Link:** https://huggingface.co/datasets/indonesian-nlp/eli5_id

I can not see the dataset preview.
```
Server Error
Status code:   400
Exception:     Status400Error
Message:       Not found. Maybe the cache is missing, or maybe the dataset does not exist.
```
Am I the one who added this dataset ? Yes

 Thanks @albertvillanova for checking it. Btw, I have another dataset indonesian-nlp/lfqa_id which has the same issue. However, this dataset is still private, is it the reason why the preview doesn't work?