RORγt+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota

Lymphoid cells that express the nuclear hormone receptor RORγt are involved in containment of the large intestinal microbiota and defense against pathogens through the production of interleukin 17 (IL-17) and IL-22. They include adaptive IL-17-producing helper T cells (T(H)17 cells), as well as innate lymphoid cells (ILCs) such as lymphoid tissue-inducer (LTi) cells and IL-22-producing NKp46+ cells. Here we show that in contrast to T(H)17 cells, both types of RORγt+ ILCs constitutively produced most of the intestinal IL-22 and that the symbiotic microbiota repressed this function through epithelial expression of IL-25. This function was greater in the absence of adaptive immunity and was fully restored and required after epithelial damage, which demonstrates a central role for RORγt+ ILCs in intestinal homeostasis. Our data identify a finely tuned equilibrium among intestinal symbionts, adaptive immunity and RORγt+ ILCs.     

Modafinil reverses hypoexcitability of the motor cortex in narcoleptic patients: A TMS study

ObjectiveAlthough many animal and human studies have been performed, the exact mechanisms of action whereby modafinil promotes wakefulness are still not completely understood. We aimed to investigate the functional effects of modafinil on motor cortex excitability in patients with narcolepsy by means of transcranial magnetic stimulation (TMS) techniques.MethodsIn a double-blind and placebo-controlled design, 24 drug-naive narcoleptic patients with cataplexy and 20 control subjects were administered modafinil or placebo over a period of 4 weeks. TMS was performed twice during the awake state before and at the end of treatment; measures of cortical excitability included central motor conduction time, resting motor threshold, short latency intracortical inhibition (SICI) and intracortical facilitation to paired-TMS. TMS measures were correlated with the conventional neurophysiological method of Multiple Sleep Latency Test (MSLT) and the subjective Epworth Sleepiness Scale (ESS).ResultsAs previously reported, motor threshold and SICI were significantly increased in patients with narcolepsy; modafinil reversed this cortical hypoexcitability, but only SICI differences reached statistical significance. The Spearman rank correlation analysis revealed the highest correlation between SICI and the MSLT; a positive correlation was also found between SICI and the ESS, as well as between RMT and both measures of daytime sleepiness.ConclusionsThis represents the first report investigating effects of modafinil on cortical excitability in human narcolepsy. Since SICI is thought to be directly related to GABA_A intracortical inhibitory activity, we demonstrated that the dose of modafinil that induces a satisfactory wakefulness-promoting response in narcoleptic patients also causes decrease in GABAergic transmission.     

The public-use National Health Interview Survey linked mortality files: methods of reidentification risk avoidance and comparative analysis

The National Center for Health Statistics (NCHS) conducts mortality follow-up for its major population-based surveys. In 2004, NCHS updated the mortality follow-up for the 1986-2000 National Health Interview Survey (NHIS) years, which because of confidentiality protections was made available only through the NCHS Research Data Center. In 2007, NCHS released a public-use version of the NHIS Linked Mortality Files that includes a limited amount of perturbed information for decedents. The modification of the public-use version included conducting a reidentification risk scenario to determine records at risk for reidentification and then imputing values for either date or cause of death for a select sample of records. To demonstrate the comparability between the public-use and restricted-use versions of the linked mortality files, the authors estimated relative hazards for all-cause and cause-specific mortality risk using a Cox proportional hazards model. The pooled 1986-2000 NHIS Linked Mortality Files contain 1,576,171 records and 120,765 deaths. The sample for the comparative analyses included 897,232 records and 114,264 deaths. The comparative analyses show that the two data files yield very similar results for both all-cause and cause-specific mortality. Analytical considerations when examining cause-specific analyses of numerically small demographic subgroups are addressed.     

Analogues of polyamine alkaloids and their synthetic advantages

Several polyamine derivatives were synthesized in order to produce novel antagonists of muscular nicotinic acetylcholine receptors. Their affinities were compared with those of philanthotoxin PhTX-343.     

Type-II error rates (beta errors) of randomized trials in orthopaedic trauma.

BACKGROUND: Although an investigator may limit bias through randomization, concealment of patient allocation, and blinding, the results of randomized trials may be less convincing when the sample size is not sufficiently large to reveal a true difference between treatment groups. When the sample size is small, randomized trials are subject to beta errors (type-II errors)--that is, the probability of concluding that no difference between treatment groups exists when, in fact, there is a difference. The purpose of this study of randomized trials involving fracture care published between 1968 and 1999 was twofold: (1) to evaluate type-II error rates and study power (1 - beta) for the primary outcomes and (2) to identify whether investigators clearly identified the primary and secondary outcomes. METHODS: To be eligible, studies were required to (1) be published in English, (2) be described as a randomized trial, (3) involve the care of adult patients with fractures, treated either operatively or nonoperatively, and (4) contain sufficient outcome information to enable study power to be calculated. Computer database searches were performed independently by two investigators to identify all potentially relevant study titles. Additional strategies to identify articles included (1) hand searches of selected orthopaedic journals from 1989 to 1999, (2) searches of the bibliographies of potentially relevant articles, and (3) review by content experts to identify missing studies. For each study, a standard power calculation was performed on the primary and secondary outcomes. For those studies in which the primary outcome was not explicitly reported, the most clinically relevant measure was chosen by consensus. Acceptable study power was agreed a priori to be > or = 80% (type-I error of < or = 0.20). RESULTS: We identified 620 potentially relevant citations from MEDLINE, of which only 187 were potentially eligible. We identified nine more articles with other searches, and application of the eligibility criteria to the 196 articles eliminated seventy-nine. Thus, we analyzed 117 studies in which a total of 19,942 patients with orthopaedic trauma had been randomized. Sample sizes ranged from ten to 662 patients (mean and standard deviation, 95 79 patients). The majority (34%) of trials involved the treatment of hip fractures. The mean overall study power among the 117 trials was 24.65% (range, 2% to 99%). The type-II error rate for primary outcomes was 90.52%. CONCLUSIONS: Mean type-II error rates in the orthopaedic trauma trials that we analyzed exceeded accepted standards. Investigators can reduce type-II error rates by performing power and sample-size calculations prior to conducting a trial.     

Trichotillomania (hair pulling disorder), skin picking disorder,and stereotypic movement disorder: toward DSM‐V

In DSM‐IV‐TR, trichotillomania (TTM) is classified as an impulse control disorder (not classified elsewhere), skin picking lacks its own diagnostic category (but might be diagnosed as an impulse control disorder not otherwise specified), and stereotypic movement disorder is classified as a disorder usually first diagnosed in infancy, childhood, or adolescence. ICD‐10 classifies TTM as a habit and impulse disorder, and includes stereotyped movement disorders in a section on other behavioral and emotional disorders with onset usually occurring in childhood and adolescence. This article provides a focused review of nosological issues relevant to DSM‐V, given recent empirical findings. This review presents a number of options and preliminary recommendations to be considered for DSM‐V: (1) Although TTM fits optimally into a category of body‐focused repetitive behavioral disorders, in a nosology comprised of relatively few major categories it fits best within a category of motoric obsessive–compulsive spectrum disorders, (2) available evidence does not support continuing to include (current) diagnostic criteria B and C for TTM in DSM‐V, (3) the text for TTM should be updated to describe subtypes and forms of hair pulling, (4) there are persuasive reasons for referring to TTM as “hair pulling disorder (trichotillomania),” (5) diagnostic criteria for skin picking disorder should be included in DSM‐V or in DSM‐Vs Appendix of Criteria Sets Provided for Further Study, and (6) the diagnostic criteria for stereotypic movement disorder should be clarified and simplified, bringing them in line with those for hair pulling and skin picking disorder. Depression and Anxiety, 2010. © 2010 Wiley‐Liss, Inc.