A partial human LCK defect causes a T cell immunodeficiency with intestinal inflammation.

Lymphocyte-specific protein tyrosine kinase (LCK) is essential for T cell antigen receptor (TCR)-mediated signal transduction. Here, we report two siblings homozygous for a novel LCK variant (c.1318C>T; P440S) characterized by T cell lymphopenia with skewed memory phenotype, infant-onset recurrent infections, failure to thrive, and protracted diarrhea. The patients' T cells show residual TCR signal transduction and proliferation following anti-CD3/CD28 and phytohemagglutinin (PHA) stimulation. We demonstrate in mouse models that complete (Lck-/-) versus partial (LckP440S/P440S) loss-of-function LCK causes disease with differing phenotypes. While both Lck-/- and LckP440S/P440S mice exhibit arrested thymic T cell development and profound T cell lymphopenia, only LckP440S/P440S mice show residual T cell proliferation, cytokine production, and intestinal inflammation. Furthermore, the intestinal disease in the LckP440S/P440S mice is prevented by CD4+ T cell depletion or regulatory T cell transfer. These findings demonstrate that P440S LCK spares sufficient T cell function to allow the maturation of some conventional T cells but not regulatory T cells-leading to intestinal inflammation.

The role of hyperbaric oxygen therapy in septic shock: is it time for human studies?

Sepsis is a life-threatening condition for which new therapies are needed. The objective of this literature review was to compile evidence related to the use of hyperbaric oxygen (HBO2) therapy in sepsis. The goal of this analysis was to determine whether human trials are indicated. The study was designed as a narrative review of literature for studies of HBO2 therapy in sepsis. Literature was reviewed to understand potentially beneficial and harmful clinical and physiological effects of HBO2 therapy in animals with sepsis. HBO2 has several physiologic mechanisms which may be beneficial in sepsis, including restoration of mitochondrial function, improved microvascular function and organ perfusion, decreased capillary leak, improved cytokine profile, direct antimicrobial effects, and enhanced antibiotic function. The studies reviewed suggest that HBO2 therapy may be most effective if administered early and in high doses. Animal trials also show that HBO2 may provide protection to the gut mucosa by preventing bacterial translocation in sepsis. HBO2 has a potential to reduce organ failure through novel sepsis mechanisms not used in other therapies. Further human studies should be performed to better elucidate the role of HBO2 in improving sepsis clinical outcomes.

Do preparatory behaviours predict alcohol consumption among UK university students?

OBJECTIVE: This study explored whether the frequency and habitual nature of engagement in three behaviours that may serve as preparation for alcohol consumption on a night out with friends - that is, contacting friends to arrange a night out, buying alcohol, drinking alone at home before going out - predicted consumption on such nights. DESIGN: Prospective correlational design. METHODS: One hundred and twenty UK university students (68 female, 50 male, two non-binary, mean age = 20.78 years, SD = 1.52) completed a survey comprising intentions, habits, and frequency and habit for the three preparatory behaviours. One week later, a second survey measured the number of nights out with friends on which alcohol was drunk (i.e., drinking frequency) and the number on which four or more alcoholic drinks were consumed (i.e, excessive drinking). Regression models were run to predict drinking frequency and excessive drinking. RESULTS: Drinking frequency was predicted only by frequency of contacting friends (B = .28, SE = .12, p = .02), and habitually drinking alone before going out (B = .20, SE = .09, p = .03). Excessive drinking was only predicted by alcohol consumption habit (B = .67, SE = .23, p = .003). CONCLUSIONS: Preceding actions may influence the frequency of alcohol consumption on nights out, independently of intentions and habits relating to alcohol consumption. While interventions to reduce consumption quantity in a single session might focus on disrupting the habits that sustain drinking episodes, efforts to reduce alcohol consumption frequency on nights out might focus on disrupting behaviours that precede alcohol consumption.

Therapeutic Targeting of Proteostasis in Amyotrophic Lateral Sclerosis-a Systematic Review and Meta-Analysis of Preclinical Research.

Background: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive fatal neurodegenerative condition. There are no effective treatments. The only globally licensed medication, that prolongs life by 2-3 months, was approved by the FDA in 1995. One reason for the absence of effective treatments is disease heterogeneity noting that ALS is clinically heterogeneous and can be considered to exist on a neuropathological spectrum with frontotemporal dementia. Despite this significant clinical heterogeneity, protein misfolding has been identified as a unifying pathological feature in these cases. Based on this shared pathophysiology, we carried out a systematic review and meta-analysis to assess the therapeutic efficacy of compounds that specifically target protein misfolding in preclinical studies of both ALS and FTD. Methods: Three databases: (i) PubMed, (ii) MEDLINE, and (iii) EMBASE were searched. All studies comparing the effect of treatments targeting protein misfolding in pre-clinical ALS or FTD models to a control group were retrieved. Results: Systematic review identified 70 pre-clinical studies investigating the effects of therapies targeting protein misfolding on survival. Meta-analysis revealed that targeting protein misfolding did significantly improve survival compared to untreated controls (p < 0.001, df = 68, α = 0.05, CI 1.05-1.16), with no evidence of heterogeneity between studies (I 2 = 0%). Further subgroup analyses, evaluating the effect of timing of these interventions, showed that, only treating prior to symptom onset (n = 33), significantly improved survival (p < 0.001, df = 31, α = 0.05, CI 1.08-1.29), although this likely reflects the inadequate sample size of later time points. Furthermore, arimoclomol was found to significantly reduce secondary outcome measures including: (i) histological outcomes, (ii) behavioral outcomes, and (iii) biochemical outcomes (p < 0.005). Conclusions: This analysis supports the hypothesis that protein misfolding plays an important role in the pathogenesis of ALS and FTD and that targeting protein misfolding, at least in pre-clinical models, can significantly improve survival, especially if such an intervention is administered prior to symptom onset.

Redox Homeostasis and Metabolism in Cancer: A Complex Mechanism and Potential Targeted Therapeutics.

Reactive Oxygen Species or "ROS" encompass several molecules derived from oxygen that can oxidize other molecules and subsequently transition rapidly between species. The key roles of ROS in biological processes are cell signaling, biosynthetic processes, and host defense. In cancer cells, increased ROS production and oxidative stress are instigated by carcinogens, oncogenic mutations, and importantly, metabolic reprograming of the rapidly proliferating cancer cells. Increased ROS production activates myriad downstream survival pathways that further cancer progression and metastasis. In this review, we highlight the relation between ROS, the metabolic programing of cancer, and stromal and immune cells with emphasis on and the transcription machinery involved in redox homeostasis, metabolic programing and malignant phenotype. We also shed light on the therapeutic targeting of metabolic pathways generating ROS as we investigate: Orlistat, Biguandes, AICAR, 2 Deoxyglucose, CPI-613, and Etomoxir.

The wizard behind the curtain: programmers as providers.

It is almost universally accepted that traditional provider-patient relationships should be governed, at least in part, by the ethical principles set forth by Beauchamp and Childress (Beauchamp and Childress, Principles of biomedical ethics, 1979). These principles include autonomy, beneficence, non-maleficence and justice (Beauchamp and Childress, Principles of biomedical ethics, 1979). Recently, however, the nature of medial practice has changed. The pervasive presence of computer technology in medicine raises interesting ethical questions. In this paper we argue that some software designers should be considered health care providers and thus be subject the ethical principles incumbent upon "traditional" providers. We argue that these ethical responsibilities should be applied explicitly rather than as a passive, implicit, set of guidelines.

Resuscitating the physician-patient relationship: emergency department communication in an academic medical center.

STUDY OBJECTIVE: We characterize communication in an urban, academic medical center emergency department (ED) with regard to the timing and nature of the medical history survey and physical examination and discharge instructions. METHODS: Audiotaping and coding of 93 ED encounters (62 medical history surveys and physical examinations, 31 discharges) with a convenience sample of 24 emergency medicine residents, 8 nurses, and 93 nonemergency adult patients. RESULTS: Patients were 68% women and 84% black, with a mean age of 45 years. Emergency medicine providers were 70% men and 80% white. Of 62 medical history surveys and physical examinations, time spent on the introduction and medical history survey and physical examination averaged 7 minutes 31 seconds (range 1 to 20 minutes). Emergency medicine residents introduced themselves in only two thirds of encounters, rarely (8%) indicating their training status. Despite physician tendency (63%) to start with an open-ended question, only 20% of patients completed their presenting complaint without interruption. Average time to interruption (usually a closed question) was 12 seconds. Discharge instructions averaged 76 seconds (range 7 to 202 seconds). Information on diagnosis, expected course of illness, self-care, use of medications, time-specified follow-up, and symptoms that should prompt return to the ED were each discussed less than 65% of the time. Only 16% of patients were asked whether they had questions, and there were no instances in which the provider confirmed patient understanding of the information. CONCLUSION: Academic EDs present unique challenges to effective communication. In our study, the physician-patient encounter was brief and lacking in important health information. Provision of patient-centered care in academic EDs will require more provider education and significant system support.