Tabernanthalog and ibogainalog inhibit the α7 and α9α10 nicotinic acetylcholine receptors via different mechanisms and with higher potency than the GABAA receptor and CaV2.2 channel.

In this study, we have investigated the pharmacological activity and structural interaction of two novel psychoplastogens, tabernanthalog (TBG) and ibogainalog (IBG) at heterologously-expressed rat (r) and human (h) nicotinic acetylcholine receptors (nAChRs), the rα1ß2γ2L γ-aminobutyric acid type A receptor (GABAAR), and the human voltage-gated N-type calcium channel (CaV2.2 channel). Both compounds inhibited the nAChRs with the following receptor selectivity: α9α10 > α7 > α3ß2 â‰… α3ß4, indicating that ß2/ß4 subunits are relatively less important for their activity. The potencies of TBG and IBG were comparable at hα7 and hα9α10 subtypes, and comparable to their rat counterparts. TBG- and IBG-induced inhibition of rα7 was ACh concentration-independent and voltage-dependent, whereas rα9α10 inhibition was ACh concentration-dependent and voltage-independent, suggesting that they interact with the α7 ion channel pore and α9α10 orthosteric ligand binding site, respectively. These results were supported by molecular docking studies showing that at the α7 model TBG forms stable interactions with luminal rings at 9', 13', and 16', whereas IBG mostly interacts with the extracellular-transmembrane junction. In the α9α10 model, however, these compounds interacted with several residues from the principal (+) and complementary (-) sides in the transmitter binding site. Ibogaminalog (DM506) also interacted with a non-luminal site at α7, and one α9α10 orthosteric site. TBG and IBG inhibited the GABAAR and CaV2.2 channels with 10 to 30-fold lower potencies. In sum, we show that TBG and IBG inhibit the α7 and α9α10 nAChRs by noncompetitive and competitive mechanisms, respectively, and with higher potency than the GABAAR and CaV2.2 channel.

Nutritional Risks in Patients Undergoing Total Pancreatectomy Islet AutoTransplantation in the POST Consortium.

BACKGROUND AND AIMS: Total pancreatectomy with islet autotransplantation (TPIAT) can relieve pain for individuals with acute recurrent or chronic pancreatitis. However, TPIAT may increase the risk of poor nutritional status with complete exocrine pancreatic insufficiency, partial duodenectomy, and intestinal reconstruction. Our study's objective was to evaluate nutritional status, anthropometrics, and vitamin levels before and after TPIAT. METHODS: The multicenter Prospective Observational Study of TPIAT (POST) collects measures including vitamins A, D, and E levels, pancreatic enzyme dose, and multivitamin (MVI) administration before and 1-year after TPIAT. Using these data, we studied nutritional and vitamin status before and after TPIAT. RESULTS: 348 TPIAT recipients were included (68% adult, 37% male, 93% Caucasian). In paired analyses at 1-year follow-up, vitamin A was low in 23% (vs 9% pre-TPIAT, p < 0.001); vitamin E was low in 11% (vs 5% pre-TPIAT, p = 0.066), and 19% had vitamin D deficiency (vs 12% pre-TPIAT, p = 0.035). Taking a fat-soluble multivitamin (pancreatic MVI) was associated with lower risk for vitamin D deficiency (p = 0.002). Adults were less likely to be on a pancreatic MVI at follow-up (34% vs 66% respectively, p < 0.001). Enzyme dosing was adequate. More adults versus children were overweight or underweight pre- and post-TPIAT. Underweight status was associated with vitamin A (p = 0.014) and E (p = 0.02) deficiency at follow-up. CONCLUSIONS: Prevalence of fat-soluble vitamin deficiencies increased after TPIAT, especially if underweight. We strongly advocate that all TPIAT recipients have close post-operative nutritional monitoring, including vitamin levels. Pancreatic MVIs should be given to minimize risk of developing deficiencies.

Effects of Tribulus terrestris L. on Sport and Health Biomarkers in Physically Active Adult Males: A Systematic Review.

Tribulus terrestris L. (TT) is a plant used in traditional Chinese medicine, Ayurvedic medicine, and sports nutrition to improve health and performance. However, no conclusive evidence exists about the potential beneficial effects of TT on sport and health biomarkers in physically active adults. Based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and the modified McMaster Critical Review Form for methodological quality assessment, we systematically reviewed studies indexed in Web of Science, Scopus, and PubMed, to assess the effects of TT on immunological, hematological, biochemical, renal, lipidic, hormonal behavior, and anti-inflammatory response in physically active adult males. Among 340 records identified in the search, a total of 7 studies met the inclusion and exclusion criteria. Overall, participants supplemented with TT displayed significant improvements in lipid profile. Inflammatory and hematological biomarkers showed moderate beneficial effects with no significant changes on renal biomarkers. No positive effects were observed on the immune system response. Additionally, no TT-induced toxicity was reported. In conclusion, there was no clear evidence of the beneficial effects of TT supplementation on muscle damage markers and hormonal behavior. More studies are needed to confirm the benefits of TT due to the limited number of studies available in the current literature.

Impact of Optimal Timing of Intake of Multi-Ingredient Performance Supplements on Sports Performance, Muscular Damage, and Hormonal Behavior across a Ten-Week Training Camp in Elite Cyclists: A Randomized Clinical Trial.

Multi-ingredient performance supplements (MIPS), ingested pre- or post-workout, have been shown to increase physiological level effects and integrated metabolic response on exercise. The purpose of this study was to determine the efficacy of pre-and post-training supplementation with its own MIPS, associated with CHO (1 g·kg-1) plus protein (0.3 g·kg-1) on exercise-related benchmarks across a training camp for elite cyclists. Thirty elite male cyclists participated in a randomized non-placebo-controlled trial for ten weeks assigned to one of three groups (n = 10 each): a control group treated with CHO plus protein after training (CG); a group treated with MIPS before training and a CHO plus protein after training, (PRE-MIPS); a group treated with CHO plus protein plus MIPS after training, (POST-MIPS). Performance parameters included (VO2max, peak; median and minimum power (W) and fatigue index (%)); hormonal response (Cortisol; Testosterone; and Testosterone/Cortisol ratio); and muscle biomarkers (Creatine kinase (CK), Lactate dehydrogenase (LDH), and Myoglobin (Mb)) were assessed. MIPS administered before or after training (p ≤ 0.05) was significantly influential in attenuating CK, LDH, and MB; stimulating T response and modulating C; and improved on all markers of exercise performance. These responses were greater when MIPS was administered post-workout.

The Effects of 6 Weeks of Tribulus terrestris L. Supplementation on Body Composition, Hormonal Response, Perceived Exertion, and CrossFit® Performance: A Randomized, Single-Blind, Placebo-Controlled Study.

Tribulus terrestris L. (TT) supplementation have been shown to enhance sports performance in many but not all studies. Moreover, data regarding the potential impact of TT supplementation on CrossFit® endurance is limited. This study aimed to determine whether TT supplementation improve body composition, hormonal response, and performance among CrossFit® athletes. In a randomized, single-blind, placebo-controlled trial, a total of 30 healthy CrossFit®-trained males were randomly allocated to receive either 770 mg of TT supplementation or a placebo daily for 6 weeks. Body mass, fat mass, fat composition, testosterone and cortisol levels, and CrossFit® performance (5 common Workouts of the Day: back squat, bench press, dead lift, Grace, and CrossFit® Total) were assessed before and after intervention. There were no significant group x time interactions for the outcomes of the study except for testosterone levels and bench press performance (p < 0.05). TT supplementation did not impact enhance performance or body composition in CrossFit® male athletes. However, TT supplementation may act as a testosterone booster helping the recovery after physical loads and mitigating fatigue.

Glycophosphopeptical AM3 Food Supplement: A Potential Adjuvant in the Treatment and Vaccination of SARS-CoV-2.

The world is currently experiencing the coronavirus disease 2019 (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome-2 (SARS-CoV-2). Its global spread has resulted in millions of confirmed infections and deaths. While the global pandemic continues to grow, the availability of drugs to treat COVID-19 infections remains limited to supportive treatments. Moreover, the current speed of vaccination campaigns in many countries has been slow. Natural substrates with biological immunomodulatory activity, such as glucans, may represent an adjuvant therapeutic agent to treat SARS-CoV-2. AM3, a natural glycophosphopeptical, has previously been shown to effectively slow, with no side effects, the progression of infectious respiratory diseases by regulating effects on innate and adaptive immunity in experimental models. No clinical studies, however, exist on the use of AM3 in SARS-CoV-2 infected patients. This review aims to summarize the beneficial effects of AM3 on respiratory diseases, the inflammatory response, modulation of immune response, and attenuation of muscle. It will also discuss its potential effects as an immune system adjuvant for the treatment of COVID-19 infections and adjuvant for SARS-CoV-2 vaccination.

Simplified and Unified Access to Cancer Proteogenomic Data.

Comprehensive cancer data sets recently generated by the Clinical Proteomic Tumor Analysis Consortium (CPTAC) offer great potential for advancing our understanding of how to combat cancer. These data sets include DNA, RNA, protein, and clinical characterization for tumor and normal samples from large cohorts of many different cancer types. The raw data are publicly available at various Cancer Research Data Commons. However, widespread reuse of these data sets is also facilitated by easy access to the processed quantitative data tables. We have created a data application programming interface (API) to distribute these processed tables, implemented as a Python package called cptac. We implement it such that users who prefer to work in R can easily use our package for data access and then transfer the data into R for analysis. Our package distributes the finalized processed CPTAC data sets in a consistent, up-to-date format. This consistency makes it easy to integrate the data with common graphing, statistical, and machine-learning packages for advanced analysis. Additionally, consistent formatting across all cancer types promotes the investigation of pan-cancer trends. The data API structure of directly streaming data within a programming environment enhances the reproducibility. Finally, with the accompanying tutorials, this package provides a novel resource for cancer research education. View the software documentation at https://paynelab.github.io/cptac/. View the GitHub repository at https://github.com/PayneLab/cptac.

Does etiology of gastroparesis determine clinical outcomes in gastric electrical stimulation treatment of gastroparesis?

BACKGROUND: Gastroparesis is a condition characterized by impaired gastric motility that may result in weight loss and malnutrition. There have been promising studies demonstrating improvement in symptoms after gastric electrical stimulation (GES) implantation for medically refractory gastroparetics [1-10]. With the heterogeneous population of gastroparetics, the aim of this study was to assess if etiology correlated with response to GES. METHODS: A retrospective review and analysis was performed on patients who underwent GES over a 10-year period at a single institution. Each patient was stratified into an etiological subset (diabetes, idiopathic, post-surgical). Patients were compared by demographics, medical and surgical history, subsequent GES explantation vs continued therapy, need for supplemental nutrition postoperatively, weight gain, weight loss or weight maintenance, and readmission rates. RESULTS: 183 patients underwent GES from 2005 to 2015. 50% were diabetic (n = 91), 42% idiopathic (n = 76), and 9% post-surgical (n = 16). Diabetic patients (DM) demonstrated the highest likelihood of continued therapy compared to post-surgical (PS) and idiopathic patients (ID) (54.7% vs 9.5% vs 35.8%, respectively, p < 0.05). DM patients saw a greater incidence of weight gain > 4 kg, compared to PS and IS patients (67.6% vs 8.1% vs. 24.3%, respectively, p < 0.05). ID patients were most likely to have it removed compared to DM and PS patients (65.7% vs 28.6% vs 5.7%, respectively, p = < 0.05). PS patients were least likely to have their GES removed. They were also least likely to utilize supplemental nutrition compared to DM and ID (9.4% vs 49.1% vs 41.51%, respectively, p < 0.05). CONCLUSIONS: Patients with gastroparesis had different clinical outcomes after GES therapy based on underlying etiology. By gaining a better understanding of the effects of GES, it can be offered to the appropriate patient.

The Surgeon's Role in Gastric Electrical Stimulation Therapy for Gastroparesis.

INTRODUCTION: Gastroparesis, which can be viewed as a syndrome featuring nausea, vomiting, and abdominal pain, and associated other symptoms and findings, is increasingly seen by surgeons. Gastroparesis is associated with a number of gastrointestinal anatomic and physiologic findings. MATERIALS AND METHODS: This article reviews the use of bioelectric therapy of neuromodulation, via gastric electrical stimulation, for patients with drug refractory gastroparesis syndromes including surgical aspects of device placement and subsequent management. RESULTS AND DISCUSSION: In addition to an overall approach to the placement and subsequent management of gastric electrical stimulation devices, several newer concepts are discussed. The role of pyloric dysfunction in gastroparesis is also discussed including how stimulation devices and pyloric therapies may be used in concert. The additions of full-thickness gastrointestinal biopsies along with other physiologic, including GI electrophysiology, as well as some serologic measures, are also discussed. In addition, evolving approaches and emerging technologies for bioelectric neuromodulation of the gastrointestinal tract are introduced. CONCLUSIONS: Gastroparesis syndromes can be approached in a systematic manner based on known pathophysiology and when indicated can be helped with surgical therapies including neuromodulation.

Carcinogenicity Assessment of Daprodustat (GSK1278863), a Hypoxia-Inducible Factor (HIF)-Prolyl Hydroxylase Inhibitor.

Daprodustat (GSK1278863) is a hypoxia-inducible factor (HIF)-prolyl hydroxylase (PHD) inhibitor in development for treatment of anemia of chronic kidney disease. Daprodustat's biological activity simulates components of the natural response to hypoxia; inhibition of PHDs results in HIF stabilization and modulation of HIF-controlled gene products, including erythropoietin. The carcinogenic potential of daprodustat was evaluated in 2-year carcinogenicity studies in Sprague-Dawley rats and CD-1 mice, where once-daily doses were administered. The mouse study also included evaluation of daprodustat's 3 major circulating human metabolites. There were no neoplastic findings that were considered treatment related in either study. Exaggerated pharmacology resulted in significantly increased red cell mass and subsequent multiorgan congestion and secondary non-neoplastic effects in both species, similar to those observed in chronic toxicity studies. In rats, these included aortic thrombosis and an exacerbation of spontaneous rodent cardiomyopathy, which contributed to a statistically significant decrease in survival in high-dose males (group terminated in week 94). Survival was not impacted in mice at any dose. Systemic exposures (area under the plasma concentration-time curve) to daprodustat at the high doses in rats and mice exceed predicted maximal human clinical exposure by ≥143-fold. These results suggest that daprodustat and metabolites do not pose a carcinogenic risk at clinical doses.

Defining Disease, Diagnosis, and Translational Medicine within a Homeostatic Perturbation Paradigm: The National Institutes of Health Undiagnosed Diseases Program Experience.

Traditionally, the use of genomic information for personalized medical decisions relies on prior discovery and validation of genotype-phenotype associations. This approach constrains care for patients presenting with undescribed problems. The National Institutes of Health (NIH) Undiagnosed Diseases Program (UDP) hypothesized that defining disease as maladaptation to an ecological niche allows delineation of a logical framework to diagnose and evaluate such patients. Herein, we present the philosophical bases, methodologies, and processes implemented by the NIH UDP. The NIH UDP incorporated use of the Human Phenotype Ontology, developed a genomic alignment strategy cognizant of parental genotypes, pursued agnostic biochemical analyses, implemented functional validation, and established virtual villages of global experts. This systematic approach provided a foundation for the diagnostic or non-diagnostic answers provided to patients and serves as a paradigm for scalable translational research.

Identification of a Novel, Small Molecule Partial Agonist for the Cyclic AMP Sensor, EPAC1.

Screening of a carefully selected library of 5,195 small molecules identified 34 hit compounds that interact with the regulatory cyclic nucleotide-binding domain (CNB) of the cAMP sensor, EPAC1. Two of these hits (I942 and I178) were selected for their robust and reproducible inhibitory effects within the primary screening assay. Follow-up characterisation by ligand observed nuclear magnetic resonance (NMR) revealed direct interaction of I942 and I178 with EPAC1 and EPAC2-CNBs in vitro. Moreover, in vitro guanine nucleotide exchange factor (GEF) assays revealed that I942 and, to a lesser extent, I178 had partial agonist properties towards EPAC1, leading to activation of EPAC1, in the absence of cAMP, and inhibition of GEF activity in the presence of cAMP. In contrast, there was very little agonist action of I942 towards EPAC2 or protein kinase A (PKA). To our knowledge, this is the first observation of non-cyclic-nucleotide small molecules with agonist properties towards EPAC1. Furthermore, the isoform selective agonist nature of these compounds highlights the potential for the development of small molecule tools that selectively up-regulate EPAC1 activity.

Electroconvulsive Therapy Considerations for Transgendered Patients.

As the transgender patient population continues to grow, health care providers will need to become aware of elements unique to the transgender community in order to provide the highest quality of care. Neuromuscular blockade with succinylcholine is routinely administered to patients undergoing electroconvulsive therapy (ECT). Decreased amounts or activity of pseudocholinesterase in serum can lead to prolonged duration of muscle paralysis. Causes of reduced action by pseudocholinesterase include genetically abnormal enzymes, reduced hepatic production, pregnancy, and various drug interactions. Estrogen supplementation taken by transitioning patients may affect the duration of neuromuscular blockade.This is a case of a 32-year-old male-to-female transgender patient with prolonged apnea following ECT treatment for severe, refractory depression. Further investigation revealed the patient was on estrogen therapy as a part of her transition and laboratory testing demonstrated reduced serum pseudocholinesterase activity. Further laboratory testing demonstrated reduced serum pseudocholinesterase activity. Succinylcholine dosing was titrated to an appropriate level to avoid prolonged apnea in subsequent ECT treatments. Physicians and other health care providers are faced with a unique population in the transgender community and must be aware of distinctive circumstances when providing care to this group. Of specific interest, many transitioning and transitioned patients can be on chronic estrogen supplementation. Neuromuscular blockade in those patients require attention from the anesthesiology care team as estrogen compounds may decrease pseudocholinesterase levels and lead to prolonged muscle paralysis from succinylcholine.

Limited Effects of Endurance or Interval Training on Visceral Adipose Tissue and Systemic Inflammation in Sedentary Middle-Aged Men.

Purpose. Limited data exists for the effects of sprint-interval training (SIT) and endurance training (ET) on total body composition, abdominal visceral adipose tissue, and plasma inflammation. Moreover, whether "active" or "passive" recovery in SIT provides a differential effect on these measures remains uncertain. Methods. Sedentary middle-aged men (n = 62; 49.5 ± 5.8 y; 29.7 ± 3.7 kg·m2) underwent abdominal computed tomography, dual-energy X-ray absorptiometry, venepuncture, and exercise testing before and after the interventions, which included the following: 12 wks 3 d·wk-1 ET (n = 15; 50-60 min cycling; 80% HRmax), SIT (4-10 × 30 s sprint efforts) with passive (P-SIT; n = 15) or active recovery (A-SIT; n = 15); or nonexercise control condition (CON; n = 14). Changes in cardiorespiratory fitness, whole-body and visceral fat mass, and plasma systemic inflammation were examined. Results. Compared to CON, significant increases in interpolated power output (P-SIT, P < 0.001; ET, P = 0.012; A-SIT, P = 0.041) and test duration (P-SIT, P = 0.001; ET, P = 0.012; A-SIT, P = 0.046) occurred after training. Final VO2 consumption was increased after P-SIT only (P < 0.001). Despite >90% exercise compliance, there was no change in whole-body or visceral fat mass or plasma inflammation (P > 0.05). Conclusion. In sedentary middle-aged men, SIT was a time-effective alternative to ET in facilitating conditioning responses yet was ineffective in altering body composition and plasma inflammation, and compared to passive recovery, evidenced diminished conditioning responses when employing active recovery.

Outcomes in the Randomized CoreValve US Pivotal High Risk Trial in Patients With a Society of Thoracic Surgeons Risk Score of 7% or Less.

Importance: Transcatheter aortic valve replacement (TAVR) is now a well-accepted alternative to surgical AVR (SAVR) for patients with symptomatic aortic stenosis at increased operative risk. There is interest in whether TAVR would benefit patients at lower risk. Objective: The Society of Thoracic Surgeons Predicted Risk of Mortality (STS PROM) has trended downward in US TAVR trials and the STS/American College of Cardiology Transcatheter Valve Therapy Registry. We hypothesized that if the Society of Thoracic Surgeons Predicted Risk of Mortality (STS PROM) alone is sufficient to define decreased risk, the contribution to survival based on the degree of invasiveness of the TAVR procedure will decrease, making it more difficult to show improved survival and benefit over SAVR. Design, Setting, and Participants: The CoreValve US Pivotal High Risk Trial was a multicenter, randomized, noninferiority trial. This retrospective analysis evaluated patients who underwent an attempted implant and had an STS PROM of 7% or less. The trial was performed at 45 US sites. Patients had severe aortic stenosis and were at increased surgical risk based on their STS PROM score and other risk factors. Interventions: Eligible patients were randomly assigned (1:1) to self-expanding TAVR or to SAVR. Main Outcomes and Measures: We retrospectively stratified patients by the overall median STS PROM score (7%) and analyzed clinical outcomes and quality of life using the Kansas City Cardiomyopathy Questionnaire in patients with an STS PROM score of 7% or less. Results: The mean (SD) ages were 81.5 (7.6) years for the TAVR group and 81.2 years (6.6) for the SAVR group. A little more than half were men (57.9% in the TAVR group and 55.8% in the SAVR group). Of 750 patients who underwent attempted implantation, 383 (202 TAVR and 181 SAVR) had an STS PROM of 7% or less (median [interquartile range]: TAVR, 5.3% [4.3%-6.1%]; SAVR, 5.3% [4.1%-5.9%]). Two-year all-cause mortality for TAVR vs SAVR was 15.0% (95% CI, 8.9-10.0) vs 26.3% (95% CI, 19.7-33.0) (log rank P = .01). The 2-year rate of stroke for TAVR vs SAVR was 11.3% vs 15.1% (log rank P = .50). Quality of life by the Kansas City Cardiomyopathy Questionnaire summary score showed significant and equivalent increases in both groups at 2 years (mean [SD] TAVR, 20.0 [25.0]; SAVR, 18.6 [23.6]; P = .71; both P < .001 compared with baseline). Medical benefit, defined as alive with a Kansas City Cardiomyopathy Questionnaire summary score of at least 60 and a less than 10-point decrease from baseline, was similar between groups at 2 years (TAVR, 51.0%; SAVR, 44.4%; P = .28). Conclusions and Relevance: Self-expanding TAVR compares favorably with SAVR in high-risk patients with STS PROM scores traditionally considered intermediate risk. Trial Registration: Clinicaltrials.gov Identifier: NCT01240902.

An Investigation of Patient Preferences for Music Played Before Electroconvulsive Therapy.

OBJECTIVE: Patients often feel anxious before electroconvulsive therapy (ECT), which can lead to avoidance of treatments. Music is a noninvasive safe option to reduce anxiety in the preoperative setting. Therefore, we examined patients' preferences of listening to music while receiving ECT by providing music-by way of headphones or speakers-to participants before treatment. METHODS: Patients receiving ECT were recruited for this study. Patients served as their own controls in 3 separate music intervention sessions: 1) randomization to music via headphones or speakers, 2) no music, 3) the remaining music intervention. Patients completed a questionnaire related to satisfaction and preferences of music being played before ECT. Patients received a final questionnaire at the end of the study asking which intervention they preferred. RESULTS: Thirty patients completed the study. Ninety percent enjoyed listening to music through speakers. Eighty percent liked listening to music through headphones. Seventeen percent preferred not having any music. The difference in preference between speakers and headphones was not significant (P = 0.563; McNemar-Bowker test). There was no association between preference at the end of the study and the initial assignment of speakers or headphones (P = 0.542 and P = 0.752, respectively; Pearson χ tests). No adverse events were reported. CONCLUSIONS: Music is a low-cost intervention with virtually no side effects that could be offered as an adjunctive therapy for patients receiving ECT. A significant proportion of patients liked hearing music before treatment.

Progesterone neuroprotection: The background of clinical trial failure.

Since the first pioneering studies in the 1990s, a large number of experimental animal studies have demonstrated the neuroprotective efficacy of progesterone for brain disorders, including traumatic brain injury (TBI). In addition, this steroid has major assets: it easily crosses the blood-brain-barrier, rapidly diffuses throughout the brain and exerts multiple beneficial effects by acting on many molecular and cellular targets. Moreover, progesterone therapies are well tolerated. Notably, increased brain levels of progesterone are part of endogenous neuroprotective responses to injury. The hormone thus emerged as a particularly promising protective candidate for TBI and stroke patients. The positive outcomes of small Phase 2 trials aimed at testing the safety and potential protective efficacy of progesterone in TBI patients then provided support and guidance for two large, multicenter, randomized and placebo-controlled Phase 3 trials, with more than 2000 TBI patients enrolled. The negative outcomes of both trials, named ProTECT III and SyNAPSE, came as a big disappointment. If these trials were successful, progesterone would have become the first efficient neuroprotective drug for brain-injured patients. Thus, progesterone has joined the numerous neuroprotective candidates that have failed in clinical trials. The aim of this review is a reappraisal of the preclinical animal studies, which provided the proof of concept for the clinical trials, and we critically examine the design of the clinical studies. We made efforts to present a balanced view of the strengths and limitations of the translational studies and of some serious issues with the clinical trials. We place particular emphasis on the translational value of animal studies and the relevance of TBI biomarkers. The probability of failure of ProTECT III and SyNAPSE was very high, and we present them within the broader context of other unsuccessful trials.

Cultural differences define diagnosis and genomic medicine practice: implications for undiagnosed diseases program in China.

Despite the current acceleration and increasing leadership of Chinese genetics research, genetics and its clinical application have largely been imported to China from the Occident. Neither genetics nor the scientific reductionism underpinning its clinical application is integral to the traditional Chinese worldview. Given that disease concepts and their incumbent diagnoses are historically derived and culturally meaningful, we hypothesize that the cultural expectations of genetic diagnoses and medical genetics practice differ between the Occident and China. Specifically, we suggest that an undiagnosed diseases program in China will differ from the recently established Undiagnosed Diseases Program at the United States National Institutes of Health; a culturally sensitive concept will integrate traditional Chinese understanding of disease with the scientific reductionism of Occidental medicine.

A silicon cell cycle in a bacterial model of calcium phosphate mineralogenesis.

The prokaryote Corynebacterium matruchotii produces calcium phosphate (bone salt) and may serve as a convenient model for examining individual factors relevant to vertebrate calcification. A factor of current clinical uncertainty is silicon. To investigate its possible role in biomineralisation advanced optical (digital deconvolution and 3D fluorescent image rendering) and electron microscopy (EDX microanalysis and elemental mapping) were applied to calcifying microbial colonies grown in graded Si concentrations (0-60mM). Cell viability was confirmed throughout by TO-PRO-3-iodide and SYTO-9 nucleic acid staining. It was observed that calcium accumulated in dense intracellular microspherical objects (types i-iii) as nanoparticles (5 nm, type i), nanospheres (30-50 nm, type ii) and filamentous clusters (0.1-0.5 µm, type iii), with a regular transitory Si content evident. With bacterial colony development (7-28 days) the P content increased from 5 to 60%, while Si was displaced from 60 to 5%, distinguishing the phenomenon from random contamination, and with a significant relationship (p<0.001) found between calcified object number and Si supplementation (optimum 0.01mM). The Si-containing, intracellular calcified objects (also positive for Mg and negative with Lysensor blue DND-167 for acidocalcisomes) were extruded naturally in bubble-like chains to complete the cycle by coating the cell surface with discrete mineral particles. These could be harvested by lysis, French press and density fractionation when Si was confirmed in a proportion. It was concluded that the unexplained orthopaedic activity of Si may derive from its special property to facilitate calcium phosphorylation in biological systems, thereby recapitulating an ancient and conserved bacterial cycle of calcification via silicification.

Circadian rhythm of blood pressure reflects the severity of cardiac impairment in familial amyloid polyneuropathy.

BACKGROUND: Cardiac amyloidosis due to familial amyloid polyneuropathy (FAP) includes restrictive cardiomyopathy, thickened cardiac walls, conduction disorders and cardiac denervation. Impaired blood pressure variability has been documented in FAP related to the Val30Met mutation. AIMS: To document blood pressure variability in FAP patients with various mutation types and its relationship to the severity of cardiac involvement. METHODS: Blood pressure variability was analysed in 49 consecutive FAP patients and was compared with a matched control population. Cardiac evaluation included echocardiography, right heart catheterization, electrophysiological study, Holter electrocardiogram and metaiodobenzylguanidine (MIBG) scintigraphy. RESULTS: A non-dipping pattern was found in 80% of FAP patients and in 35% of control patients (P<0.0001); this was due to a significantly lower diurnal blood pressure in FAP patients (FAP group, 113 ± 21 mmHg; control group, 124 ± 8 mmHg; P<0.0001), whereas nocturnal blood pressures were similar. Among FAP patients, a non-dipping pattern was significantly associated with haemodynamic involvement, cardiac thickening or conduction disorders. These associations did not depend on the average blood pressure levels. Impaired blood pressure variability was more frequent and more pronounced in patients with multiple criteria for severe cardiac amyloidosis. CONCLUSION: Low blood pressure variability is common in cardiac amyloidosis due to FAP. A non-dipping pattern was more frequently observed in FAP patients with haemodynamic impairment, cardiac thickening or conduction disorders. It is suggested that impairment of circadian rhythm of blood pressure reflects the severity of cardiac amyloidosis due to FAP.