Metabolic adaptation following gastric bypass surgery: results from a 2-year observational study.

BACKGROUND/OBJECTIVES: Metabolic adaptation is the lowering of basal metabolic rate (BMR) beyond what is predicted from changes in fat mass (FM) and fat-free mass (FFM) and may hamper weight-loss progression. It is unclear whether metabolic adaptation occurs following gastric bypass surgery (GBP) and if it persists. The aim of this study was to evaluate the reduction in BMR that is not explained by changes in body composition in patients following GBP compared to a weight-stable comparator group. SUBJECTS: Thirty-one patients [77.4% female; mean BMI 45.5(SD 7.0) kg/m2; age 47.4(11.6)y] who underwent GBP, and 32 time-matched comparators [50% female; BMI 27.2(4.6) kg/m2; age 41.8(13.6)y) were evaluated at 1-month pre-surgery, 3-, 12- and 24-months post-surgery. METHODS: BMR was measured under standardised residential conditions using indirect calorimetry and body composition using DXA. Linear regression analyses assessed metabolic adaptation post-surgery. RESULTS: After surgery, patients lost a quarter of their body weight [-25.6%(1.8%); p < 0.0001] consisting mainly of FM (4:1 FM to FFM loss ratio) at 24-months post-surgery. Absolute BMR (MJ/d) reduced by 25.7% at 24-months post-surgery with values becoming similar to the comparator group from 3-months post-surgery. Positive associations were observed between changes in BMR and changes in FFM and FM (P < 0.03). Metabolic adaptation was present in patients during the 1) rapid weight loss phase (6.9 kg/month at 3-months post-surgery) (p = 0.011), 2) slower weight loss phase (1.6 kg/month from 3 to 12-months post-surgery) (p < 0.0001), and, 3) weight maintenance phase (24-months post-surgery) (p = 0.00073). However, the degree of metabolic adaptation observed in GBP patients was similar to the weight-stable comparator group (no metabolic adaptation) from 12-months post-surgery onwards (3-months; p = 0.01, 12-months; p = 0.26, 24-months post-surgery; p = 0.70). CONCLUSION: These results suggest that there is a potential biological mechanism of surgery that attenuates the expected postoperative downregulation in BMR thus helping GBP patients maintain weight loss.

Remote monitoring of patients with rheumatoid arthritis in a low disease activity state: a mixed methods evaluation across six hospitals in London, UK.

OBJECTIVES: This study evaluated the scale-up of a remote monitoring service, capturing monthly Rheumatoid Arthritis Impact of Disease scores and patient-generated text messages, for patients with rheumatoid arthritis (RA; in remission or with low disease activity) attending routine outpatient clinics across six hospitals. We explored patients and staff experiences and implementation outcomes. METHODS: A pragmatic, mixed methods approach was used, with active patient involvement throughout. We undertook a rapid review, analysed service-level data, and conducted a patient survey and patient and staff interviews, informed by the Capability, Opportunity, Motivation, Behaviour (COM-B) and Exploration, Preparation, Implementation, Sustainment (EPIS) theoretical frameworks. RESULTS: The review included 37 articles, covering themes of patient and clinician acceptability, engagement, feasibility and clinical impact. Service-level data (n = 202) showed high levels of patient engagement with the service. The patient survey (n = 155) showed patients felt the service was easy to use, had confidence in it and felt it improved access to care. Patient interview (n = 22) findings mirrored those of the survey. Motivating factors included increased responsiveness and ease of contact with clinical teams. Views from staff interviews (n = 16) were more mixed. Some implementation barriers were specific to roll-out sites. Prioritization of staff needs was emphasized. CONCLUSION: Patients were positive about the service and engagement was high. Staff views and engagement were more mixed. Results suggest that equal levels of patient and staff engagement are required for sustainability. These findings further our understanding of the implementation challenges to scaling remote monitoring interventions for patients with rheumatoid arthritis in routine care settings.

Detunable wireless Litzcage coil for human head MRI at 1.5 T.

Inductively coupled radiofrequency (RF) coils are an inexpensive and simple method to realize wireless RF coils in magnetic resonance imaging (MRI), which can significantly ease the MRI scan setup and improve patient comfort because they do not require bulky components such as cables, baluns, preamplifiers, and connectors. However, volume-type wireless coils are typically operated in transmit/receive mode because detuning such coils is much more challenging due to their complex structure and multiple resonant modes. Meanwhile, adding too many detuning circuits to a wireless coil would decrease the coil's quality factor, impair the signal-to-noise ratio, and increase the cost. In this work, we proposed, constructed, and tested a novel wireless volume coil based on the Litzcage design for 1.5-T head imaging. Being an inductively coupled coil, it has a much simpler structure, resulting in a lighter weight and less bulky design. Despite its simpler structure, it exhibits comparable imaging performance with a commercial receive array, providing an alternative to conventional wired coils with a high cost and complex structure. The unique figure-of-8 conductor pattern within the rungs ensures that the proposed wireless Litzcage can be efficiently detuned with minimal detuning circuits.

Mitochondrial DNA replication is essential for neurogenesis but not gliogenesis in fetal neural stem cells.

Mitochondria are unique organelles that have their own genome (mtDNA) and perform various pivotal functions within a cell. Recently, evidence has highlighted the role of mitochondria in the process of stem cell differentiation, including differentiation of neural stem cells (NSCs). Here we studied the importance of mtDNA function in the early differentiation process of NSCs in two cell culture models: the CGR8-NS cell line that was derived from embryonic stem cells by a lineage selection technique, and primary NSCs that were isolated from embryonic day 14 mouse fetal forebrain. We detected a dramatic increase in mtDNA content upon NSC differentiation to adapt their mtDNA levels to their differentiated state, which was not accompanied by changes in mitochondrial transcription factor A expression. As chemical mtDNA depletion by ethidium bromide failed to generate living ρ° cell lines from both NSC types, we used inhibition of mtDNA polymerase-γ by 2'-3'-dideoxycytidine to reduce mtDNA replication and subsequently cellular mtDNA content. Inhibition of mtDNA replication upon NSC differentiation reduced neurogenesis but not gliogenesis. The mtDNA depletion did not change energy production/consumption or cellular reactive oxygen species (ROS) content in the NSC model used. In conclusion, mtDNA replication is essential for neurogenesis but not gliogenesis in fetal NSCs through as yet unknown mechanisms, which, however, are largely independent of energy/ROS metabolism.

Longitudinal analysis of cortisol changes during pubertal development in indigenous Qom girls.

Pubertal research has primarily focused on hypothalamic-pituitary-gonadal axis (HPG) regulation of puberty, though the hypothalamic-pituitary-adrenal axis (HPA) is increasingly considered critical. Heightened HPA function proxied by increasing cortisol levels may play a role in accelerated pubertal timing. However, the extent to which cortisol varies across ages and its relation to pubertal changes in linear growth are less well substantiated. We explored relationships between age, linear growth, adiposity, C-peptide (proxy for insulin), and cortisol across puberty, and we tested whether higher cortisol levels are associated with earlier ages at menarche and peak height velocity. We utilize longitudinal data (n = 777 urine samples) from Qom females ages 7-14 (n = 46) and test our pre-registered analysis using Bayesian longitudinal mixed effects models and joint modeling techniques. We find limited evidence supporting the overarching hypothesis that HPA upregulation is associated with pubertal maturation or timing. We find some evidence that HPA upregulation, as proxied by cortisol, may be more clearly related to differences in relative linear growth at early-mid puberty, as measured by height-for-age z-scores. Transdisciplinary perspectives on puberty, including the assumption that stressors acting via cortisol accelerate pubertal development, are discussed.

Magnetic resonance metrics for identification of cuprizone-induced demyelination in the mouse model of neurodegeneration: a review.

Neurodegenerative disorders, including Multiple Sclerosis (MS), are heterogenous disorders which affect the myelin sheath of the central nervous system (CNS). Magnetic Resonance Imaging (MRI) provides a non-invasive method for studying, diagnosing, and monitoring disease progression. As an emerging research area, many studies have attempted to connect MR metrics to underlying pathophysiological presentations of heterogenous neurodegeneration. Most commonly, small animal models are used, including Experimental Autoimmune Encephalomyelitis (EAE), Theiler's Murine Encephalomyelitis (TMEV), and toxin models including cuprizone (CPZ), lysolecithin, and ethidium bromide (EtBr). A contrast and comparison of these models is presented, with focus on the cuprizone model, followed by a review of literature studying neurodegeneration using MRI and the cuprizone model. Conventional MRI methods including T1 Weighted (T1W) and T2 Weighted (T2W) Imaging are mentioned. Quantitative MRI methods which are sensitive to diffusion, magnetization transfer, susceptibility, relaxation, and chemical composition are discussed in relation to studying the CPZ model. Overall, additional studies are needed to improve both the sensitivity and specificity of MRI metrics for underlying pathophysiology of neurodegeneration and the relationships in attempts to clear the clinico-radiological paradox. We therefore propose a multiparametric approach for the investigation of MR metrics for underlying pathophysiology.

Evaluation of "Care Plus," A Multidisciplinary Program to Improve Population Health for Patients With High Utilization.

With rising health care costs, health systems have adopted alternative care models targeting high-need, high-cost patients to improve chronic disease management and population health. Intensive primary care teams may reduce health care utilization by tackling medical and psychosocial needs specific to this patient population. This study presents health care utilization trends from a high-intensity primary care program that employs a multidisciplinary team (including clinicians, psychologists, pharmacists, chaplaincy, and community health workers) and community partnerships. Using descriptive statistics and Poisson rates of differences, this study evaluates patient and utilization characteristics of those enrolled (n = 341) versus declined (n = 54) program participation from 2013 to 2020. Both enrolled and declined patients experienced significant reduction in emergency department and inpatient utilization, but differences between enrolled and declined patients were not statistically significant. Programs aimed at decreasing health care utilization for high-need, high-cost, medically complex patients may be best supported by interventions that simultaneously address social and behavioral health needs.

A Cost-Effectiveness Model to Determine Ostomy-Related Costs of Care and Health Outcomes Among People With an Ostomy in Canada Using a Ceramide-Infused Skin Barrier.

PURPOSE: The aim of this study was to determine whether a difference exists in the financial impact of the use of a 2-piece ceramide-infused skin barrier (CIB) versus standard of care barrier (SOC) in Ontario and Alberta using a cost-effectiveness model over a 1-year period for people with a fecal or urinary ostomy. DESIGN: A cost-effectiveness model adapted from a previously published work. SUBJECTS AND SETTING: The model was populated with data inputs from a hypothetical cohort of 1000 individuals in Ontario and 4000 in Alberta. Model results were assessed for robustness via the use of deterministic and probabilistic sensitivity analyses. The provinces of Ontario and Alberta were chosen because cost data were readily accessible. The combined population of these provinces accounts for 50% of Canada's population. RESULTS: An expected cost savings of Can$443.13 (US $322.60) and Can$243.84 (US $177.52) per user for the hypothetical cohort of 1000 individuals in Ontario and 4000 in Alberta per year was obtained for those using a CIB versus a non-infused skin barrier in Ontario and Alberta, respectively. The incremental cost effectiveness ratio (ICER) of CIB to SOC per peristomal skin complication (PSC) avoided and per quality-adjusted life day (QALD) gained was approximately Can$2702 (US $1967)/PSC and Can$1266 (US $922)/QALD for Ontario and approximately Can$1487 (US $1083)/PSC and Can$697 (US $507)/QALD for Alberta. Analysis indicated CIBs remained cost-effective across all sensitivity analyses performed. CONCLUSIONS: Finding suggest that a CIB is cost-effective when compared to a barrier not infused with ceramide when applied to persons with an ostomy and residing in the provinces of Alberta and Ontario.

When idiopathic male infertility is rooted in maternal malnutrition during the perinatal period in mice†.

Infertility represents a growing burden worldwide, with one in seven couples presenting difficulties conceiving. Among these, 10-15% of the men have idiopathic infertility that does not correlate with any defect in the classical sperm parameters measured. In the present study, we used a mouse model to investigate the effects of maternal undernutrition on fertility in male progeny. Our results indicate that mothers fed on a low-protein diet during gestation and lactation produce male offspring with normal sperm morphology, concentration, and motility but exhibiting an overall decrease of fertility when they reach adulthood. Particularly, in contrast to control, sperm from these offspring show a remarkable lower capacity to fertilize oocytes when copulation occurs early in the estrus cycle relative to ovulation, due to an altered sperm capacitation. Our data demonstrate for the first time that maternal nutritional stress can have long-term consequences on the reproductive health of male progeny by affecting sperm physiology, especially capacitation, with no observable impact on spermatogenesis and classical quantitative and qualitative sperm parameters. Moreover, our experimental model could be of major interest to study, explain, and ultimately treat certain categories of infertilities.

Food Intake Following Gastric Bypass Surgery: Patients Eat Less but Do Not Eat Differently.

BACKGROUND: Lack of robust research methodology for assessing ingestive behavior has impeded clarification of the mediators of food intake following gastric bypass (GBP) surgery. OBJECTIVES: To evaluate changes in directly measured 24-h energy intake (EI), energy density (ED) (primary outcomes), eating patterns, and food preferences (secondary outcomes) in patients and time-matched weight-stable comparator participants. METHODS: Patients [n = 31, 77% female, BMI (in kg/m2) 45.5 ± 1.3] and comparators (n = 32, 47% female, BMI 27.2 ± 0.8) were assessed for 36 h under fully residential conditions at baseline (1 mo presurgery) and at 3 and 12 mo postsurgery. Participants had ad libitum access to a personalized menu (n = 54 foods) based on a 6-macronutrient mix paradigm. Food preferences were assessed by the Leeds Food Preference Questionnaire. Body composition was measured by whole-body DXA. RESULTS: In the comparator group, there was an increase in relative fat intake at 3 mo postsurgery; otherwise, no changes were observed in food intake or body composition. At 12 mo postsurgery, patients lost 27.7 ± 1.6% of initial body weight (P < 0.001). The decline in EI at 3 mo postsurgery (-44% from baseline, P < 0.001) was followed by a partial rebound at 12 mo (-18% from baseline), but at both times, dietary ED and relative macronutrient intake remained constant. The decline in EI was due to eating the same foods as consumed presurgery and by decreasing the size (g, MJ), but not the number, of eating occasions. In patients, reduction in explicit liking at 3 mo (-11.56 ± 4.67, P = 0.007) and implicit wanting at 3 (-15.75 ± 7.76, P = 0.01) and 12 mo (-15.18 ± 6.52, P = 0.022) for sweet foods were not matched by reduced intake of these foods. Patients with the greatest reduction in ED postsurgery reduced both EI and preference for sweet foods. CONCLUSIONS: After GBP, patients continue to eat the same foods but in smaller amounts. These findings challenge prevailing views about the dynamics of food intake following GBP surgery. This trial was registered as clinicaltrials.gov as NCT03113305.

Human Milk Oligosaccharide Compositions Illustrate Global Variations in Early Nutrition.

BACKGROUND: Human milk oligosaccharides (HMOs) are an abundant class of compounds found in human milk and have been linked to the development of the infant, and specifically the brain, immune system, and gut microbiome. OBJECTIVES: Advanced analytical methods were used to obtain relative quantitation of many structures in approximately 2000 samples from over 1000 mothers in urban, semirural, and rural sites across geographically diverse countries. METHODS: LC-MS-based analytical methods were used to profile the compounds with broad structural coverage and quantitative information. The profiles revealed their structural heterogeneity and their potential biological roles. Comparisons of HMO compositions were made between mothers of different age groups, lactation periods, infant sexes, and residing geographical locations. RESULTS: A common behavior found among all sites was a decrease in HMO abundances during lactation until approximately postnatal month 6, where they remained relatively constant. The greatest variations in structural abundances were associated with the presence of α(1,2)-fucosylated species. Genomic analyses of the mothers were not performed; instead, milk was phenotyped according to the abundances of α(1,2)-fucosylated structures. Mothers from the South American sites tended to have higher proportions of phenotypic secretors [mothers with relatively high concentrations of α(1,2)-fucosylated structures] in their populations compared to the rest of the globe, with Bolivia at ∼100% secretors, Peru at ∼97%, Brazil at ∼90%, and Argentina at ∼85%. Conversely, the cohort sampled in Africa manifested the lowest proportion of secretors (South Africa ∼ 63%, the Gambia ∼ 64%, and Malawi ∼ 75%). Furthermore, we compared total abundances of HMOs in secretors compared with nonsecretors and found that nonsecretors have lower abundances of HMOs compared to secretors, regardless of geographical location. We also observed compositional differences of the 50+ most abundant HMOs between milk types and geographical locations. CONCLUSIONS: This study represents the largest structural HMO study to date and reveals the general behavior of HMOs during lactation among different populations.

[Epistaxis Requiring Intervention After Swab for SARS-CoV-2]. / Interventionsbedürftige Epistaxis nasi nach SARS-CoV-2-Abstrich.

INTRODUCTION: Since May 2020, the first nasopharyngeal POC tests for SARS-CoV-2 diagnostic have been available. Due to the long passage through the nasal cavity, there is a risk of injury with subsequent epistaxis. METHODS: We describe the course of disease of two female patients who suffered from massive epistaxis requiring intervention after an externally performed nasopharyngeal swab. RESULTS: After nasal tamponade, one patient underwent clipping of the sphenopalatine artery under general anesthesia. The other patient suffered from nasal bleeding with hemorrhagic shock requiring transfusion. She was intubated and admitted to our hospital. CONCLUSION: The nasopharyngeal swab for diagnosis of SARS-CoV-2 can lead to life-threatening complications in rare cases. Considering that daily more than 5 million corona tests are being carried out worldwide as part of the current pandemic, complications should not be neglected. It is necessary that the person performing the swab has a detailed understanding of the anatomy involved. Alternative test methods were further assessed with regard to their sensitivity. With regard to the future need for SARS-CoV-2 tests, alternative and lower-risk test procedures must be investigated and established.

Comparing helpful and hindering processes in good and poor outcome cases: A qualitative metasynthesis of eight Hermeneutic Single Case Efficacy Design studies.

Objective: We tested qualitative metasynthesis of a series of Hermeneutic Single Case Efficacy Design (HSCED) studies as a method for comparing within-session processes that may explain good and poor therapeutic outcome. Method: We selected eight HSCED studies according to change in clients' scores on the Strathclyde Inventory (SI), a brief self-report instrument used to measure outcome in person-centered psychotherapy. Four of the case studies investigated the experience of clients whose pre-post change in SI scores showed improvement by the end of therapy, and the other four focused on clients whose change in SI scores indicated deterioration. We conducted a qualitative metasynthesis, adopting a generic descriptive-interpretive approach to analyze and compare the data generated by the HSCED studies. Results: In contrast to improvers, deteriorators appeared to be less ready to engage in therapeutic work at the beginning of therapy, and found the process more difficult; their therapists were less able to respond to these difficulties in a responsive, empathic manner; deteriorators were less able to cope successfully with changes of therapist and, eventually, gave up on therapy. Conclusion: We found that our qualitative metasynthesis of a series of HSCED studies produced a plausible explanation for the contrasting outcomes that occurred.

Myeloid malignancies with translocation t(4;12)(q11-13;p13): molecular landscape, clonal hierarchy and clinical outcomes.

Translocation t(4;12)(q11-13;p13) is a recurrent but very rare chromosomal aberration in acute myeloid leukaemia (AML) resulting in the non-constant expression of a CHIC2/ETV6 fusion transcript. We report clinico-biological features, molecular characteristics and outcomes of 21 cases of t(4;12) including 19 AML and two myelodysplastic syndromes (MDS). Median age at the time of t(4;12) was 78 years (range, 56-88). Multilineage dysplasia was described in 10 of 19 (53%) AML cases and CD7 and/or CD56 expression in 90%. FISH analyses identified ETV6 and CHIC2 region rearrangements in respectively 18 of 18 and 15 of 17 studied cases. The t(4;12) was the sole cytogenetic abnormality in 48% of cases. The most frequent associated mutated genes were ASXL1 (n = 8/16, 50%), IDH1/2 (n = 7/16, 44%), SRSF2 (n = 5/16, 31%) and RUNX1 (n = 4/16, 25%). Interestingly, concurrent FISH and molecular analyses showed that t(4;12) can be, but not always, a founding oncogenic event. Median OS was 7.8 months for the entire cohort. In the 16 of 21 patients (76%) who received antitumoral treatment, overall response and first complete remission rates were 37% and 31%, respectively. Median progression-free survival in responders was 13.7 months. Finally, t(4;12) cases harboured many characteristics of AML with myelodysplasia-related changes (multilineage dysplasia, MDS-related cytogenetic abnormalities, frequent ASXL1 mutations) and a poor prognosis.

Nonischemic cardiomyopathy with reduced ejection fraction secondary to hyperthyroidism.

ABSTRACT: Dilated cardiomyopathy is a form of heart failure characterized by left ventricular dilation with impaired systolic function. Causes may include ischemic heart disease, hypertensive heart disease, valvular heart disease, endocrine disorders, substance use, and viral diseases. This case report describes a patient with new-onset heart failure, initially diagnosed as idiopathic dilated cardiomyopathy with pericarditis secondary to a virus but later found to be secondary to hyperthyroidism.

A Systematic Review of the Effects of Perinatal Alcohol Exposure and Perinatal Marijuana Exposure on Adult Neurogenesis in the Dentate Gyrus.

BACKGROUND: Marijuana and alcohol are both substances that, when used during pregnancy, may have profound effects on the developing fetus. There is evidence to suggest that both drugs have the capacity to affect working memory, one function of the hippocampal formation; however, there is a paucity of data on how perinatal exposure to alcohol or cannabis impacts the process of adult neurogenesis. METHODS: This systematic review examines immunohistochemical data from adult rat and mouse models that assess perinatal alcohol or perinatal marijuana exposure. A comprehensive list of search terms was designed and used to search 3 separate databases. All results were imported to Mendeley and screened by 2 authors. Consensus was reached on a set of final papers that met the inclusion criteria, and their results were summarized. RESULTS: Twelve papers were identified as relevant, 10 of which pertained to the effects of perinatal alcohol on the adult hippocampus, and 2 pertained to the effects of perinatal marijuana on the adult hippocampus. Cellular proliferation in the dentate gyrus was not affected in adult rats and mice exposed to alcohol perinatally. In general, perinatal alcohol exposure did not have a significant and reliable effect on the maturation and survival of adult born granule neurons in the dentate gyrus. In contrast, interneuron numbers appear to be reduced in the dentate gyrus of adult rats and mice exposed perinatally to alcohol. Perinatal marijuana exposure was also found to reduce inhibitory interneuron numbers in the dentate gyrus. CONCLUSIONS: Perinatal alcohol exposure and perinatal marijuana exposure both act on inhibitory interneurons in the hippocampal formation of adult rats. These findings suggest simultaneous perinatal alcohol and marijuana exposure (SAM) may have a dramatic impact on inhibitory processes in the dentate gyrus.

Plasma concentrations and ACE-inhibitory effects of tryptophan-containing peptides from whey protein hydrolysate in healthy volunteers.

PURPOSE: The tryptophan-containing dipeptides isoleucine-tryptophan (IW) and tryptophan-leucine (WL) are angiotensin-converting enzyme (ACE)-inhibitors in vitro. These peptides are released by enzymatic hydrolysis of bovine whey protein. To exhibit ACE inhibition in vivo, peptides need to be absorbed into the circulatory system. This study aimed to determine the in vivo ACE-inhibitory potency of a whey protein hydrolysate (MPH), containing IW and WL, and to quantify plasma concentrations of these peptides after oral administration of MPH in healthy volunteers. Additionally, changes in blood pressure were investigated. RESULTS: After intake of 5 and 50 g MPH, plasma ACE activity was reduced to 86.4 ± 5.9 and 75.1 ± 6.9% of baseline activity, respectively. Although a clear ACE inhibition was measured, no effect on blood pressure was seen. Basal plasma concentrations of the tryptophan-containing dipeptides were 2.8 ± 0.7 nM for IW and 10.1 ± 1.8 nM for WL. After intake of 5-50 g MPH, peptide concentrations were dose dependently elevated to values between 12.5 ± 8.4 and 99.1 ± 58.7 nM for IW and 15.0 ± 4.3-34.9 ± 19.4 nM for WL. Administration of intact whey protein showed a minor ACE inhibition, probably caused by release of inhibitory peptides during gastrointestinal digestion. The increase of WL in plasma after intake of intact protein was similar to that determined after intake of MPH. In contrast, resulting IW concentrations were much lower after intake of intact whey protein when compared to MPH administration. CONCLUSION: After intake of MPH, plasma ACE activity decreased in parallel to the increase of IW and WL plasma concentrations. However, the resulting peptide concentrations cannot fully explain the reduction of ACE activity in plasma with a direct enzyme inhibition. Therefore, this study points to a gap in the understanding of the inhibitory action of these peptides in vivo. Thus, to further develop innovative food additives with ACE activity diminishing capabilities, it appears mandatory to better characterize the mode of action of these peptides.

The impact of SOCS1 mutations in diffuse large B-cell lymphoma.

Mutations in SOCS1 are frequent in primary mediastinal B-cell lymphoma and classical Hodgkin lymphoma. In the latter, SOCS1 mutations affect the length of the encoded protein (major mutations) and are associated with shorter patient survival. Two independent studies examined the prognostic impact of SOCS1 mutations in diffuse large B-cell lymphoma (DLBCL) and showed differing results. This may be due to the small number of included patients, the heterogeneity of patients' demographics and the distinct treatment schemes in these studies. To overcome the size limitations of these previous studies, we assessed SOCS1 mutations in the RICOVER-60 cohort. The cohort uniformly consists of elderly patients (aged 61-80 years) treated with the CHOP-14 scheme (cyclophosphamide, hydroxydaunorubicin, vincristine, prednisolone at 14-day intervals) with or without an additional rituximab treatment. Patient outcomes were analysed with regard to overall SOCS1 mutation frequency, major and minor mutations and a novel impact-based classifier - against the treatment modalities. Patients harbouring putative pathogenic SOCS1 mutations showed significant reduced overall survival within the CHOP plus rituximab group. Hence, putative pathogenic SOCS1 mutations seem to efface the beneficial effect of the therapeutic CD20 antibody. Comparing published data of whole exome and transcriptome sequencing of a large DLBCL cohort confirmed that predicted deleterious SOCS1 mutations forecast pre-eminent survival in early onset DLBCL.

Clinical study of 19 patients with SCN8A-related epilepsy: Two modes of onset regarding EEG and seizures.

OBJECTIVE: To describe the mode of onset of SCN8A-related severe epilepsy in order to facilitate early recognition, and eventually early treatment with sodium channel blockers. METHODS: We reviewed the phenotype of patients carrying a mutation in the SCN8A gene, among a multicentric cohort of 638 patients prospectively followed by several pediatric neurologists. We focused on the way clinicians made the diagnosis of epileptic encephalopathy, the very first symptoms, electroencephalography (EEG) findings, and seizure types. We made genotypic/phenotypic correlation based on epilepsy-associated missense variant localization over the protein. RESULTS: We found 19 patients carrying a de novo mutation of SCN8A, representing 3% of our cohort, with 9 mutations being novel. Age at onset of epilepsy was 1 day to 16 months. We found two modes of onset: 12 patients had slowly emerging onset with rare and/or subtle seizures and normal interictal EEG (group 1). The first event was either acute generalized tonic-clonic seizure (GTCS; Group 1a, n = 6) or episodes of myoclonic jerks that were often mistaken for sleep-related movements or other movement disorders (Group 1b, n = 6). Seven patients had a sudden onset of frequent tonic seizures or epileptic spasms with abnormal interictal EEG leading to rapid diagnosis of epileptic encephalopathy. Sodium channel blockers were effective or nonaggravating in most cases. SIGNIFICANCE: SCN8A is the third most prevalent early onset epileptic encephalopathy gene and is associated with two modes of onset of epilepsy.

Effects of natural peptides from food proteins on angiotensin converting enzyme activity and hypertension.

Cardiovascular diseases are the leading cause of death. The underlying pathophysiology is largely contributed by an overactivation of the renin-angiotensin-aldosterone-system (RAAS). Herein, angiotensin II (AngII) is a key mediator not only in blood pressure control and vascular tone regulation, but also involved in inflammation, endothelial dysfunction, atherosclerosis, hypertension and congestive heart failure. Since more than three decades suppression of AngII generation by inhibition of the angiotensin-converting enzyme (ACE) or blockade of the AngII-receptor has shown clinical benefit by reducing hypertension, atherosclerosis and other inflammation-associated cardiovascular diseases. Besides pharmaceutical ACE-inhibitors some natural peptides derived from food proteins reduce in vitro ACE activity. Several animal studies and a few human clinical trials have shown antihypertensive effects of such peptides, which might be attractive as food additives to prevent age-related RAAS activation. However, their inhibitory potency on in vitro ACE activity does not always correlate with an antihypertensive impact. While some peptides with high inhibitory activity on ACE-activity in vitro show no antihypertensive effect in vivo, other peptides with only a moderate ACE inhibitory activity in vitro cause such effects. The explanation for this conflicting phenomenon between inhibitory activity and antihypertensive effect remains unclear to date. This review shall critically address the effects of natural peptides derived from different food proteins on the cardiovascular system and the possible underlying mechanisms. A central aspect will be to point to conceptual gaps in the current understanding of the action of these peptides with respect to in vivo blood pressure lowering effects.