Metabolic networks of the human gut microbiota.

The human gut microbiota controls factors that relate to human metabolism with a reach far greater than originally expected. Microbial communities and human (or animal) hosts entertain reciprocal exchanges between various inputs that are largely controlled by the host via its genetic make-up, nutrition and lifestyle. The composition of these microbial communities is fundamental to supply metabolic capabilities beyond those encoded in the host genome, and contributes to hormone and cellular signalling that support the dynamic adaptation to changes in food availability, environment and organismal development. Poor functional exchange between the microbial communities and their human host is associated with dysbiosis, metabolic dysfunction and disease. This review examines the biology of the dynamic relationship between the reciprocal metabolic state of the microbiota-host entity in balance with its environment (i.e. in healthy states), the enzymatic and metabolic changes associated with its imbalance in three well-studied diseases states such as obesity, diabetes and atherosclerosis, and the effects of bariatric surgery and exercise.

Effects of Optimization Technique on Simulated Muscle Activations and Forces.

Two optimization techniques, static optimization (SO) and computed muscle control (CMC), are often used in OpenSim to estimate the muscle activations and forces responsible for movement. Although differences between SO and CMC muscle function have been reported, the accuracy of each technique and the combined effect of optimization and model choice on simulated muscle function is unclear. The purpose of this study was to quantitatively compare the SO and CMC estimates of muscle activations and forces during gait with the experimental data in the Gait2392 and Full Body Running models. In OpenSim (version 3.1), muscle function during gait was estimated using SO and CMC in 6 subjects in each model and validated against experimental muscle activations and joint torques. Experimental and simulated activation agreement was sensitive to optimization technique for the soleus and tibialis anterior. Knee extension torque error was greater with CMC than SO. Muscle forces, activations, and co-contraction indices tended to be higher with CMC and more sensitive to model choice. CMC's inclusion of passive muscle forces, muscle activation-contraction dynamics, and a proportional-derivative controller to track kinematics contributes to these differences. Model and optimization technique choices should be validated using experimental activations collected simultaneously with the data used to generate the simulation.

A feedback loop between dipeptide-repeat protein, TDP-43 and karyopherin-α mediates C9orf72-related neurodegeneration.

Accumulation and aggregation of TDP-43 is a major pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia. TDP-43 inclusions also characterize patients with GGGGCC (G4C2) hexanucleotide repeat expansion in C9orf72 that causes the most common genetic form of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Functional studies in cell and animal models have identified pathogenic mechanisms including repeat-induced RNA toxicity and accumulation of G4C2-derived dipeptide-repeat proteins. The role of TDP-43 dysfunction in C9ALS/FTD, however, remains elusive. We found G4C2-derived dipeptide-repeat protein but not G4C2-RNA accumulation caused TDP-43 proteinopathy that triggered onset and progression of disease in Drosophila models of C9ALS/FTD. Timing and extent of TDP-43 dysfunction was dependent on levels and identity of dipeptide-repeat proteins produced, with poly-GR causing early and poly-GA/poly-GP causing late onset of disease. Accumulating cytosolic, but not insoluble aggregated TDP-43 caused karyopherin-α2/4 (KPNA2/4) pathology, increased levels of dipeptide-repeat proteins and enhanced G4C2-related toxicity. Comparable KPNA4 pathology was observed in both sporadic frontotemporal dementia and C9ALS/FTD patient brains characterized by its nuclear depletion and cytosolic accumulation, irrespective of TDP-43 or dipeptide-repeat protein aggregates. These findings identify a vicious feedback cycle for dipeptide-repeat protein-mediated TDP-43 and subsequent KPNA pathology, which becomes self-sufficient of the initiating trigger and causes C9-related neurodegeneration.

Impact of renal impairment on outcomes with lenalidomide and dexamethasone treatment in the FIRST trial, a randomized, open-label phase 3 trial in transplant-ineligible patients with multiple myeloma.

Renal impairment is associated with poor prognosis in myeloma. This analysis of the pivotal phase 3 FIRST trial examined the impact of renally adapted dosing of lenalidomide and dexamethasone on outcomes of patients with different degrees of renal impairment. Transplant-ineligible patients not requiring dialysis were randomized 1:1:1 to receive continuous lenalidomide and dexamethasone until disease progression (n=535) or for 18 cycles (72 weeks; n=541), or melphalan, prednisone, and thalidomide for 12 cycles (72 weeks; n=547). Follow-up is ongoing. Patients were grouped by baseline creatinine clearance into no (≥ 80 mL/min [n=389]), mild (≥ 50 to < 80 mL/min [n=715]), moderate (≥ 30 to < 50 mL/min [n=372]), and severe impairment (< 30 mL/min [n=147]) subgroups. Continuous lenalidomide and dexamethasone therapy reduced the risk of progression or death in no, mild, and moderate renal impairment subgroups vs. melphalan, prednisone, and thalidomide therapy (HR = 0.67, 0.70, and 0.65, respectively). Overall survival benefits were observed with continuous lenalidomide and dexamethasone treatment vs. melphalan, prednisone, and thalidomide treatment in no or mild renal impairment subgroups. Renal function improved from baseline in 52.6% of lenalidomide and dexamethasone-treated patients. The safety profile of continuous lenalidomide and dexamethasone was consistent across renal subgroups, except for grade 3/4 anemia and rash, which increased with increasing severity of renal impairment. Continuous lenalidomide and dexamethasone treatment, with renally adapted lenalidomide dosing, was effective for most transplant-ineligible patients with myeloma and renal impairment. Trial registration: ClinicalTrials.gov (NCT00689936); EudraCT (2007-004823-39). Funding: Intergroupe Francophone du Myélome and the Celgene Corporation.

Effect of continuous positive airway pressure treatment for obstructive sleep apnoea on visual processing of degraded words.

BACKGROUND: In a previous uncontrolled study, continuous positive airway pressure (CPAP) therapy for obstructive sleep apnoea (OSA) improved vision in patients with diabetic macular oedema. OBJECTIVES: We investigated whether the above improvement in vision (or visual processing) might have been due to reduced sleepiness, rather than a true improvement in retinal function. METHODS: Twelve normal control subjects and 20 patients with OSA were tested for their ability to recognise degraded words, by means of a computer programme displaying 5-letter words every 4 s for 10 min, with variable amounts of the bottom half of the word missing; the percentage of the word necessary to achieve correct identification on average half the time was 'hunted' (the test score). All subjects were tested twice, 2-3 weeks apart; the OSA group after the commencement of CPAP. The Epworth Sleepiness Score (ESS) in patients was measured at the same visit. RESULTS: The test score at visit 1 was 26.7% for normal subjects and 31.6% for patients with OSA. At visit 2, the test score was 25.0% for normal subjects and 29.9% for patients with OSA. The groups showed a small and identical improvement over the trial period in the test score, of 1.7% (p = 0.01 and p = 0.03 for the normal and OSA groups, respectively). The group with OSA experienced a drop in ESS of 7.5 (SD 5.5) points following treatment. CONCLUSION: The small and identical improvement in both groups suggests only a similar learning effect rather than any improvement due to reduced sleepiness.

Enhancing the Tribological Properties of Low-Density Polyethylene Using Hard Carbon Microfillers.

The application of low-density polyethylene (LDPE) has been confined to packaging applications due to its inadequate mechanical and tribological characteristics. We propose enhancing LDPE by integrating hard carbon spheres (CSs) to improve its strength, frictional characteristics, and wear resistance. LDPE/CS composites were created by blending LDPE with varying CS amounts (0.5-8 wt.%). Analysis using scanning electron microscopy and Raman spectroscopy confirmed CS presence in the LDPE matrix, with X-ray diffraction showing no microstructural changes post-blending. Thermal characterization exhibited notable improvements in thermal stability (~4%) and crystallinity (~7%). Mechanical properties such as hardness and Young's modulus were improved by up to 4% and 24%, respectively. Tribological studies on different composite samples with varying surface roughness under various load and speed conditions revealed the critical role of surface roughness in reducing friction by decreasing real contact area and adhesive interactions between asperities. Increased load and speed amplified shear stress on asperities, possibly leading to deformation and failure. Notably, integrating CSs into LDPE, starting at 1 wt.%, effectively reduced friction and wear. The composite with the highest loading (8 wt.%) displayed the most significant tribological enhancement, achieving a remarkable 75% friction reduction and a substantial 78% wear reduction.

High grade phyllodes tumor with osteosarcomatous differentiation: Case report and review of the literature.

Phyllodes tumors (PTs) are rare fibroepithelial malignancies of the breast, accounting for less than 1% of malignant breast tumors. PTs are usually solitary tumors but can be associated with other malignancies, such as DCIS or invasive carcinomas and sarcomas. Osteosarcomatous differentiation of a malignant phyllodes tumor is rare, and differentiation of this rare breast tumor from other entities is of vital importance to clinicians due for appropriate treatment and prognosis. We present a case of rare high-grade phyllodes tumor with osteosarcomatous differentiation presenting on mammogram as a calcified lobulated mass; ultrasound revealed a 1.5 cm irregularly calcified mass, suggestive of bone. An ultrasound-guided core biopsy and subsequent lumpectomy revealed a cellular stroma with osteoid stromal matrix and cytologic atypia with bone formation. At 18 months postprocedure, a recurrence was identified at the previous surgical site, and the patient underwent a mastectomy. Here we present a single case of high-grade PT with osteosarcomatous differentiation and a comprehensive literature review, highlighting the mammographic and histologic characteristics of this rare presentation.

A Prospective Cohort Study on the Periparturient Muscle Tissue Mobilisation in High Producing Dairy Cows.

Excessive periparturient fat mobilisation and its association with dairy cattle health and fertility is well documented; however, the role of muscle mobilisation has not been studied extensively. The objectives of this study were to (i) investigate the changes in the thickness of the longissimus dorsi muscle in high producing dairy cows during the periparturient period, (ii) identify factors associated with these changes, and (iii) describe their possible associations with cattle reproductive performance. Data were collected from a total of 500 lactations from 455 cows on three different UK farms. Muscle thickness (MT) (Longissimus dorsi) and back fat thickness (BFT) measurements were collected at three different time-points during the periparturient period using ultrasonography. Body condition score (BCS) was also assessed at the same time-points and blood samples were collected for the measurement of non-esterified fatty acids. Farm fertility records were used and genomically estimated breeding values were also available. Associations between variables were analysed with the use of multivariable linear and logistic regression models; Cox proportional hazard analysis was used for fertility outcomes. Muscle thickness decreased pre- to post-calving on all three farms, though they were notable between farm differences. Those animals with a lower BCS pre-calving had a higher MT loss; significant fat mobilisation occurred between the calving and early lactation period. Muscle thickness changes and fat mobilisation were not associated in this study. An increased time to first service was described for those animals that mobilised more muscle tissue. Our study advances the understanding of periparturient muscle tissue mobilisation in dairy cattle and highlights its potential associations with cattle fertility.

Subjective social status is associated with happiness but not weight status or psychological distress: An analysis of three prospective birth cohorts from low- and middle-income countries.

Background: Subjective social status (SSS, perception of social position relative to a frame of reference) has been associated with physical, mental and socio-emotional wellbeing. However, these associations may be susceptible to unmeasured confounding by life course objective socio-economic position (SEP; such as wealth, education and employment) and life satisfaction. Purpose: To estimate the association of position on ladders of perceived community respect and perceived economic status with weight, distress and wellbeing, independent of objective SEP in cohorts from three low and middle-income countries. Methods: We used data from birth cohorts in Guatemala (n = 1258), Philippines (n = 1323) and South Africa (n = 1393). We estimated the association of perceived community respect and perceived economic status with body mass index (kg/m2), the World Health Organization's Self-Reported Questionnaire-20 (SRQ-20) for psychological distress, and Lyubomirsky's Subjective Happiness Scale. We estimated these associations using robust linear regression models adjusting for indicators of life course objective SEP, early life characteristics, adult covariates, and life satisfaction. Results: Participants in South Africa (age 27-28y) rated themselves higher on average for both the respect (7 vs 5 in Guatemala and 6 in Philippines) and economic (5 vs 3 in Guatemala and 4 in Philippines) ladder measures. Position on neither community respect nor economic ladders were associated with BMI or psychological distress. Higher position on community respect (Guatemala: 0.03, 95%CI: 0.01, 0.04; Philippines: 0.03, 95% CI: 0.02, 0.05; South Africa: 0.07, 95%CI: 0.04, 0.09) and economic (Guatemala: 0.02, 95%CI: 0, 0.04; Philippines: 0.04, 95%CI: 0.02, 0.07; South Africa: 0.07, 95%CI: 0.04, 0.10) ladders were associated with greater happiness. Conclusions: Subjective social status showed small but consistent associations with happiness in birth cohorts independent of life-course SEP.

Factors influencing the outcome of a second autologous stem cell transplant (ASCT) in relapsed multiple myeloma: a study from the British Society of Blood and Marrow Transplantation Registry.

Autologous stem cell transplant as primary (first ASCT) therapy in multiple myeloma (MM) is standard practice. The role of a second ASCT as management of relapsed disease remains uncertain. We conducted a retrospective case-matched control analysis on patients (n = 106) who underwent a second ASCT compared with conventional chemotherapy (CCT) as for relapsed MM. The median age was 53 years (range: 26-75) and median follow-up 48 months (range: 8, 136). The cumulative incidence of 1 and 5 years nonrelapse mortality (NRM) was 7% (95% confidence interval [CI] 3%-13%) and 12% (95% CI 7%-19%), with a second ASCT inducing a greater partial remission (PR) rate of 63%. The 4-year overall survival (OS) rate was 33% (95% CI 24%-45%). Factors associated with improved OS and progression-free survival (PFS) included younger age (<55 years), ß(2)MG <2.5 mg/L at diagnosis, a remission duration of >9 months from first ASCT, and a greater PR in response to their first ASCT. In a matched-cohort analysis with patients receiving conventional chemotherapy (CCT), the same factors were associated with improved OS, with the exception of a longer remission duration (>18 months) from first ASCT. Second ASCT in relapsed MM is associated with superior OS and PFS compared with CCT, offering a potential consolidative option for selected patients.

Socioeconomic position over the life-course and subjective social status in relation to nutritional status and mental health among Guatemalan adults.

OBJECTIVE: We study how life course objective socioeconomic position (SEP) predicts subjective social status (SSS) and the extent to which SSS mediates the association of objective SEP with nutritional status and mental health outcomes. METHODS: We use data from participants of the INCAP Longitudinal Study 1969-2018 (n = 1258) from Guatemala. We use the MacArthur ladder for two measures of SSS - perceived community respect and perceived economic status. We estimate the association of SSS with health outcomes after adjusting for early life characteristics and life course objective SEP (wealth, schooling, employment) using linear regression. We use path analysis to study the extent of mediation by SSS on the health outcomes of body mass index (BMI; kg/m2), psychological distress (using the WHO Self-Reported Questionnaire; SRQ-20) and happiness, using the Subjective Happiness Scale (SHS). RESULTS: Median participant rating was 5 [IQR: 3-8] for the perceived community respect and 3 [IQR: 1-5] for the perceived economic status, with no differences by sex. Objective SEP in early life and adulthood were predictive of both measures of SSS in middle adulthood as well as health outcomes (BMI, SRQ-20 and SHS). Perceived community respect (z-scores; 1 z = 3.1 units) was positively associated with happiness (0.13, 95 % CI: 0.07, 0.19). Perceived economic status (z-scores; 1 z = 2.3 units) was inversely associated with psychological distress (-0.28, 95 % CI: -0.47, -0.09). Neither measure of SSS was associated with BMI. Neither perceived community respect nor perceived economic status attenuated associations of objective SEP with health outcomes on inclusion as a mediator. CONCLUSIONS: Subjective social status was independently associated with happiness and psychological distress in middle adulthood after adjusting for objective SEP. Moreover, association of objective SEP with health was not mediated by SSS, suggesting potentially independent pathways.

The role of nitric oxide and reactive oxygen species in the positive inotropic response to mechanical stretch in the mammalian myocardium.

The endothelial nitric oxide synthase (eNOS) has been implicated in the rapid (Frank-Starling) and slow (Anrep) cardiac response to stretch. Our work and that of others have demonstrated that a neuronal nitric oxide synthase (nNOS) localized to the myocardium plays an important role in the regulation of cardiac function and calcium handling. However, the effect of nNOS on the myocardial response to stretch has yet to be investigated. Recent evidence suggests that the stretch-induced release of angiotensin II (Ang II) and endothelin 1 (ET-1) stimulates myocardial superoxide production from NADPH oxidases which, in turn, contributes to the Anrep effect. nNOS has also been shown to regulate the production of myocardial superoxide, suggesting that this isoform may influence the cardiac response to stretch or ET-1 by altering the NO-redox balance in the myocardium. Here we show that the increase in left ventricular (LV) myocyte shortening in response to the application of ET-1 (10 nM, 5 min) did not differ between nNOS(-/-) mice and their wild type littermates (nNOS(+/+)). Pre-incubating LV myocytes with the NADPH oxidase inhibitor, apocynin (100 microM, 30 min), reduced cell shortening in nNOS(-/-) myocytes only but prevented the positive inotropic effects of ET-1 in both groups. Superoxide production (O(2)(-)) was enhanced in nNOS(-/-) myocytes compared to nNOS(+/+); however, this difference was abolished by pre-incubation with apocynin. There was no detectable increase in O(2)(-) production in ET-1 pre-treated LV myocytes. Inhibition of protein kinase C (chelerythrine, 1 microM) did not affect cell shortening in either group, however, protein kinase A inhibitor, PKI (2 microM), significantly reduced the positive inotropic effects of ET-1 in both nNOS(+/+) and nNOS(-/-) myocytes. Taken together, our findings show that the positive inotropic effect of ET-1 in murine LV myocytes is independent of nNOS but requires NADPH oxidases and protein kinase A (PKA)-dependent signaling. These results may further our understanding of the signaling pathways involved in the myocardial inotropic response to stretch.

Estimation of the prevalence of idiopathic epilepsy and structural epilepsy in a general population of 900 dogs undergoing MRI for epileptic seizures.

Due to variation in study designs the prevalence of idiopathic epilepsy (IE) and structural epilepsy (SE) in dogs is largely unknown. The objective was to provide estimates of the prevalence of IE and SE in a large population of dogs undergoing MRI for epileptic seizures. A retrospective study on 900 dogs undergoing MRI for seizures was performed. MRI scans, summary clinical history and neurological examination from the VetCT database were reviewed and a diagnosis assigned by board-certified radiologists. Structural lesions were identified as a cause of seizures in 45.1 per cent (n=406) of cases. No structural lesions were identified in 54.9 per cent (n=494) of cases with presumed IE diagnosed in 53.8 per cent (n=484) of dogs. Dogs between six months and six years were more often associated with IE (P<0.001), small breeds were overrepresented with suspected inflammatory brain disease (P=0.001) and large entire dogs more often diagnosed with extra-axial neoplasms (P=0.001). Over 31.0 per cent of dogs with suspected IE were six years or older. This study is the largest of its kind in dogs and provides accurate estimates of underlying causes of epilepsy. MRI findings should be considered in the context of a detailed clinical history and neurological examination.

Malignant melanoma in submandibular gland-A rare diagnostic dilemma.

Diagnostic surprises such as melanoma occurring within unusual sites such as submandibular salivary glands are possible. The role of a discerning pathologist with the aid of histochemistry and MDTs is crucial in such circumstances.

A Prospective Cohort Study on the Development of Claw Horn Disruption Lesions in Dairy Cattle; Furthering our Understanding of the Role of the Digital Cushion.

Claw horn disruption lesion (CHDL) is the collective term used to describe non-infectious foot lesions such as sole ulcers (SU), sole hemorrhage (SH), and white line disease (WLD) that commonly affect dairy cattle. The potential role of the bovine digital cushion, an anatomical structure located under the pedal bone and composed mostly of adipose and connective tissue, in the aetiopathogenesis of CHDL has recently been the subject of several studies. The aim of this prospective cohort study is to identify risk factors associated with the development of CHDL and to add further evidence regarding the role of the digital cushion. In order to achieve that we collected data from 500 lactations; 455 dairy cows from 3 farms were enrolled in this study. Data were collected from each animal on three occasions: 3-4 weeks before expected calving date, 1 week post calving, and 8-10 weeks post-calving. At each occasion, sole soft tissue thickness (the combined depth of the digital cushion and corium, SSTT) was measured using B-mode ultrasonography. At 8-10 weeks post-calving foot trimming was undertaken and the presence of CHDLs was recorded. Univariable analysis was undertaken between variables of interest, before multivariable regression models were constructed. Mixed effects multivariable linear regression models were created to describe the changes in SSTT and associations with various explanatory variables. Multivariable logistic regression models with the presence of SU, SH, or WLD as an outcome were also built. SSTT was shown to decrease from calving to early lactation (EL). Primiparous animals were found to have smaller SSTT, than multiparous animals. Animals with greater BCS had greater SSTT. Cows with a SU in early lactation had lower SSTT both at pre-calving and calving inspections comparing to cows without a SU. Cows that developed mastitis within 30 days of calving had approximately four times higher odds of developing SU compared to cows that did not develop mastitis. Our study advances our understanding of animal level risk factors associated with the development of CHDL and highlights the importance of the periparturient period.

Aberrant Splicing of SDHC in Families With Unexplained Succinate Dehydrogenase-Deficient Paragangliomas.

CONTEXT: Germline mutations in the succinate dehydrogenase genes (SDHA/B/C/D, SDHAF2-collectively, "SDHx") have been implicated in paraganglioma (PGL), renal cell carcinoma (RCC), gastrointestinal stromal tumor (GIST), and pituitary adenoma (PA). Negative SDHB tumor staining is indicative of SDH-deficient tumors, usually reflecting an underlying germline SDHx mutation. However, approximately 20% of individuals with SDH-deficient tumors lack an identifiable germline SDHx mutation. METHODS: We performed whole-exome sequencing (WES) of germline and tumor DNA followed by Sanger sequencing validation, transcriptome analysis, metabolomic studies, and haplotype analysis in 2 Italian-Australian families with SDH-deficient PGLs and various neoplasms, including RCC, GIST, and PA. RESULTS: Germline WES revealed a novel SDHC intronic variant, which had been missed during previous routine testing, in 4 affected siblings of the index family. Transcriptome analysis demonstrated aberrant SDHC splicing, with the retained intronic segment introducing a premature stop codon. WES of available tumors in this family showed chromosome 1 deletion with loss of wild-type SDHC in a PGL and a somatic gain-of-function KIT mutation in a GIST. The SDHC intronic variant identified was subsequently detected in the second family, with haplotype analysis indicating a founder effect. CONCLUSIONS: This is the deepest intronic variant to be reported among the SDHx genes. Intronic variants beyond the limits of standard gene sequencing analysis should be considered in patients with SDH-deficient tumors but negative genetic test results.

Medially-stabilized total knee arthroplasty does not alter knee laxity and balance in cadaveric knees.

Instability after total knee arthroplasty (TKA) can lead to suboptimal outcomes and revision surgery. Medially-stabilized implants aim to more closely replicate normal knee motion than other implants following TKA, but no study has investigated knee laxity (motion under applied loads) and balance (i.e., difference in varus/valgus motion under load) following medially-stabilized TKA. The primary purposes of this study were to investigate how medially-stabilized implants change knee laxity in non-arthritic, cadaveric knees, and if it produces a balanced knee after TKA. Force-displacement data were collected on 18 non-arthritic cadaveric knees before and after arthroplasty using medially-stabilized implants. Varus-valgus and anterior-posterior laxity and varus-valgus balance were compared between native and medially-stabilized knees at 0°, 20°, 60°, and 90° under three different loading conditions. Varus-valgus and anterior-posterior laxities were not different between native and medially-stabilized knees under most testing conditions (p ≥ 0.068), but differences of approximately 2° less varus-valgus laxity at 20° of flexion and 4 mm more anterior-posterior laxity at 90° were present from native laxities (p < 0.017) Medially-stabilized implant balance had ≤1.5° varus bias at all flexion angles. Future studies should confirm if the consistent laxity afforded by the medially-stabilized implant is associated with better and more predictable postoperative outcomes. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:335-349, 2019.