Fatigue task-dependent effect on spatial distribution of lumbar muscles activity.

This study aims to identify how spatial distribution of lumbar muscle activity is modulated by different fatigue tasks. Twenty healthy adults performed two different isometric trunk extension endurance tasks (the modified Sorensen test and the inverted modified Sorensen test) until exhaustion. During these tasks, bilateral superficial lumbar muscle activity was recorded using high-density electromyography. The spatial distribution of activation within these muscles was obtained using the centroid coordinates in the medio-lateral and cranio-caudal directions. The effects of task and endurance time (left and right sides) were investigated using repeated measures ANOVA. Results revealed a significant lateral shift of the centroid throughout the fatigue tasks on both sides and no difference between tasks. Significant task × time interaction effects were found for the cranio-caudal direction on both sides showing a significantly more caudal location of the centroid in the modified Sorensen test compared to the inverted test at the beginning of the tasks. Our findings suggest that spatial distribution of lumbar muscle activity is task-dependent in a pre-fatigue stage while an alternative but similar muscle recruitment strategy is used in both tasks to maintain performance in the later stages of muscle fatigue.

Range-wide indicators of African great ape density distribution.

Species distributions are influenced by processes occurring at multiple spatial scales. It is therefore insufficient to model species distribution at a single geographic scale, as this does not provide the necessary understanding of determining factors. Instead, multiple approaches are needed, each differing in spatial extent, grain, and research objective. Here, we present the first attempt to model continent-wide great ape density distribution. We used site-level estimates of African great ape abundance to (1) identify socioeconomic and environmental factors that drive densities at the continental scale, and (2) predict range-wide great ape density. We collated great ape abundance estimates from 156 sites and defined 134 pseudo-absence sites to represent additional absence locations. The latter were based on locations of unsuitable environmental conditions for great apes, and on existing literature. We compiled seven socioeconomic and environmental covariate layers and fitted a generalized linear model to investigate their influence on great ape abundance. We used an Akaike-weighted average of full and subset models to predict the range-wide density distribution of African great apes for the year 2015. Great ape densities were lowest where there were high Human Footprint and Gross Domestic Product values; the highest predicted densities were in Central Africa, and the lowest in West Africa. Only 10.7% of the total predicted population was found in the International Union for Conservation of Nature Category I and II protected areas. For 16 out of 20 countries, our estimated abundances were largely in line with those from previous studies. For four countries, Central African Republic, Democratic Republic of the Congo, Liberia, and South Sudan, the estimated populations were excessively high. We propose further improvements to the model to overcome survey and predictor data limitations, which would enable a temporally dynamic approach for monitoring great apes across their range based on key indicators.

DRESS is a Mess: A Case of Cross Reactivity Between Lacosamide and Lamotrigine.

Drug reaction with eosinophilia with systemic symptoms (DRESS) syndrome is a rare drug reaction often presenting with both cutaneous manifestations and potentially life-threatening internal organ involvement. The precise incidence of DRESS is still unclear as it is easily missed due to its highly variable clinical presentation. However, with an expected mortality rate of approximately 10 percent, it is important for clinicians to be familiar with pharmacologic etiologies commonly implicated in the pathogenesis. We present a case of DRESS syndrome attributed to cross-reactivity between two commonly used anticonvulsants- lacosamide and lamotrigine.

Lactulose-induced pneumatosis intestinalis following colonoscopy: a case report.

Pneumatosis intestinalis (PI) occurs when gas is discovered in the intestinal wall and is categorized into two types: primary PI which is idiopathic and mainly occurs in the colon, and secondary PI which occurs more often in the small bowel but has variable presentation and etiology. We report a case of a patient status post-orthotopic deceased liver transplantation complicated by a portal vein thrombus on chronic lactulose for portosystemic encephalopathy who presented due to pyelonephritis and persistent diarrhea. The patient underwent colonoscopy with random biopsies and subsequently developed acute sepsis with Escherichia coli bacteremia. The findings of PI were noted on computed tomography imaging obtained 5 days post-colonoscopy, due to persistent post-procedure abdominal pain. The patient was treated with discontinuation of lactulose, supportive care, and antibiotics for her bacteremia with resolution of her PI 3 days later. This suggests that a combination of factors may lead to the development of PI, and while some cases require emergent intervention including surgery, others may be treated conservatively. Awareness of risk factors that may precipitate PI and specific clinical predictors may help to both mitigate and manage PI appropriately.

Colonic Intussusception Secondary to Hereditary Angioedema.

Hereditary angioedema (HAE) is a rare genetic disease with numerous gastrointestinal manifestations. Intussusception, although rare, has been a reported complication with documentation of bowel wall edema on endoscopy during an acute flare. With the advent of synthetic C1 esterase inhibitors, this disease has become more effectively treatable. This case report shows a HAE flare complicated by colonic intussusception, treated with C1 esterase inhibitor, with complete endoscopic resolution seen on hospital day 5. This case provides evidence that with proper medical treatment, an HAE flare with intussusception has the potential to resolve without any further need for surgical or endoscopic intervention.

Naproxen-induced thrombocytopenia.

Thrombocytopenia has many mechanisms with broad differentials. A detailed history and physical, with timely diagnostic testing, is necessary to parse out the underlying etiology. Clinicians should maintain a high suspicion for drug-induced thrombocytopenia when there is an acute drop in the platelet level after exposure to commonly implicated drugs. Drug-induced thrombocytopenia is not well defined, as reporting is voluntary and not critically reviewed. Oftentimes, the culprit is not the drug itself, but a drug metabolite, which is difficult to prove with drug-dependent antibody testing. Here we present a case where naproxen led to hemarthrosis secondary to drug-induced thrombocytopenia.

COVID-19 in the geriatric population.

OBJECTIVES: The global COVID-19 pandemic has caused rapid and monumental changes around the world. Older people, who already experience higher rates of social isolation and loneliness, are more susceptible to adverse effects as a result of the social distancing protocols enacted to slow the spread of COVID-19. Based on prior outbreaks, we speculate the detrimental outcomes and offer solutions. METHODS: Reviewing the literature on the detrimental effects of social isolation and loneliness and higher mortality in the older population. Utilizing psychological study outcomes from prior major outbreaks such as in SARS, Ebola, H1N1 influenza, and Middle East respiratory syndrome offer predictions and the susceptibility in the geriatric age group. RESULTS: Organizations such as the WHO, Centers for Disease Control, and American Association of Retired Persons have put measures in place to provide networking on a local, regional, and national level. These efforts are designed to start mitigating such detrimental effects. A necessary follow-up to this pandemic will be gathering data on unique populations such as the geriatric community, to better mitigate adverse outcomes given the certainty that COVID-19 will not be the last global viral outbreak. CONCLUSIONS: The results of worsened social isolation and loneliness is associated with significantly increased morbidity and mortality in the geriatric population. Various solutions including virtual interactions with loved ones, engaging in physical activity, continuing any spiritual or religious prayers remotely, and community services to provide aid for the older population are all efforts to minimize social isolation and loneliness.

Should Bangladeshi Race Be Considered as an Independent Risk Factor for Multi Vessel Coronary Artery Disease?

INTRODUCTION: Coronary Artery Disease (CAD) continues to be on the rise not only in the Western developed world but also affecting the South Asian race, particularly Bangladeshis. The objectives of this study were as follows: To determine whether or not risk factors of Bangladeshis differ from non-Bangladeshis, whether there is any difference in the extent of CAD for both groups, and if there are risk factors that can significantly affect the extent of CAD. METHODS: All patients with a diagnosis of CAD admitted to our 800-bed tertiary care hospital between January 2001 and December 2015 were retrospectively analyzed. We reviewed the age, sex, body-mass index (BMI), cardiac risk factors such as family history of CAD, dyslipidemia, hypertension, diabetes and smoking. We also reviewed coronary angiographic findings of these consecutive 150 Bangladeshis and a randomly selected group of 193 non-Bangladeshis. RESULTS: A total of 343 medical records were evaluated, this included two groups: 193 non-Bangladeshis and 150 Bangladeshi subjects. The Bangladeshi group was older than the non-Bangladeshi group (63.49 vs 59.22, p-value=0.001), and included a larger proportion of males than the non-Bangladeshi group (28.7% vs 15.68%, p-value=0.0116). Bangladeshi subjects are more likely to be smokers than non-Bangladeshi (11.75% vs 6.67%, χ2=12.7, p-value=0.0004). Non-obstructive, 1-vessel, 2-vessel and 3-vessel accounts for 13.33%, 36.67%, 22%, and 28% for Bangladeshis, and 16.39%, 20.77% 34.43% and 28.42% for non-Bangladeshis, respectively. The difference of extent of CAD is significant between two groups (χ2 =12.397, p-value=0.0061). The findings suggest that Bangladeshi ethnicity has almost 2 times the likelihood of having 1-vessel CAD at coronary angiography (OR=2.361, 95% CI 1.452-3.839, p=0.0005). CONCLUSION: This study is a pivotal starting point for further evaluating the link between Bangladeshis and CAD. In our study we found that being Bangladeshi increases the risk of having CAD and may be an independent risk factor for multi-vessel CAD.

Reliable reference genes for the quantification of mRNA in human T-cells and PBMCs stimulated with live influenza virus.

BACKGROUND: Quantitative PCR (qPCR) is a powerful tool that is particularly well-suited to measure mRNA levels in clinical samples, especially those with relatively low cell counts. However, a caveat of this approach is that reliable, stably expressed reference (housekeeping) genes are vital in order to ensure reproducibility and appropriate biological inference. In this study, we evaluated the expression stability of six reference genes in peripheral blood mononuclear cells (PBMCs) and isolated CD3+ T-cells from young and old adults (n = 10), following ex vivo stimulation with mock (unstimulated) or live influenza virus. Our genes included: ß-actin (ACTB), glyercaldehyde-3-phostphate dehydrogenase (GAPDH), ribosomal protein L13a (RPL13a), ribosomal protein S18 (RPS18), succinate dehydrogenase complex flavoprotein subunit A (SDHA), and ubiquitin-conjugating enzyme E2D2 (UBE2D2). RESULTS: Reference gene expression varied significantly depending on cell type and stimulation conditions, but not age. Using the comparative ΔCt method, and the previously published software BestKeeper, NormFinder, and geNorm, we show that in PBMCs and T-cells, UBE2D2 and RPS18 were the most stable reference genes, followed by ACTB; however, the expression of UBE2D2 and RPS18 was found to increase with viral stimulation in isolated T-cells, while ACTB expression did not change significantly. No age-related differences in stability were observed for any gene CONCLUSIONS: This study suggests the use of a combination of UBE2D2, RPS18, and ACTB for the study of influenza responses in PBMCs and T-cells, although ACTB alone may be the most optimal choice if choosing to compare target gene expression before and after viral stimulation. Both GAPDH and RPL13a were found to be poor reference genes and should be avoided for studies of this nature.

Dispersal and reproductive careers of male mountain gorillas in Bwindi Impenetrable National Park, Uganda.

Dispersal is a key event in the life of an animal and it influences individual reproductive success. Male mountain gorillas exhibit both philopatry and dispersal, resulting in a mixed one-male and multimale social organization. However, little is known about the relationship between male dispersal or philopatry and reproductive careers in Bwindi mountain gorillas. Here we analyze data spanning from 1993 to 2017 on social groups in Bwindi Impenetrable National Park, Uganda to examine the proportion of males that disperse, age of dispersal, pathways to attaining alpha status, fate of dispersing males and philopatric males, and male tenure length as well as make comparisons of these variables to the Virunga mountain gorilla population. We report previously undocumented cases of dispersal by immature males and old males and we also observed the only known case of a fully mature male immigrating into a breeding group. We used genetic tracking of known individuals to estimate that a minimum of 25% of males that disperse to become solitary males eventually form new groups. No differences were found between the Bwindi and Virunga population in the age of male dispersal, the proportion of males that disperse, the age of alpha male acquisition, and dominance tenure length. The lack of differences may be due to small sample sizes or because the observed ecological variability does not lead to life history differences between the populations. Males in both populations follow variable strategies to attain alpha status leading to the variable one-male and multimale social organization, including dispersal to become solitary and eventually form a group, via group fissioning, usurping another alpha male, or inheriting the alpha position when a previous group leader dies.

Splicing arrays reveal novel RBM10 targets, including SMN2 pre-mRNA.

BACKGROUND: RBM10 is an RNA binding protein involved in message stabilization and alternative splicing regulation. The objective of the research described herein was to identify novel targets of RBM10-regulated splicing. To accomplish this, we downregulated RBM10 in human cell lines, using small interfering RNAs, then monitored alternative splicing, using a reverse transcription-PCR screening platform. RESULTS: RBM10 knockdown (KD) provoked alterations in splicing events in 10-20% of the pre-mRNAs, most of which had not been previously identified as RBM10 targets. Hierarchical clustering of the genes affected by RBM10 KD revealed good conservation of alternative exon inclusion or exclusion across cell lines. Pathway annotation showed RAS signaling to be most affected by RBM10 KD. Of particular interest was the finding that splicing of SMN pre-mRNA, encoding the survival of motor neuron (SMN) protein, was influenced by RBM10 KD. Inhibition of RBM10 resulted in preferential expression of the full-length, exon 7 retaining, SMN transcript in four cancer cell lines and one normal skin fibroblast cell line. SMN protein is expressed from two genes, SMN1 and SMN2, but the SMN1 gene is homozygously disrupted in people with spinal muscular atrophy; as a consequence, all of the SMN that is expressed in people with this disease is from the SMN2 gene. Expression analyses using primary fibroblasts from control, carrier and spinal muscle atrophy donors demonstrated that RBM10 KD resulted in preferential expression of the full-length, exon 7 retaining, SMN2 transcript. At the protein level, upregulation of the full-length SMN2 was also observed. Re-expression of RBM10, in a stable RBM10 KD cancer cell line, correlated with a reversion of the KD effect, demonstrating specificity. CONCLUSION: Our work has not only expanded the number of pre-mRNA targets for RBM10, but identified RBM10 as a novel regulator of SMN2 alternative inclusion.

RBM10 promotes transformation-associated processes in small cell lung cancer and is directly regulated by RBM5.

Lung cancers are the leading cause of cancer-related deaths worldwide, with small cell lung cancer (SCLC) being the most aggressive type. At the time of diagnosis, SCLC has usually already metastasized, and an astonishing 95% of patients eventually succumb to the disease. This highlights the need for more effective SCLC screening and treatment options. Interestingly, the earliest and most frequent genetic alteration associated with lung cancers involves a lesion in the region to which the RNA binding protein RBM5 maps. We have recently shown that a decrease in RBM5 expression may be a key step in SCLC development, as RBM5 regulated many transformation-associated processes in SCLC cells. RBM5 is structurally and functionally similar to another RNA binding protein, RBM10. Both proteins have tumor-suppressor properties in a variety of cancer cell lines, and it has been suggested that RBM5 expression can influence RBM10. Due to their similarities, and the recent evidence that RBM10 is mutated in up to 21% of lung cancers, we hypothesized that RBM10 would share RBM5's tumor-suppressor properties in SCLC. Using transcriptome analysis and functional assays, we show, however, that RBM10's function was opposite to what we hypothesized; in the endogenously RBM5-null GLC20 SCLC cell line, RBM10 actually promoted cell proliferation and other transformation-associated processes. Using RNA immunoprecipitation followed by next generation sequencing (RIP-Seq) and Western blotting, we demonstrate that RBM5 post-transcriptionally regulated RBM10 expression via direct interaction with specific RBM10 splice variants. We propose a working model describing the impact of this interaction on cellular processes. Our results provide evidence that RBM10 expression, in RBM5-null tumors, may contribute to tumor growth and metastasis. Measurement of both RBM10 and RBM5 expression in clinical samples may therefore hold prognostic and/or potentially predictive value.

RBM5 reduces small cell lung cancer growth, increases cisplatin sensitivity and regulates key transformation-associated pathways.

Small cell lung cancer (SCLC) is the most aggressive type of lung cancer, with almost 95% of patients succumbing to the disease. Although RBM5, a tumor suppressor gene, is downregulated in the majority of lung cancers, its role in SCLC is unknown. Using the GLC20 SCLC cell line, which has a homozygous deletion encompassing the RBM5 gene locus, we established stable RBM5 expressing sublines and investigated the effects of RBM5 re-expression. Transcriptome and target identification studies determined that RBM5 directly regulates the cell cycle and apoptosis in SCLC cells, as well as significantly downregulates other important transformation-associated pathways such as angiogenesis and cell adhesion. RNA sequencing of paired non-tumor and tumor SCLC patient specimens showed decreased RBM5 expression in the tumors, and expression alterations in the majority of the same pathways that were altered in the GLC20 cells and sublines. Functional studies confirmed RBM5 expression slows SCLC cell line growth, and increases sensitivity to the chemotherapy drug cisplatin. Overall, our work demonstrates the importance of RBM5 expression to the non-transformed state of lung cells and the consequences of its deletion to SCLC development and progression.

Insight into the role of alternative splicing within the RBM10v1 exon 10 tandem donor site.

BACKGROUND: RBM10 is an RNA binding protein involved in the regulation of transcription, alternative splicing and message stabilization. Mutations in RBM10, which maps to the X chromosome, are associated with TARP syndrome, lung and pancreatic cancers. Two predominant isoforms of RBM10 exist, RBM10v1 and RBM10v2. Both variants have alternate isoforms that differ by one valine residue, at amino acid 354 (RBM10v1) or 277 (RBM10v2). It was recently observed that a novel point mutation at amino acid 354 of RBM10v1, replacing valine with glutamic acid, correlated with preferential expression of an exon 11 inclusion variant of the proliferation regulatory protein NUMB, which is upregulated in lung cancer. FINDINGS: We demonstrate, using the GLC20 male-derived small cell lung cancer cell line - confirmed to have only one X chromosome - that the two (+/-) valine isoforms of RBM10v1 and RBM10v2 result from alternative splicing. Protein modeling of the RNA Recognition Motif (RRM) within which the alteration occurs, shows that the presence of valine inhibits the formation of one of the two α-helices associated with RRM tertiary structure, whereas the absence of valine supports the α-helical configuration. We then show 2-fold elevated expression of the transcripts encoding the minus valine RBM10v1 isoform in GLC20 cells, compared to those encoding the plus valine isoform. This expression correlates with preferential expression of the lung cancer-associated NUMB exon 11 inclusion variant. CONCLUSIONS: Our observations suggest that the ability of RBM10v1 to regulate alternative splicing depends, at least in part, on a structural alteration within the second RRM domain, which influences whether RBM10v1 functions to support or repress splicing. A model is presented.

Recent divergences and size decreases of eastern gorilla populations.

Compared with other African apes, eastern gorillas (Gorilla beringei) have been little studied genetically. We used analysis of autosomal DNA genotypes obtained from non-invasively collected faecal samples to estimate the evolutionary histories of the two extant mountain gorilla populations and the closely related eastern lowland gorillas. Our results suggest that eastern lowland gorillas and mountain gorillas split beginning some 10 000 years ago, followed 5000 years ago by the split of the two mountain gorilla populations of Bwindi Impenetrable National Park and the Virungas Massif. All three populations have decreased in effective population size, with particularly substantial 10-fold decreases for the mountain gorillas. These dynamics probably reflect responses to habitat changes resulting from climate fluctuations over the past 20 000 years as well as increasing human influence in this densely populated region in the last several thousand years.

Fine-scale genetic structure analyses suggest further male than female dispersal in mountain gorillas.

BACKGROUND: Molecular studies in social mammals rarely compare the inferences gained from genetic analyses with field information, especially in the context of dispersal. In this study, we used genetic data to elucidate sex-specific dispersal dynamics in the Virunga Massif mountain gorilla population (Gorilla beringei beringei), a primate species characterized by routine male and female dispersal from stable mixed-sex social groups. Specifically, we conducted spatial genetic structure analyses for each sex and linked our genetically-based observations with some key demographic and behavioural data from this population. RESULTS: To investigate the spatial genetic structure of mountain gorillas, we analysed the genotypes of 193 mature individuals at 11 microsatellite loci by means of isolation-by-distance and spatial autocorrelation analyses. Although not all males and females disperse, female gorillas displayed an isolation-by-distance pattern among groups and a signal of dispersal at short distances from their natal group based on spatial autocorrelation analyses. In contrast, male genotypes were not correlated with spatial distance, thus suggesting a larger mean dispersal distance for males as compared to females. Both within sex and mixed-sex pairs were on average genetically more related within groups than among groups. CONCLUSIONS: Our study provides evidence for an intersexual difference in dispersal distance in the mountain gorilla. Overall, it stresses the importance of investigating spatial genetic structure patterns on a sex-specific basis to better understand the dispersal dynamics of the species under investigation. It is currently poorly understood why some male and female gorillas disperse while others remain in the natal group. Our results on average relatedness within and across groups confirm that groups often contain close relatives. While inbreeding avoidance may play a role in driving female dispersal, we note that more detailed dyadic genetic analyses are needed to shed light on the role of inbreeding avoidance as an ultimate cause of female dispersal in mountain gorillas.

Ly49Q positively regulates type I IFN production by plasmacytoid dendritic cells in an immunoreceptor tyrosine-based inhibitory motif-dependent manner.

Plasmacytoid dendritic cells (pDC) are the major producers of type I IFN during the initial immune response to viral infection. Ly49Q, a C-type lectin-like receptor specific for MHC-I, possesses a cytoplasmic ITIM and is highly expressed on murine pDC. Using Ly49Q-deficient mice, we show that, regardless of strain background, this receptor is required for maximum IFN-α production by pDC. Furthermore, Ly49Q expression on pDC, but not myeloid dendritic cells, is necessary for optimal IL-12 secretion, MHC-II expression, activation of CD4(+) T cell proliferation, and nuclear translocation of the master IFN-α regulator IFN regulatory factor 7 in response to TLR9 agonists. In contrast, the absence of Ly49Q did not affect plasmacytoid dendritic cell-triggering receptor expressed on myeloid cells expression or pDC viability. Genetic complementation revealed that IFN-α production by pDC is dependent on an intact tyrosine residue in the Ly49Q cytoplasmic ITIM. However, pharmacological inhibitors and phosphatase-deficient mice indicate that Src homology 2 domain-containing phosphatase 1 (SHP)-1, SHP-2, and SHIP phosphatase activity is dispensable for this function. Finally, we observed that Ly49Q itself is downregulated on pDC in response to CpG exposure in an ITIM-independent manner. In conclusion, Ly49Q enhances TLR9-mediated signaling events, leading to IFN regulatory factor 7 nuclear translocation and expression of IFN-I genes in an ITIM-dependent manner that can proceed without the involvement of SHP-1, SHP-2, and SHIP.

Negative density-dependent dispersal in the American black bear (Ursus americanus) revealed by noninvasive sampling and genotyping.

Although the dispersal of animals is influenced by a variety of factors, few studies have used a condition-dependent approach to assess it. The mechanisms underlying dispersal are thus poorly known in many species, especially in large mammals. We used 10 microsatellite loci to examine population density effects on sex-specific dispersal behavior in the American black bear, Ursus americanus. We tested whether dispersal increases with population density in both sexes. Fine-scale genetic structure was investigated in each of four sampling areas using Mantel tests and spatial autocorrelation analyses. Our results revealed male-biased dispersal pattern in low-density areas. As population density increased, females appeared to exhibit philopatry at smaller scales. Fine-scale genetic structure for males at higher densities may indicate reduced dispersal distances and delayed dispersal by subadults.