Indolent Small Intestinal CD4+ T-cell Lymphoma Is a Distinct Entity with Unique Biologic and Clinical Features

Enteropathy-associated T-cell lymphomas (EATL) are rare and generally aggressive types of peripheral T-cell lymphomas. Rare cases of primary, small intestinal CD4+ T-cell lymphomas with indolent behavior have been described, but are not well characterized. We describe morphologic, phenotypic, genomic and clinical features of 3 cases of indolent primary small intestinal CD4+ T-cell lymphomas. All patients presented with diarrhea and weight loss and were diagnosed with celiac disease refractory to a gluten free diet at referring institutions. Small intestinal biopsies showed crypt hyperplasia, villous atrophy and a dense lamina propria infiltrate of small-sized CD4+ T-cells often with CD7 downregulation or loss. Gastric and colonic involvement was also detected (n = 2 each). Persistent, clonal TCRβ gene rearrangement products were detected at multiple sites. SNP array analysis showed relative genomic stability, early in disease course, and non-recurrent genetic abnormalities, but complex changes were seen at disease transformation (n = 1). Two patients are alive with persistent disease (4.6 and 2.5 years post-diagnosis), despite immunomodulatory therapy; one died due to bowel perforation related to large cell transformation 11 years post-diagnosis. Unique pathobiologic features warrant designation of indolent small intestinal CD4+ T-cell lymphoma as a distinct entity, greater awareness of which would avoid misdiagnosis as EATL or an inflammatory disorder, especially celiac disease

Biotribology of the ageing skin—why we should care

Ageing of populations has emerged as one of the most pressing societal, economic and healthcare challenges currently facing most nations across the globe. The ageing process itself results in degradation of physiological functions and biophysical properties of organs and tissues, and more particularly those of the skin. Moreover, in both developed and emerging economies, population ageing parallels concerning increases in lifestyle-associated conditions such as Type 2 diabetes, obesity and skin cancers. When considered together, these demographic trends call for even greater urgency to find clinical and engineering solutions for the numerous age-related deficits in skin function. From a tribological perspective, detrimental alterations of skin biophysical properties with age have fundamental consequences on how one interacts with the body's inner and outer environments. This stems from the fact that, besides being the largest organ of the human body, and also nearly covering its entirety, the skin is a multifunctional interface which mediates these interactions. The aim of this paper is to present a focused review to discuss some of the consequences of skin ageing from the viewpoint of biotribology, and their implications on health, well-being and human activities. Current and future research questions/challenges associated with biotribology of the ageing skin are outlined. They provide the background and motivation for identifying future lines of research that could be taken up by the biotribology and biophysics communities

Barriers and facilitators to combined ART initiation in pregnant women with HIV: lessons learnt from a PMTCT B+ pilot program in Swaziland

In January 2013, Swaziland launched a PMTCT B+ implementation study in rural Shiselweni. We aimed to identify patient and health service determinants of combined antiretroviral therapy (ART) initiation, to help guide national implementation of PMTCT B+

Patterns of analgesic use, pain and self-efficacy: a cross-sectional study of patients attending a hospital rheumatology clinic

Background: Many people attending rheumatology clinics use analgesics and non-steroidal anti-inflammatories for persistent musculoskeletal pain. Guidelines for pain management recommend regular and pre-emptive use of analgesics to reduce the impact of pain. Clinical experience indicates that analgesics are often not used in this way. Studies exploring use of analgesics in arthritis have historically measured adherence to such medication. Here we examine patterns of analgesic use and their relationships to pain, self-efficacy and demographic factors. Methods: Consecutive patients were approached in a hospital rheumatology out-patient clinic. Pattern of analgesic use was assessed by response to statements such as 'I always take my tablets every day.' Pain and self-efficacy (SE) were measured using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Arthritis Self-Efficacy Scale (ASES). Influence of factors on pain level and regularity of analgesic use were investigated using linear regression. Differences in pain between those agreeing and disagreeing with statements regarding analgesic use were assessed using t-tests. Results: 218 patients (85% of attendees) completed the study. Six (2.8%) patients reported no current pain, 26 (12.3%) slight, 100 (47.4%) moderate, 62 (29.4%) severe and 17 (8.1%) extreme pain. In multiple linear regression self efficacy and regularity of analgesic use were significant (p < 0.01) with lower self efficacy and more regular use of analgesics associated with more pain. Low SE was associated with greater pain: 40 (41.7%) people with low SE reported severe pain versus 22 (18.3%) people with high SE, p < 0.001. Patients in greater pain were significantly more likely to take analgesics regularly; 13 (77%) of those in extreme pain reported always taking their analgesics every day, versus 9 (35%) in slight pain. Many patients, including 46% of those in severe pain, adjusted analgesic use to current pain level. In simple linear regression, pain was the only variable significantly associated with regularity of analgesic use: higher levels of pain corresponded to more regular analgesic use (p = 0.003). Conclusion: Our study confirms that there is a strong inverse relationship between self-efficacy and pain severity. Analgesics are often used irregularly by people with arthritis, including some reporting severe pain

Strong Association of De Novo Copy Number Mutations with Autism

We tested the hypothesis that de novo copy number variation (CNV) is associated with autism spectrum disorders (ASDs). We performed comparative genomic hybridization (CGH) on the genomic DNA of patients and unaffected subjects to detect copy number variants not present in their respective parents. Candidate genomic regions were validated by higher-resolution CGH, paternity testing, cytogenetics, fluorescence in situ hybridization, and microsatellite genotyping. Confirmed de novo CNVs were significantly associated with autism (P = 0.0005). Such CNVs were identified in 12 out of 118 (10%) of patients with sporadic autism, in 2 out of 77 (3%) of patients with an affected first-degree relative, and in 2 out of 196 (1%) of controls. Most de novo CNVs were smaller than microscopic resolution. Affected genomic regions were highly heterogeneous and included mutations of single genes. These findings establish de novo germline mutation as a more significant risk factor for ASD than previously recognized

Detection of copy number variation from array intensity and sequencing read depth using a stepwise Bayesian model

Abstract Background Copy number variants (CNVs) have been demonstrated to occur at a high frequency and are now widely believed to make a significant contribution to the phenotypic variation in human populations. Array-based comparative genomic hybridization (array-CGH) and newly developed read-depth approach through ultrahigh throughput genomic sequencing both provide rapid, robust, and comprehensive methods to identify CNVs on a whole-genome scale. Results We developed a Bayesian statistical analysis algorithm for the detection of CNVs from both types of genomic data. The algorithm can analyze such data obtained from PCR-based bacterial artificial chromosome arrays, high-density oligonucleotide arrays, and more recently developed high-throughput DNA sequencing. Treating parameters--e.g., the number of CNVs, the position of each CNV, and the data noise level--that define the underlying data generating process as random variables, our approach derives the posterior distribution of the genomic CNV structure given the observed data. Sampling from the posterior distribution using a Markov chain Monte Carlo method, we get not only best estimates for these unknown parameters but also Bayesian credible intervals for the estimates. We illustrate the characteristics of our algorithm by applying it to both synthetic and experimental data sets in comparison to other segmentation algorithms. Conclusions In particular, the synthetic data comparison shows that our method is more sensitive than other approaches at low false positive rates. Furthermore, given its Bayesian origin, our method can also be seen as a technique to refine CNVs identified by fast point-estimate methods and also as a framework to integrate array-CGH and sequencing data with other CNV-related biological knowledge, all through informative priors.</p

Treatment of rheumatoid arthritis: a global perspective on the use of antirheumatic drugs

Modern therapy for rheumatoid arthritis (RA) is based on knowledge of the severity of the natural history of the disease. RA patients are approached with early and aggressive treatment strategies, methotrexate as an anchor drug, biological targeted therapies in those with inadequate response to methotrexate, and “tight control,” aiming for remission and low disease activity according to quantitative monitoring. This chapter presents a rationale for current treatment strategies for RA with antirheumatic drugs, a review of published reports concerning treatments in clinical cohorts outside of clinical trials, and current treatments at 61 sites in 21 countries in the QUEST-RA database

De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28 × 10−11). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 × 10−15). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease