C282Y/H63D Compound Heterozygosity Is a Low Penetrance Genotype for Iron Overload-related Disease.

Background: Hereditary hemochromatosis (HH) occurs due to mutations in the HFE gene. While the C282Y mutation is the most common genotype reported in HH, other genotypes are found less frequently, indicating variable degrees of penetrance. We studied the penetrance of the C282Y/H63D compound heterozygote genotype in developing clinically significant iron overload. Methods: We have completed a retrospective analysis on every individual within Newfoundland & Labrador who were diagnosed as C282Y/H63D compound heterozygote between 1996 and 2009 through a molecular genetics study. We collected data for up to 10 years following the initial genotyping using electronic health records, including laboratory values, phlebotomy status, radiologic reports and clinic records. Iron overload status was classified based on the HealthIron study. Results: Between 1996 and 2009, 247 individuals with available health records tested positive for C282Y/H63D compound heterozygosity. Over the 10 years of our study, 5.3% of patients exhibited iron overload-related disease on the background of documented iron overload. Including these individuals, 10.1% of patients had documented iron overload, 23.1% of patients had a provisional iron overload and the remaining 66.8% of patients had no evidence of iron overload. Only 44 patients had documented phlebotomies, likely based on their severe phenotype at baseline. Despite phlebotomy, the prevalence of iron overload was higher among these patients. The penetrance of compound heterozygosity was also significantly higher among men (P < 0.01). Conclusion: C282Y/H63D compound heterozygosity is a low penetrance genotype in HH. This is the largest reported cohort of C282Y/H63D compound heterozygotes in North America with an extended follow-up.

Inventory decisions on the transportation system and carbon emissions under COVID-19 effects: A sensitivity analysis.

The COVID-19 pandemic has created multiple problems in the existing transportation system. The contribution of this study is to guide logistics managers as they make ordering decisions within a disrupted transportation system. In the overall supply chain system, inventory decisions have been either compromised or challenged. Traditional inventory decisions that consider preplanned transportation facilities (and speeds) are currently becoming obsolete, predominantly in post-COVID times due to delays in the delivery of products and higher delivery costs. Therefore, businesses such as retailers must align ordering and pricing decisions to maintain a sustainable profit. To address this issue, this study investigates optimum inventory decisions under the pandemic's effects while considering the transportation cost as proportional to COVID-19 intensity. This study also considers product deterioration, time-dependent holding costs, price-dependent demands, and carbon emissions from vehicle operation and intends to establish a harmonious relationship among these attributes. The optimization of green technology investment is studied to reduce emissions due to transportation. Some theoretical derivations and numerical examples are given, and they are followed by a sensitivity analysis to extract important managerial insights into the effect of COVID-19. The manager can set an optimal selling price and the cycle length by carefully planning the number of trips in considering the rate of the outbreak and its effect on the increasing transportation cost.

Emphysematous cystitis as a potential marker of severe Crohn's disease.

BACKGROUND: Emphysematous cystitis (EC) is characterized by the presence of air within the bladder wall, often a complication of urinary tract infection (UTI) by gas-producing organisms. However, EC has also been reported in the setting of infectious colitis suggesting an alternate etiology. We report a rare case of EC in the setting of severe Crohn's colitis with no clinical evidence of UTI. CASE PRESENTATION: A 43-year old female presented with a 2-month history of bloody diarrhea consisting of 8-12 bowel movements a day, weight loss of 10 kg and peripheral edema. She also had multiple ulcerated lesions on her abdominal wall and in the perianal region. Initial CT scan was significant for pancolitis, anasarca and EC. The follow-up CT cystogram, flexible cystoscopy and pelvic MRI confirmed the diagnosis of EC and ruled out any fistulous tracts in the pelvis including enterovesical/colovesical fistula. The patient did not report any urinary symptoms and the urinalysis was within normal limits. An extensive infectious workup was negative. Despite the paucity of infectious findings, the EC was empirically treated with an intravenous third-generation cephalosporin. Colonoscopy was significant for multiple ulcerated and hyperemic areas with pseudopolyps all throughout the right, transverse and left colon. Biopsies confirmed Crohn's colitis with no evidence of granulomata or dysplasia. Immunohistochemistry was negative for CMV. The perianal and abdominal wall lesions were suspected to be pyoderma gangrenosum although biopsies were equivocal. The colitis was initially treated with intravenous steroids followed by biologic therapy with Infliximab. Despite appropriate escalation of therapies, the patient developed colonic perforation requiring subtotal colectomy. CONCLUSION: This is a rare case of EC in a patient with severe Crohn's colitis. There was no evidence of urinary tract infection or fistulising disease. According to our review, this is the first reported incident of EC in a patient with inflammatory bowel disease without any prior intra-abdominal surgeries. While active Crohn's disease alone is a critical illness, we conclude that concomitant EC may be a poor prognostic factor.

Relationship between diabetes self-care practices and control of periodontal disease among type2 diabetes patients in Bangladesh.

INTRODUCTION: The prevalence of periodontal disease is high in diabetes patients worldwide, including Bangladesh. Although associations of periodontal disease outcomes and clinical determinants of diabetes have been investigated, few studies have reported on the relationship between periodontal diseases outcomes with modifiable factors, such as self-care and oral hygiene practices, in patients with diabetes. Moreover, in order to develop targeted strategies, it is also important to estimate their aggregated contribution separately from that of the established sociodemographic and diabetics related clinical determinates. Therefore, this study was performed to elucidate 1) the relationship of diabetes patients' self-care and oral hygiene practices to periodontal disease and 2) the relative contributions of selected factors to periodontal disease outcome in type 2 diabetes patients. METHODS: The data were obtained from the baseline survey of a multicentre, prospective cohort study. A total of 379 adult patients with type 2 diabetes from three diabetic centres in Dhaka, Rajshahi and Barishal, received periodontal examinations using the community periodontal index (CPI) probe, glycated haemoglobin examination, other clinical examinations, and structured questionnaires. Multiple logistics regression analyses were performed to assess the associations between selected factors and prevalence of any periodontal disease and its severity. RESULTS: More than half of the participants were female (53.8%) and 66.8% of the total participants was 21-50 years old. The prevalence of any (CPI code 2+3+4; 75.7%) and severe form (CPI code 4; 35.1%) of periodontal disease were high in type 2 diabetes patients. In multivariate analysis, the odds of periodontal disease increased with unfavourable glycaemic control indicated by HbA1c ≥ 7%, and decreased by 64%, 85% and 92% with adherence to recommended diet, physical activity, and oral hygiene practices, respectively. Diabetes self-care practice explained the highest proportion of the variance (13.9%) followed by oral hygiene practices (10.9%) by modelling any periodontal disease versus no disease. Variables of diabetes conditions and oral hygiene practices explained 10.9% and 7.3% of the variance by modelling severe (CPI code 4) or moderate (CPI code 3) forms of periodontal disease versus mild form of periodontal disease. Findings also conferred that while poor diabetes control had an individually adverse association with any form of periodontal diseases and its severity, the risk of diseases was moderated by oral hygiene practices. CONCLUSIONS: This study suggested that, in addition to diabetes-related clinical determinants, self-care practices, and oral hygiene practices must be taken into consideration for prevention and control of periodontal disease in patients with diabetes.

Variceal Bleed and Portal Hypertensive Gastropathy in a Noncirrhotic Patient with Isolated Splenomegaly.

Portal hypertension caused by cirrhosis is the most common etiology of esophageal varices. However, abnormalities of the splenoportal axis in the absence of liver disease may also cause portal hypertension resulting in varices. We report a rare case of esophageal variceal bleed in a noncirrhotic patient with isolated splenomegaly secondary to chronic granulocyte colony stimulating factor (G-CSF) therapy. The patient is a 26-year-old male with Cohen syndrome who required long-term G-CSF treatment for chronic neutropenia. He presented with large volume hematemesis and pancytopenia in the setting of known splenomegaly with no evidence of cirrhosis. An urgent EGD revealed active variceal bleeding and portal hypertensive gastropathy. The patient was appropriately resuscitated and underwent a successful transjugular intrahepatic portosystemic shunt and CT-guided coil placement for the bleeding varices. We are the first to report variceal bleed as a complication of long-term G-CSF use, a life-threatening consequence that requires urgent intervention.

Mediators of the association between low socioeconomic status and poor glycemic control among type 2 diabetics in Bangladesh.

Although low socioeconomic status (SES) is related to poor glycemic control, the underlying mechanisms remain unclear. We examined potentially modifiable factors involved in the association between low SES and poor glycemic control using data from the baseline survey of a multicenter, prospective cohort study. Five hundred adult type 2 diabetes patients were recruited from three diabetes centers. Glycemic control was poorer in diabetic individuals with low SES than in those with higher SES. Adverse health-related behaviors, such as non-adherence to medication (adjusted odds ratio [AOR] = 1.07, 95% confidence interval [CI] 1.04-1.13) and diet (AOR = 1.04, 95% CI 1.02-1.06); existing comorbidities, such as depressive symptoms (AOR = 1.05, 95% CI 1.04-1.09); and non-adherence to essential health service-related practices concerning diabetes care, such as irregular scheduled clinic visits (AOR = 1.04, 95% CI 1.03-1.06) and not practicing self-monitoring of blood glucose (AOR = 1.05, 95% CI 1.03-1.07), mediated the relationship between social adversity and poor glycemic control specially in urban areas of Bangladesh. Those identified factors provide useful information for developing interventions to mitigate socioeconomic disparities in glycemic control.

Synergistic Benefits of Combined Aerobic and Cognitive Training on Fluid Intelligence and the Role of IGF-1 in Chronic Stroke.

BACKGROUND: Paired exercise and cognitive training have the potential to enhance cognition by "priming" the brain and upregulating neurotrophins. METHODS: Two-site randomized controlled trial. Fifty-two patients >6 months poststroke with concerns about cognitive impairment trained 50 to 70 minutes, 3× week for 10 weeks with 12-week follow-up. Participants were randomized to 1 of 2 physical interventions: Aerobic (>60% VO2peak using <10% body weight-supported treadmill) or Activity (range of movement and functional tasks). Exercise was paired with 1 of 2 cognitive interventions (computerized dual working memory training [COG] or control computer games [Games]). The primary outcome for the 4 groups (Aerobic + COG, Aerobic + Games, Activity + COG, and Activity + Games) was fluid intelligence measured using Raven's Progressive Matrices Test administered at baseline, posttraining, and 3-month follow-up. Serum neurotrophins collected at one site (N = 30) included brain-derived neurotrophic factor (BDNF) at rest (BDNFresting) and after a graded exercise test (BDNFresponse) and insulin-like growth factor-1 at the same timepoints (IGF-1rest, IGF-1response). RESULTS: At follow-up, fluid intelligence scores significantly improved compared to baseline in the Aerobic + COG and Activity + COG groups; however, only the Aerobic + COG group was significantly different (+47.8%) from control (Activity + Games -8.5%). Greater IGF-1response at baseline predicted 40% of the variance in cognitive improvement. There was no effect of the interventions on BDNFresting or BDNFresponse; nor was BDNF predictive of the outcome. CONCLUSIONS: Aerobic exercise combined with cognitive training improved fluid intelligence by almost 50% in patients >6 months poststroke. Participants with more robust improvements in cognition were able to upregulate higher levels of serum IGF-1 suggesting that this neurotrophin may be involved in behaviorally induced plasticity.

Serum levels of insulin-like growth factor-1 and brain-derived neurotrophic factor as potential recovery biomarkers in stroke.

OBJECTIVES: Our objectives were: 1) to determine whether maximal aerobic exercise increased serum neurotrophins in chronic stroke and 2) to determine the factors that predict resting and exercise-dependent levels. METHODS: We investigated the potential predictors of resting and exercise-dependent serum insulin-like growth factor-1 and brain-derived neurotrophic factor among 35 chronic stroke patients. Predictors from three domains (demographic, disease burden, and cardiometabolic) were entered into 4 separate stepwise linear regression models with outcome variables: resting insulin-like growth factor, resting brain-derived neurotrophic factor, exercise-dependent change in insulin-like growth factor, and exercise-dependent change brain-derived neurotrophic factor. RESULTS: Insulin-like growth factor decreased after exercise (p = 0.001) while brain-derived neurotrophic factor did not change (p = 0.38). Greater lower extremity impairment predicted higher resting brain-derived neurotrophic factor (p = 0.004, r2 = 0.23). Higher fluid intelligence predicted greater brain-derived neurotrophic factor response to exercise (p = 0.01, r2 = 0.18). There were no significant predictors of resting or percent change insulin-like growth factor-1. DISCUSSION: Biomarkers have the potential to characterize an individual's potential for recovery from stroke. Neurotrophins such as insulin-like growth factor-1 and brain-derived neurotrophic factor are thought to be important in neurorehabilitation; however, the factors that modulate these biomarkers are not well understood. Resting brain-derived neurotrophic factor and percent change in brain-derived neurotrophic factor were related to physical and cognitive recovery in chronic stroke, albeit weakly. Insulin-like growth factor-1 was not an informative biomarker among chronic stroke patients. The novel finding that fluid intelligence positively correlated with exercise-induced change in brain-derived neurotrophic factor warrants further research.

Defining Optimal Aerobic Exercise Parameters to Affect Complex Motor and Cognitive Outcomes after Stroke: A Systematic Review and Synthesis.

Although poststroke aerobic exercise (AE) increases markers of neuroplasticity and protects perilesional tissue, the degree to which it enhances complex motor or cognitive outcomes is unknown. Previous research suggests that timing and dosage of exercise may be important. We synthesized data from clinical and animal studies in order to determine optimal AE training parameters and recovery outcomes for future research. Using predefined criteria, we included clinical trials of stroke of any type or duration and animal studies employing any established models of stroke. Of the 5,259 titles returned, 52 articles met our criteria, measuring the effects of AE on balance, lower extremity coordination, upper limb motor skills, learning, processing speed, memory, and executive function. We found that early-initiated low-to-moderate intensity AE improved locomotor coordination in rodents. In clinical trials, AE improved balance and lower limb coordination irrespective of intervention modality or parameter. In contrast, fine upper limb recovery was relatively resistant to AE. In terms of cognitive outcomes, poststroke AE in animals improved memory and learning, except when training was too intense. However, in clinical trials, combined training protocols more consistently improved cognition. We noted a paucity of studies examining the benefits of AE on recovery beyond cessation of the intervention.

Private rare deletions in SEC16A and MAMDC4 may represent novel pathogenic variants in familial axial spondyloarthritis.

OBJECTIVE: Axial spondyloarthritis (AxSpA) represents a group of inflammatory axial diseases that share common clinical and histopathological manifestations. Ankylosing spondylitis (AS) is the best characterised subset of AxSpA, and its genetic basis has been extensively investigated. Given that genome-wide association studies account for only 25% of AS heritability, the objective of this study was to discover rare, highly penetrant genetic variants in AxSpA pathogenesis using a well-characterised, multigenerational family. METHODS: HLA-B*27 genotyping and exome sequencing was performed on DNA collected from available family members. Variant frequency was assessed by mining publically available datasets and using fragment analysis of unrelated AxSpA cases and unaffected controls. Gene expression was performed by qPCR, and protein expression was assessed by western blot analysis and immunofluorescence microscopy using patient-derived B-cell lines. Circular dichroism spectroscopy was performed to assess the impact of discovered variants on secondary structure. RESULTS: This is the first report identifying two rare private familial variants in a multigenerational AxSpA family, an in-frame SEC16A deletion and an out-of-frame MAMDC4 deletion. Evidence suggests the causative mechanism for SEC16A appears to be a conformational change induced by deletion of three highly conserved amino acids from the intrinsically disordered Sec16A N-terminus and RNA-mediated decay for MAMDC4. CONCLUSIONS: The results suggest that it is the presence of rare syntenic SEC16A and MAMDC4 deletions that increases susceptibility to AxSpA in family members who carry the HLA-B*27 allele.

Mcl1 regulates the terminal mitosis of neural precursor cells in the mammalian brain through p27Kip1.

Cortical development requires the precise timing of neural precursor cell (NPC) terminal mitosis. Although cell cycle proteins regulate terminal mitosis, the factors that influence the cell cycle machinery are incompletely understood. Here we show in mice that myeloid cell leukemia 1 (Mcl1), an anti-apoptotic Bcl-2 protein required for the survival of NPCs, also regulates their terminal differentiation through the cell cycle regulator p27(Kip1). A BrdU-Ki67 cell profiling assay revealed that in utero electroporation of Mcl1 into NPCs in the embryonic neocortex increased NPC cell cycle exit (the leaving fraction). This was further supported by a decrease in proliferating NPCs (Pax6(+) radial glial cells and Tbr2(+) neural progenitors) and an increase in differentiating cells (Dcx(+) neuroblasts and Tbr1(+) neurons). Similarly, BrdU birth dating demonstrated that Mcl1 promotes premature NPC terminal mitosis giving rise to neurons of the deeper cortical layers, confirming their earlier birthdate. Changes in Mcl1 expression within NPCs caused concomitant changes in the levels of p27(Kip1) protein, a key regulator of NPC differentiation. Furthermore, in the absence of p27(Kip1), Mcl1 failed to induce NPC cell cycle exit, demonstrating that p27(Kip1) is required for Mcl1-mediated NPC terminal mitosis. In summary, we have identified a novel physiological role for anti-apoptotic Mcl1 in regulating NPC terminal differentiation.

Mcl-1 regulates the survival of adult neural precursor cells.

Since the discovery of neural precursor cells (NPCs) in the adult mammalian brain, there has been a lot of excitement surrounding the potential for regeneration in the adult brain. For instance, many studies have shown that a significant number of NPCs will migrate to a site of injury and differentiate into all of the neural lineages. However, one of the main challenges affecting endogenous neural regeneration is that many of the NPCs that migrate to the injury site ultimately undergo apoptosis. Therefore, we sought to determine whether myeloid cell leukemia-1 (Mcl-1), an anti-apoptotic Bcl-2 protein, would promote the survival of adult NPCs by impeding apoptosis. To do this, we first confirmed that Mcl-1 is endogenously expressed within the adult NPC population using BrdU labeling assays. Next, we conditionally deleted Mcl-1 in adult NPCs using cre/lox technology and expressed Cre from the NPC-specific promoter Nestin. In vitro, cells that had Mcl-1 conditionally deleted had a 2-fold increase in apoptosis when compared to controls. In vivo, we used electroporation to conditionally delete Mcl-1 in adult NPCs and assessed apoptosis at 72h. after electroporation. As in our in vitro results, there was a 2-fold increase in apoptosis when Mcl-1 was conditionally deleted. Finally, we found that Mcl-1 over-expression reduced the endogenous rate of adult NPC apoptosis 2-fold in vitro. Collectively, these results demonstrate that Mcl-1 is crucial for the survival of adult NPCs and may be a promising target for future neural regeneration therapies.