Scleroderma: Not an orphan disease any more

Scleroderma (or systemic sclerosis) is a rare disease associated with significant morbidity and mortality. Although previously thought to have a uniformly poor prognosis, the outlook has changed in recent years. We review recent insights into the pathogenesis, clinical features, assessment and management of scleroderma.     

Oxidative stress and DNA damage in newborns born to mothers with hyperglycemia – a prospective cohort study

Background: Hyperglycemic mothers have increased oxidative stress during pregnancy, which can adversely affect the outcome in their neonates.

Objectives: To measure the oxidative stress and DNA damage in newborns born to mothers with hyperglycemia and correlate their immediate outcome with the amount of oxidative stress and DNA damage.

Methods: This prospective cohort study conducted in a tertiary care teaching hospital, South India included three groups – newborns born to pregestational diabetic mothers, gestational diabetic mothers, and euglycemic mothers with 24 newborns in each. Oxidative stress parameters – malondialdehyde (MDA), total antioxidant capacity (TAC), and DNA damage (comet assay) were assessed in umbilical cord blood. Association between these parameters and immediate neonatal outcome among three groups were studied.

Results: Newborns born to diabetic mothers had more MDA levels and DNA damage compared to euglycemic mothers. There was a positive correlation between comet parameters and MDA levels. There was an inverse correlation between comet parameters and TAC. Newborns born to diabetic mothers were at high risk to develop respiratory distress syndrome, hypoglycemia, and sepsis.

Conclusions: Newborns born to diabetic mothers had increased oxidative stress and DNA damage compared to those born to mothers with euglycemia.     

Blessing and a curse of outpatient management of delayed graft function

Delayed graft function (DGF) is a common complication occurring most often after deceased donor kidney transplant with several donor characteristics as well as immunologic factors that lead to its development post-transplant. These patients require dialysis and close kidney function monitoring until sufficient allograft function is achieved. This has resulted in limited options for DGF management, either prolonged hospitalization until graft function improves to the point where dialysis is no longer needed or discharge back to their home dialysis unit with periodic follow up in the transplant clinic. DGF is associated with a higher risk for acute rejection, premature graft failure, and 30-d readmission; therefore, these patients need close monitoring, immunosuppression management, and prompt allograft biopsy if prolonged DGF is observed. This may not occur if these patients are discharged back to their home dialysis unit. To address this issue, the University of Wisconsin-Madison created a clinic in 2011 specialized in outpatient DGF management. This clinic was able to successfully reduce hospital length of stay without an increase in 30-d readmission, graft loss, and patient death.     

Social Vulnerability Indices as a Risk Factor for Heart Failure Readmissions

Objectives: The objective of our study was to use the parameters of social vulnerability index (SVI) to observe their association with the 30-day hospital readmissions in the heart failure population.Methods: Data required for analysis were extracted from the electronic medical record. The geographic SVI data was then merged with the clinical data. Qualitative variables and reported as frequency and quantitative variables and reported as the mean ± standard deviation. Variables from univariate analysis with a P value of ≤ 0.10 were evaluated using multivariate logistic regression with stepwise backward variable selection and receiver operating curve (ROC) analysis.Results: The odds ratio of readmission predicted by HOSPITAL score was 1.137 (P value = 0.004, 95% CI = 1.041-1.241). SVI parameter recording disability showed odds ratio of 1.521 (P value = 0.006, 95% CI = 1.125-2.058) and SVI parameter tracking vehicle ownership showed odds ratio of 15.355 (P value = 0.014, 95% CI = 1.755 – 134.383). The ROCs were generated for three scenarios: (i) HOSPITAL score only which had area under the curve (AUC) of 0.702 (P value = 0.015), (ii) SVI indicators tracking vehicle ownership and disability resulted in the AUC of 0.589 (P value = 0.016), and (iii) all of the above combined increased the AUC increased to 0.718 (P value = 0.015).Conclusions: Two social parameters (limited vehicle access and prevalence of disability) from the SVI showed a strong association with 30-day hospital readmissions.     

Reciprocal regulation of mTOR complexes in pancreatic islets from humans with type 2 diabetes

Aims/hypothesis

Mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of nutritional status at the cellular and organismic level. While mTORC1 mediates beta cell growth and expansion, its hyperactivation has been observed in pancreatic islets from animal models of type 2 diabetes and leads to beta cell loss. We sought to determine whether such mTORC1 activation occurs in humans with type 2 diabetes or in metabolically stressed human islets and whether mTORC1 blockade can restore beta cell function of diabetic islets.

Methods

Human islets isolated from non-diabetic controls and individuals with type 2 diabetes, as well as human islets and INS-1E cells exposed to increased glucose (22.2 mmol/l), were examined for mTORC1/2 activity by western blotting analysis of phosphorylation of mTORC1 downstream targets ribosomal protein S6 kinase 1 (S6K1), S6 and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) and mTORC2 downstream targets Akt and N-myc downstream regulated 1 (NDRG1). mTORC1/2 complexes’ integrity was assessed by immunoprecipitation and subsequent western blot analysis. Cell-type specific expression of activated mTORC1 in human islets was examined by immunostaining of pS6 (Ser 235/236) in human islet sections. Beta cell function was measured by glucose-stimulated insulin secretion (GSIS).

Results

While mTORC2 signalling was diminished, mTORC1 activity was markedly increased in islets from patients with type 2 diabetes and in islets and beta cells exposed to increased glucose concentrations. Under high-glucose conditions in metabolically stressed human islets, we identified a reciprocal regulation of different mTOR complexes, with functional upregulation of mTORC1 and downregulation of mTORC2. pS6 immunostaining showed beta cell-specific upregulation of mTORC1 in islets isolated from patients with type 2 diabetes. Inhibition of mTORC1–S6K1 signalling improved GSIS and restored mTORC2 activity in islets from patients with type 2 diabetes as well as in islets isolated from diabetic db/db mice and mice fed a high-fat/high-sucrose diet.

Conclusions/interpretation

Our data show the aberrant mTORC1 activity in islets from patients with type 2 diabetes, in human islets cultured under diabetes-associated increased glucose conditions and in diabetic mouse islets. This suggests that elevated mTORC1 activation is a striking pathogenic hallmark of islets in type 2 diabetes, contributing to impaired beta cell function and survival in the presence of metabolic stress.

     

Multiple myeloma masquerading as severe seropositive rheumatoid arthritis with subcutaneous nodules and mononeuritis multiplex

Multiple myeloma can rarely mimic seronegative rheumatoid arthritis (RA). We report a 55‐year‐old woman who presented with longstanding deforming polyarthritis with extensive subcutaneous nodules, tenosynovitis, anti‐cyclic citrullinated peptide positivity and mononeuritis multiplex. Even though the clinical picture was consistent with seropositive RA, the absence of bone erosion or joint space narrowing on hand and knee radiographs led us to question the diagnosis of RA. Further investigation revealed a diagnosis of multiple myeloma with cutaneous amyloid deposits, based on serum immunofixation, bone marrow aspiration and biopsy of a subcutaneous nodule. The only clue to suspect myeloma from the basic investigations and clinical examination was mild hypercalcemia. This case serves to reiterate the need to maintain a heightened suspicion for other diagnoses even when RA appears most likely.     

Cholesterol crystal embolization following plaque rupture: a systemic disease with unusual features

Cholesterol crystal embolic (CCE) syndrome is often a clinically challenging condition that has a poor prognostic implication. It is a result of plaque rupture with release of cholesterol crystals into the circulation that embolize into various tissue organs. Plaque rupture seems to be triggered by an expanding necrotic core during cholesterol crystallization forming sharp tipped crystals that perforate and tear the fibrous cap. Embolizing cholesterol crystals then initiate both local and systemic inflammation that eventually lead to vascular fibrosis and obstruction causing symptoms that can mimic other vasculitic conditions. In fact, animal studies have demonstrated that cholesterol crystals can trigger an inflammatory response via NLRP3 inflammasome similar to that seen with gout. The diagnosis of CCE syndrome often requires a high suspicion of the condition. Serum inflammation biomarkers including elevated sedimentation rate, abnormal renal function tests and eosinophilia are useful but non-specific. Common target organ involvement includes the skin, kidney, and brain. Various testing including fundoscopic eye examination and other non-invasive procedures such as trans-esophageal echocardiography and magnetic resonance imaging may be helpful in identifying the embolic source. Treatment includes aspirin and clopidogrel, high dose statin and possibly steroids. In rare cases, mechanical intervention using covered stents may help isolate the ruptured plaque. Anticoagulation with warfarin is not recommended and might even be harmful. Overall, CCE syndrome is usually a harbinger of extensive and unstable atherosclerotic disease that is often associated with acute cardiovascular events.     

Using art in an intergenerational program to improve students’ attitudes toward people with dementia

ABSTRACT

This study explored the effects of participating in an intergenerational service learning program called Opening Mind through Arts (OMA) on college students’ attitudes toward people with dementia. In this program, students were paired one-on-one with elders who have dementia to support the elders’ creation of visual art projects. They met weekly for one semester. The Dementia Attitude Scale was administered at the beginning and end of the semester to measure changes in students’ attitudes. The study included 156 students participating in OMA and assessed if their participation makes a difference in the degree of change in overall attitudes, knowledge, and comfort level toward people with dementia. Results revealed a significant improvement in students’ overall attitudes, comfort level, and attitude toward people with dementia. The results highlight the importance of intergenerational service learning in improving college students’ overall attitudes and increase their confidence and comfort working with people with dementia.