Endocapsular hypopyon: a clinical sign of localized endophthalmitis

Chronic intraocular infection following cataract extraction and intraocular lens (IOL) implantation has been documented by several authors. We report a case of chronic, bacterial endophthalmitis that clinically correlates with previous pathologic studies in which the focus of infection was sequestered in the capsular sac between the IOL and the posterior lens capsule. Successful management did not require IOL removal.     

Autosomal dominant cerebrovascular amyloidosis: Properties of peripheral blood lymphocytes

Selected Properties of Peripheral blood lymphocytes (PBLs) from five ambulatory affected individuals of a kindred with autosomal dominant cerebrovascular amyloidosis were studied. The percentage of PBLs bearing surface membrane immunoglobulin (SmIg + cells) was increased in the patient group (30 ± 3% versus 20 ± 2%; p < 0.05). The Percentage of PBLs forming early and total E-rosettes was comparable in patient and control groups. Mitogenic response to concanavalin A (Con A) was suggestively reduced in the patient group, measured both by total ³Hthymidine incorporation and by comparison of stimulation indices. Mitogenic response to phytohemagglutinin and pokeweed was comparable in the two groups. Capping of Con A by PBLs was significantly reduced in the patient group compared with the controls (13 ± 1% versus 26 ± 2%; p < 0.01). The findings of reduced Con A response and increased SmIg⁺ cells support the hypothesis that immune dysfunction contributes to the development of amyloidosis. The reduced capping suggests altered membrane properties in this autosomal dominant disorder.     

Peripheral neuropathy, high serum IgM, and paraproteinemia in mother and son

A mother and son had peripheral neuropathy, abnormal elevation of serum IgM, and paraproteinemia. These patients may have a familial disorder of immune regulation with antibody-mediated neuropathy or a familial neuropathy with a secondary immune response.     

Early cessation of breastfeeding amongst women in South Africa: an area needing urgent attention to improve child health

ABSTRACT: BACKGROUND: Breastfeeding is a critical component of interventions to reduce child mortality. Exclusive breastfeeding practice is extremely low in South Africa and there has been no improvement in this over the past ten years largely due to fears of HIV transmission. Early cessation of breastfeeding has been found to have negative effects on child morbidity and survival in several studies in Africa. This paper reports on determinants of early breastfeeding cessation among women in South Africa. METHODS: This is a sub group analysis of a community-based cluster-randomized trial (PROMISE EBF) promoting exclusive breastfeeding in three South African sites (Paarl in the Western Cape Province, and Umlazi and Rietvlei in KwaZulu-Natal) between 2006 and 2008 (ClinicalTrials.gov no: NCT00397150). Infant feeding recall of 22 food and fluid items was collected at 3, 6, 12 and 24?weeks postpartum. Women's experiences of breast health problems were also collected at the same time points. 999 women who ever breastfed were included in the analysis. Univariable and multivariable logistic regression analysis adjusting for site, arm and cluster, was performed to determine predictors of stopping breastfeeding by 12?weeks postpartum. RESULTS: By 12?weeks postpartum, 20% of HIV-negative women and 40% of HIV-positive women had stopped all breastfeeding. About a third of women introduced other fluids, most commonly formula milk, within the first 3?days after birth. Antenatal intention not to breastfeed and being undecided about how to feed were most strongly associated with stopping breastfeeding by 12?weeks (Adjusted odds ratio, AOR 5.6, 95% CI 3.4 - 9.5 and AOR 4.1, 95% CI 1.6 - 10.8, respectively). Also important was self-reported breast health problems associated with a 3-fold risk of stopping breastfeeding (AOR 3.1, 95%CI 1.7 - 5.7) and the mother having her own income doubled the risk of stopping breastfeeding (AOR 1.9, 95% CI 1.3 - 2.8). CONCLUSION: Early cessation of breastfeeding is common amongst both HIV-negative and positive women in South Africa. There is an urgent need to improve antenatal breastfeeding counselling taking into account the challenges faced by working women as well as early postnatal lactation support to prevent breast health problems.     

A truncated analogue of CCL2 mediates anti-fibrotic effects on murine fibroblasts independently of CCR2

The truncated [1+9-76] CCL2 analogue, also known as 7ND, has been described in numerous reports as an anti-inflammatory and anti-fibrotic agent in a wide spectrum of animal models, e.g. models of cardiovascular disease, graft versus host disease and bleomycin-induced pulmonary fibrosis. 7ND has been reported to function as a competitive inhibitor of CCL2 signaling via CCR2 in human in vitro systems. In contrast, the mechanistic basis of 7ND action in animal models has not been previously reported. Here we have studied how 7ND interacts with CCL2 and CCR2 of murine origin. Surprisingly, 7ND was shown to be a weak inhibitor of murine CCL2/CCR2 signaling and displaced murine CCL2 (JE) from the receptor with a K(i)>1 μM. Using surface plasmon resonance, we found that 7ND binds murine CCL2 with a K(d) of 670 nM, which may indicate that 7ND inhibits murine CCL2/CCR2 signaling by a dominant negative mechanism rather than by competitive binding to the CCR2 receptor. In addition we observed that sub-nanomolar levels of 7ND mediate anti-fibrotic effects in CCR2 negative fibroblasts cultured from fibrotic lung of bleomycin-induced mice. Basal levels of extracellular matrix proteins were reduced (collagen type 1 and fibronectin) as well as expression levels of α-smooth muscle actin and CCL2. Our conclusion from these data is that the previously reported effects of 7ND in murine disease models most probably are mediated via mechanisms independent of CCR2.     

Reduction in albuminuria with dapagliflozin cannot be predicted by baseline clinical characteristics or changes in most other risk markers

The sodium glucose co-transporter-2 inhibitor dapagliflozin has been shown to decrease urinary albumin-to-creatinine ratio (UACR). This effect, however, varies among individual patients. In this study, we assessed the baseline characteristics and concurrent changes in other cardiovascular risk markers that might be associated with UACR response to dapagliflozin. A pooled analysis of 11 phase 3 randomized, controlled clinical trials was performed. UACR change from baseline after 24 weeks treatment with dapagliflozin 10 mg/d in 531 patients with type 2 diabetes and UACR ≥30 mg/g at baseline was determined. UACR response was defined as >30% reduction from baseline at 24 weeks, whereas UACR non-response was defined as ≤30% reduction at 24 weeks. A total of 288 (54%) patients were classified as responders and 243 (46%) as non-responders. At 24 weeks, the UACR-adjusted mean change from baseline was −71.2% and 25.9% in responders and non-responders, respectively. Baseline characteristics were similar between both groups. Changes in HbA1c and body weight were comparable across groups. Responders showed a numerically larger reduction in estimated glomerular filtration rate and systolic blood pressure versus non-responders. UACR reduction to dapagliflozin is an individual characteristic that cannot be predicted by baseline clinical features or changes in metabolic variables. Whether UACR response would improve long-term renal and cardiovascular outcomes remains to be determined.     

Dissociation of accumulated genetic risk and disease severity in patients with schizophrenia

Genotype–phenotype correlations of common monogenic diseases revealed that the degree of deviation of mutant genes from wild-type structure and function often predicts disease onset and severity. In complex disorders such as schizophrenia, the overall genetic risk is still often >50% but genotype–phenotype relationships are unclear. Recent genome-wide association studies (GWAS) replicated a risk for several single-nucleotide polymorphisms (SNPs) regarding the endpoint diagnosis of schizophrenia. The biological relevance of these SNPs, however, for phenotypes or severity of schizophrenia has remained obscure. We hypothesized that the GWAS ‘top-10'' should as single markers, but even more so upon their accumulation, display associations with lead features of schizophrenia, namely positive and negative symptoms, cognitive deficits and neurological signs (including catatonia), and/or with age of onset of the disease prodrome as developmental readout and predictor of disease severity. For testing this hypothesis, we took an approach complementary to GWAS, and performed a phenotype-based genetic association study (PGAS). We utilized the to our knowledge worldwide largest phenotypical database of schizophrenic patients (n>1000), the GRAS (Göttingen Research Association for Schizophrenia) Data Collection. We found that the ‘top-10'' GWAS-identified risk SNPs neither as single markers nor when explored in the sense of a cumulative genetic risk, have any predictive value for disease onset or severity in the schizophrenic patients, as demonstrated across all core symptoms. We conclude that GWAS does not extract disease genes of general significance in schizophrenia, but may yield, on a hypothesis-free basis, candidate genes relevant for defining disease subgroups.     

Efficacy and Safety of Dapagliflozin by Baseline Glycemic Status: A Prespecified Analysis From the DAPA-CKD Trial

OBJECTIVEThe Dapagliflozin and Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) study demonstrated risk reduction for kidney and cardiovascular outcomes with dapagliflozin versus placebo in participants with chronic kidney disease (CKD) with and without diabetes. We compared outcomes according to baseline glycemic status.RESEARCH DESIGN AND METHODSWe enrolled participants with CKD, estimated glomerular filtration rate (eGFR) 25–75 mL/min/1.73 m², and urinary albumin-to-creatinine ratio 200–5,000 mg/g. The primary composite end point was sustained eGFR decline ≥50%, end-stage kidney disease, or kidney or cardiovascular death.RESULTSOf 4,304 participants, 738 had normoglycemia, 660 had prediabetes, and 2,906 had type 2 diabetes. The effect of dapagliflozin on the primary outcome was consistent (P for interaction = 0.19) in normoglycemia (hazard ratio [HR] 0.62 [95% CI 0.39, 1.01]), prediabetes (HR 0.37 [0.21, 0.66]), and type 2 diabetes (HR 0.64 [0.52, 0.79]). We found no evidence for effect modification on any outcome. Adverse events were similar, with no major hypoglycemia or ketoacidosis in participants with normoglycemia or prediabetes.CONCLUSIONSDapagliflozin safely reduced kidney and cardiovascular events independent of baseline glycemic status.     

Role of osteoprotegerin (OPG) in cancer

OPG (osteoprotegerin), a secreted member of the TNF (tumour necrosis factor) receptor superfamily, has a variety of biological functions which include the regulation of bone turnover. OPG is a potent inhibitor of osteoclastic bone resorption and has been investigated as a potential therapeutic for the treatment of both osteoporosis and tumour-induced bone disease. Indeed, in murine models of cancer-induced bone disease, inhibition of osteoclastic activity by OPG was also associated with a reduction in tumour burden. The discovery that OPG can bind to and inhibit the activity of TRAIL (TNF-related apoptosis-inducing ligand) triggered extensive research into the potential role of OPG in the regulation of tumour cell survival. A number of reports from studies using in vitro models have shown that OPG protects tumour cells from the effects of TRAIL, thereby possibly providing tumour cells that produce OPG with a survival advantage. However, the ability of OPG to act as a tumour cell survival factor remains to be verified using appropriate in vivo systems. A third area of interest has been the use of OPG as a prognostic marker in various cancer types, including myeloma, breast and prostate cancer. This review provides an overview of the role of OPG in cancer, both in cancer-induced bone disease and in tumour growth and survival.