Renal findings and glomerular pathology in diabetic subjects

BACKGROUND: To describe the relationship between proteinuria, hematuria, and renal insufficiency, on one hand, and glomerular pathology, on the other hand, in a consecutive biopsy series of diabetic patients. SUBJECTS AND METHODS: All diabetic subjects (n = 200) biopsied from 1979 to 1995 at Tampere University Hospital were identified in retrospect. The clinician-based indication (any unexplained renal finding) for renal biopsy was consistent during the years and was: proteinuria alone in 68%; combined with hematuria in 10%; with renal insufficiency in 10%; with both in 9%, and with isolated hematuria or renal failure in 3%. One third of the subjects had proteinuria of >/=3 g/24 h and 16% a serum creatinine level of >/=200 microM. Glomerulopathy was found in 171 specimens and defined as nodular diabetic (group A), diffuse diabetic (group B) and primary (group C). The 24-hour urinary protein excretion rate [mean (range)] was 3.5 (1.6-6.9), 1.0 (0.5-3.5), and 3.6 (1.1-6.6) g in groups A, B and C, respectively (ANOVA p = 0.001). The corresponding serum creatinine values [mean (SD)] were 175 (115), 105 (142) and 169 (138) microM (p = 0.001). Results: Nodular diabetic glomerulopathy was found in 40%, diffuse diabetic glomerulopathy in 42% and primary glomerulopathy in 18%. A primary glomerulopathy was found in any indication and in both types of diabetes (prevalence range 14-26%). The best multivariate logistic regression model obtained (chi(2) = 13.5, p = 0.008) in predicting the presence of diabetic glomerulosclerosis (group A + B) in contrast to a primary glomerulopathy (group C) included retinopathy (p = 0.04), renal insufficiency (p = 0.03), hematuria (p = 0.12) and type of diabetes (p = 0.10). CONCLUSION: In this series of diabetic subjects, biopsied due to proteinuria, hematuria and not severe renal insufficiency, 18% had evidence of a primary glomerulopathy.     

Death following ingestion of MDMA (ecstasy) and moclobemide

Four deaths following the ingestion of moclobemide and MDMA ('ecstasy') are described. The probable cause of death in each case was serotonin syndrome as a result of an interaction between the two drugs. As none of the victims had been prescribed moclobemide it seems that each had taken the drug to enhance the effects of MDMA, with fatal consequences. Warnings are needed against misinformed attempts to potentiate the pharmacological effects of illicit drugs.     

Very acute cardiac toxicity during BEAC chemotherapy in non-Hodgkin's lymphoma patients undergoing autologous stem cell transplantation

Cardiotoxicity is potentially the most threatening nonhaematological side effect of high-dose CY. We prospectively evaluated the very acute cardiac effects of high-dose CY in 17 adult non-Hodgkin's lymphoma (NHL) patients receiving CY 1500 mg/m2/day as a part of BEAC high-dose therapy (HDT). Magnetic resonance imaging (MRI) and plasma natriuretic peptide (NT-proBNP, NT-proANP) measurements were performed prior to HDT (d-7) and just after completing HDT (d-2). After the high-dose CY left atrial end-systolic area increased from 15.2+/-1.2 to 18.5+/-1.4 cm2 (P=0.001), left ventricular end-diastolic volume from 136.1+/-12.3 to 156.6+/-11.1 cm3 (P=0.04) and left ventricular end-systolic volume from 67.4+/-7.8 to 75.3+/-7.1 cm3 (P=0.018). However, no significant change in left ventricular ejection fraction (LVEF) was observed. At the same time, plasma levels of NT-proBNP increased from 134.9+/-53.3 to 547.1+/-168.4 pmol/l (P=0.003) and NT-proANP from 481.1+/-105.5 to 1056.6+/-193.1 pmol/l (P=0.001), respectively. To conclude, high-dose CY results in very acute cardiac toxicity characterised by enlargement of the heart chambers in NHL patients previously treated with anthracyclines. This toxicity can be detected with increased concentrations of circulating natriuretic peptides but not with LVEF measurement.     

Synthesis and in vitro anti-proliferative evaluation of naphthalimide–chalcone/pyrazoline conjugates as potential SERMs with computational validation

A series of naphthalimide-chalcone/pyrazoline conjugates was prepared and evaluated for their anti-breast cancer potential against estrogen responsive, i.e. MCF-7 (ER+), and triple-negative, i.e. MDA-MB-231 (ER−), cell lines. The structure-activity-relationship (SAR) was deduced based on the influence of linker length, substituents on the phenyl ring and the generated functionalities, on anti-proliferative activities. Docking simulations further delineate the type of interactions of the designed molecules with the selected targets. This report discloses the scope of triazole tethered naphthalimide-chalcone/pyrazoline conjugates as anti breast cancer agents.

Design, synthesis and anti-proliferative evaluation of naphthalimide–chalcone/pyrazoline conjugates.     

Dental students' perceptions of dental specialties and factors influencing specialty and career choices

The goals of this study were to 1) evaluate dental students' perceptions of dental specialties, 2) identify factors that play an important role in students' decision to pursue specialty training or career choices, and 3) establish a baseline of students' perceptions of the dental fields with the best future in terms of salary, personal and patient quality of life, and overall impact on the dental profession. Surveys were distributed to 494 students at the University of Pennsylvania School of Dental Medicine. Data were collected from 380 traditional four-year students and thirty advanced standing students. Chi-square tests, multivariate analysis, and logistic regressions were used to determine associations and independent contributions of student demographics to their perceptions of dental specialties and factors influencing specialty training or career choices. Debt was a statistically significant factor (p<0.001) in choosing specialty training or career independent of gender, age, or class year. Enjoyment of providing care in a specialty or field was identified as the single most important factor in choosing a specialty career. Half of the respondents had decided not to specialize. Pursuing postdoctoral general dentistry training and private practice in general dentistry were the most commonly reported plans after completion of dental school. Suggestions are made for ways to inform students about specialty training.     

Neural functional and structural correlates of childhood maltreatment in women with intimate-partner violence-related posttraumatic stress disorder

Childhood maltreatment (CM) is a strong risk factor for development of posttraumatic stress disorder (PTSD) upon adult exposure to extreme adverse events. However, the neural underpinnings of this relationship are not well understood. Here, we test the hypothesis that severity of CM history is positively correlated with emotion-processing limbic and prefrontal brain activation/connectivity and negatively correlated with prefrontal gray matter volumes in women with PTSD due to intimate-partner violence (IPV-PTSD). Thirty-three women with IPV-PTSD underwent structural and functional magnetic resonance imaging while completing a facial emotion processing task. Multivariate regressions examined the relationship of CM to patterns of activation, connectivity, and gray matter volumes. CM severity was: (a) positively correlated with ventral ACC activation while processing angry faces; (b) negatively correlated with dorsal ACC and insula activation while processing fear and angry faces, arising from positive correlations with the shape-matching baseline; (c) positively correlated with limbic–prefrontal connectivity while processing fear faces but negatively correlated with amygdalo–insular connectivity while processing fear and angry; and (d) negatively correlated with prefrontal gray matter volumes. These results suggest CM exposure may account for variability in limbic/prefrontal brain function and prefrontal structure in adulthood PTSD and offer one potential mechanism through which CM confers risk to future development of PTSD.     

Arginine-α, β-dehydrophenylalanine Dipeptide Nanoparticles for pH-Responsive Drug Delivery

Purpose

Nanoparticles (NPs) exhibiting responsiveness towards pH variations in organs, tissue microenvironments and cellular compartments can significantly add on to the drug delivery potential. Here, we have developed NPs from an amphipathic dipeptide, Arginine-α, β-dehydrophenylalanine (RΔF), and tried to explore their pH responsive drug delivery potential in various cancer cells.

Methods

RΔF-NPs were architectured by harnessing the process of molecular self-assembly followed by the assessment of effect of pH on NPs morphology using zetasizer, SEM and CD. FTIR and PXRD analysis of the dipeptide and doxorubicin (Dox) were carried out for compatibility assessment followed by encapsulation of Dox in RΔF-NPs. RΔF-Dox-NPs were evaluated for pH dependent release as well as for in-vitro cellular internalization and efficacy in cancer cells.

Results

RΔF self-assembled to form monodispersed particles at pH 7. SEM analysis revealed a loss of overall particle morphology along with particle aggregation at highly acidic and basic pH respectively. The NPs demonstrated a slow and sustained release behaviour at pH 7 (97.64?±?4.71% after 36 h) in comparison to pH 2 (90.27?±?1.45% after 8 h) and pH 10 (96.39?±?3.87% after 12 h). In-vitro efficacy studies carried-out in various cancer cells revealed that RΔF-Dox-NPs exhibited higher efficacy with 1.65, 1.95 and 13.34 fold lower IC₅₀ values in comparison to Dox in C6, HCT-116 and AGS cell lines.

Conclusions

RΔF-Dox-NPs with higher drug release at acidic pH, enhanced internalization in cancer cells along with higher cytotoxic potential can act as effective pH responsive drug delivery systems.