Modulating the endoplasmic reticulum stress response with trans-4,5-dihydroxy-1,2-dithiane prevents chemically induced renal injury in vivo.

Agents that disrupt functions of the endoplasmic reticulum (ER) induce expression of ER stress-response genes including ER chaperones. Increased expression of the major ER chaperone, Grp78, protects cells, including renal epithelial cells, from chemically induced injury and death in vitro. In this study, we determined if pharmacological manipulation of the ER stress-response gene is an effective strategy to protect the kidney from chemical stress in vivo. Treatment with trans-4,5-dihydroxy-1,2-dithiane (DTTox), a novel inducer of ER stress proteins, stimulated a time-and dose-dependent increase in Grp78 expression in the kidney, but it did not cause detectable injury. Furthermore, prior treatment with DTTox protected the proximal tubular epithelium against a subsequent challenge with the nephrotoxicant S-(1,1,2,2,-tetrafluoroethyl)-L-cysteine (TFEC). In contrast, activating a heat shock response did not have a protective effect. Prior treatment with DTTox did not reduce covalent binding of radiolabeled reactive metabolites of (35)S-TFEC to renal proteins, indicating that protection was not due to an effect on the metabolic activation of TFEC to the reactive metabolite(s) responsible for renal injury. Antisense grp78 expression in the renal epithelial cell line LLC-PK1 blocked the DTTox-induced Grp78 increase and ablated the protective effect against TFEC damage, indicating that the induction of grp78 expression and the ER stress response were critical for the protective effect of DTTox. These findings suggest that increased expression of Grp78 plays a major role in the protection of renal epithelial cells from reactive intermediate-induced chemical injury in vivo and that pharmacological manipulation is an effective strategy to prevent damage by some classes of nephrotoxicants.     

Progression of clinical tuberculosis is associated with a Th2 immune response signature in combination with elevated levels of SOCS3

In this study, we explored the local cytokine/chemokine profiles in patients with active pulmonary or pleural tuberculosis (TB) using multiplex protein analysis of bronchoalveolar lavage and pleural fluid samples. Despite increased pro-inflammation compared to the uninfected controls; there was no up-regulation of IFN-γ or the T cell chemoattractant CCL5 in the lung of patients with pulmonary TB. Instead, elevated levels of IL-4 and CCL4 were associated with high mycobacteria-specific IgG titres as well as SOCS3 (suppressors of cytokine signaling) mRNA and progression of moderate-to-severe disease. Contrary, IL-4, CCL4 and SOCS3 remained low in patients with extrapulmonary pleural TB, while IFN-γ, CCL5 and SOCS1 were up-regulated. Both SOCS molecules were induced in human macrophages infected with Mycobacterium tuberculosis in vitro. The Th2 immune response signature found in patients with progressive pulmonary TB could result from inappropriate cytokine/chemokine responses and excessive SOCS3 expression that may represent potential targets for clinical TB management.     

An aminoacridine derivative for radionuclide therapy: DNA binding properties studied in a novel cell-free in vitro assay

Radiolabelled DNA-binding compounds can be used to increase the efficiency of radionuclide cancer therapy of disseminated disease. In this work, the aminoacridine compound N-[3-(acridine-9-ylamino)-propyl]-3-iodobenzamide (A3) labelled with the Auger-emitting nuclide 125I using Chloramine-T was studied. Optimal labelling conditions of 125I-A3 were investigated and the interaction with DNA was studied using a novel cell-free in vitro assay with naked human genomic DNA in agarose plugs. This novel assay showed to be simple and reliable. The results verify that 125I-A3 specifically binds DNA with low dissociation and is potent in causing double-strand breaks, yielding 1.0-1.4 breaks per decay. In conclusion, 125I-A3 is a most suitable DNA-binding compound for future therapeutic studies of Auger-electron emitters like 125I.     

The associations of hormone replacement therapy and preventive practices in minority women

OBJECTIVES: Minority women are less likely to use hormone replacement therapy (HRT), and the health characteristics associated with HRT use in this population are not well studied. We sought to examine the sociodemographic characteristics, health and preventive practices associated with HRT use among minority women. DESIGN: Survey SETTING: Inpatient and outpatient units of a teaching hospital. PARTICIPANTS: A convenience sample of 333 minority women aged 50 and above. VARIABLES: HRT use, demographic and lifestyle characteristics, and selected preventive practices. RESULTS: 14% of the study population, all minority women were using HRT. Regular exercise (p=0.03), and good perceived health status (p=0.02) were significant predictors of HRT use. None of the cancer screening measures studied were associated with HRT use. CONCLUSIONS: Only a small proportion of minority women were using HRT. Regular exercise and perceived good health were significant predictors of HRT use.     

Evaluation of antiretroviral treatment in two private medical centers in Addis, Ethiopia

Ethiopia is one of the countries affected severely by the HIV/AIDS epidemic in sub-Saharan Africa. The disease is gradually fatal without antiretroviral therapy (ARV). The experience with antiretroviral therapy is limited in this country. This study is the first of its kind that has evaluated the status and implication of the clinical use of ARV drugs in Ethiopia. The guidelines for the initiation of treatment, the strengths and weaknesses of such treatment and the implications of similar intervention in a wider scale were assessed. Clinical records of 33 patients under follow-up and treatment with ARV in Hayat Hospital and Bethezatha Medical Center were identified. Data were collected from the medical records using a tool designed for the purpose. All 33 patients were receiving ARV for a mean duration of about 4 months. Twenty- three (69.7%) were males and 10 (30.3%) were females and the mean age was 38 years. Fifteen (45.5%) were married, fourteen (40.7%) were single, one (3%) divorced and there was no record for three (9.1%). Fifteen (45.5%) were businessmen, seven (21.2%) were private employees, four (12.1%) civil servants and in the remaining seven (21.2%) their occupation was not recorded. The decision to initiate ARV therapy was entirely based on the presence of symptomatic HIV disease. CD4+ lymphocyte count was done in 24 (72.7%) and basic hematological tests were done for all. However, biochemical investigations were incomplete in all of them. Triple therapy was started for all patients and the cost of the drugs was covered by their family in eleven (33.3%), by the patients in twenty-two (66.7%). Side effects of the drugs were noted in ten (30.3%) that resulted in change of the regimen in two and drug interruption in one. Response to treatment was entirely based on clinical parameters only. Twenty-three patients (69.7%) were noted to improve while nine (27.3%) remained the same and death occurred in one (3%). Standard triple therapy was used in all patients in this study and symptomatic HIV disease was the reason for the initiation of treatment. The improvement observed was not substantiated by immunological or virological parameters. Thus, the impacts of ARVs cannot be measured and the response documented in this study can be due to the effective treatment of opportunistic infections. Hence a standard protocol should be developed based on the minimum set-up required for the initiation of ARV therapy.     

Racial differences in preventive practices of African-American and Hispanic women

OBJECTIVES: To compare the use of preventive practices of Hispanic- and African-American women aged 50 and older. DESIGN: A cross-sectional survey. SETTING: Inpatient and outpatient units of a teaching hospital located in South Central Los Angeles. PARTICIPANTS: Convenience sample of 337 women aged 50 and older. MEASUREMENTS: Demographic and lifestyle characteristics and selected preventive practices. Preventive practices reported were self-breast examination, mammography, Papanicolaou (Pap) smear, digital rectal examination and stool occult blood examination, sigmoidoscopy, chemoprophylaxis, and immunization. Information was obtained in a face-to-face interview. RESULTS: African-American women were more likely to have had a Pap smear ever and to have used aspirin prophylaxis than Hispanic women. CONCLUSION: There were no major differences in the use of preventive services by the two ethnic groups except for Pap smear and aspirin use. Immunization and colorectal cancer screening rates were low in African-American and Hispanic women.     

The Effect of Urban Street Gang Densities on Small Area Homicide Incidence in a Large Metropolitan County, 1994–2002

The presence of street gangs has been hypothesized as influencing overall levels of violence in urban communities through a process of gun–drug diffusion and cross-type homicide. This effect is said to act independently of other known correlates of violence, i.e., neighborhood poverty. To test this hypothesis, we independently assessed the impact of population exposure to local street gang densities on 8-year homicide rates in small areas of Los Angeles County, California. Homicide data from the Los Angeles County Coroners Office were analyzed with original field survey data on street gang locations, while controlling for the established covariates of community homicide rates. Bivariate and multivariate regression analyses explicated strong relationships between homicide rates, gang density, race/ethnicity, and socioeconomic structure. Street gang densities alone had cumulative effects on small area homicide rates. Local gang densities, along with high school dropout rates, high unemployment rates, racial and ethnic concentration, and higher population densities, together explained 90% of the variation in local 8-year homicide rates. Several other commonly considered covariates were insignificant in the model. Urban environments with higher densities of street gangs exhibited higher overall homicide rates, independent of other community covariates of homicide. The unique nature of street gang killings and their greater potential to influence future local rates of violence suggests that more direct public health interventions are needed alongside traditional criminal justice mechanisms to combat urban violence and homicides. An erratum to this article can be found at     

Increased Arterial Augmentation and Augmentation Index as Surrogate Parameters for Arteriosclerosis in Subjects with Diabetes Mellitus and Nondiabetic Subjects with Cardiovascular Disease

Background

Arterial augmentation (AP) and the augmentation index (Aix) are surrogate parameters of arterial stiffness and are commonly used as predictors for cardiovascular risk. The aim of this study is to compare these parameters in diabetic subjects and nondiabetic cardiovascular risk subjects with healthy control subjects.

Methods

One hundred sixty-six nonsmoking subjects aged between 35 and 70 years were included in the study, which included 100 subjects with cardiovascular disease but not diabetes (mean age 62.73±8.75 years), 33 subjects with type 2 diabetes (66.58±2.69 years), and 33 healthy controls (51.89±8.91 years). In these subjects, arterial stiffness was measured by the difference between the second and the first systolic peak of the central pressure waveform, and the Aix was calculated as the percentage of Aix from pulse pressure.

Results

Arterial augmentation was increased in subjects with diabetes (DM) with 10.21±6.97 mm Hg and in subjects with cardiovascular disease but not diabetes (CV) with 10.74±5.29 mm Hg in comparison to healthy controls (C) with 6.59±3.97 mm Hg (p < 0.0005 DM vs C; p < 0.00005 CV vs C). Moreover, Aix was increased with 26.00±9.91% in CV subjects compared to healthy controls with 19.84±9.37% (p < 0.02 CV vs C). The augmentation index was increased with 21.12±11.21% in subjects with type 2 diabetes mellitus compared to controls, but failed to be statistically significant. There was no statistical significance in arterial augmentation or the augmentation index between CV and diabetic subjects.

Conclusion

The results of our study revealed a comparable increased augmentation index as a surrogate measure of arterial stiffness and arteriosclerosis in subjects with diabetes mellitus and in nondiabetic subjects with cardiovascular disease.     

Reliability of Lightguide Spectrophotometry (O2C?) for the Investigation of Skin Tissue Microvascular Blood Flow and Tissue Oxygen Supply in Diabetic and Nondiabetic Subjects

Background and Aims

Skin microvascular assessment has progressed to an important evaluation in patients with diabetes mellitus. This study was done to evaluate a new device using micro-lightguide spectrophotometry in the assessment of skin microvascular function.

Material and Methods

Twenty nondiabetic subjects (age 46.6 ± 14.8 years; mean ± SD) and 20 diabetic patients (age 59.4 ± 8.4 years) participated in repeated microvascular measurements using micro-lightguide spectrophotometry. This technique allows simultaneous, noninvasive measurement of microvascular blood flow and hemoglobin oxygenation (SO₂) at the same anatomical area in different tissue layers. A skin probe was placed on nonhairy skin at the thenar eminence of the left hand for the measurement of SO₂, and the postischemic reactive hyperemia response (PRH) was measured in skin and underlying muscle tissue.

Results

Repeated measurements in PRH revealed a good correlation at the superficial skin layer (r = 0.97, p < 0.0001) with a coefficient of variation at 9.2 ± 1.7% and at the superficial muscle layer (r = 0.80, p < 0.0002) with a coefficient of variation at 9.7 ± 1.5%. A slightly weaker correlation was observed for the SO₂ measurement at the skin layer (r = 0.69 ± p < 0.0001) with a coefficient of variation at 17.5 ± 3.8% and at the muscle layer (r = 0.48; p = 0.0016) with a coefficient of variation at 18.1 ± 10.5%.

Conclusions

Lightguide spectrophotometry is an easy, noninvasive, and reliable method for simultaneous measurement of superficial microvascular blood flow by laser Doppler fluxmetry and skin oxygenation by spectrophotometry. Further studies are required to clarify the validity of these measures in special patient populations such as diabetes mellitus with specified microvascular complications.