Kidney dysfunction in the low-birth weight murine adult: implications of oxidative stress.

Maternal undernutrition (MUN) during pregnancy leads to low-birth weight (LBW) neonates that have a reduced kidney nephron endowment and higher morbidity as adults. Using a severe combined caloric and protein-restricted mouse model of MUN to generate LBW mice, we examined the progression of renal insufficiency in LBW adults. Through 6 mo of age, LBW males experienced greater albuminuria (ELISA analysis), a more rapid onset of glomerular hypertrophy, and a worse survival rate than LBW females. In contrast, both sexes experienced a comparable progressive decline in renal vascular density (immunofluorescence analysis), renal blood flow (Laser-Doppler flowmetry analysis), glomerular filtration rate (FITC-sinistrin clearance analysis), and a progressive increase in systemic blood pressure (measured via tail-cuff method). Isolated aortas from both LBW sexes demonstrated reduced vasodilation in response to ACh, indicative of reduced nitric oxide bioavailability and endothelial dysfunction. ELISA and immunofluorescence analysis revealed a significant increase of circulating reactive oxygen species and NADPH oxidase type 4 (NOX4) expression in both LBW sexes, although these increases were more pronounced in males. Although more effective in males, chronic tempol treatment did improve all observed pathologies in both sexes of LBW mice. Chronic NOX4 inhibition with GKT137831 was more effective than tempol in preventing pathologies in LBW males. In conclusion, despite some minor differences, LBW female and male adults have a reduced nephron endowment comparable with progressive renal and vascular dysfunction, which is associated with increased oxidative stress and subsequent endothelial dysfunction. Tempol treatment and/or NOX4 inhibition attenuates renal and vascular dysfunction in LBW adults.

TGFα-PE38 enhances cytotoxic T-lymphocyte killing of breast cancer cells.

The aim of the present study was to determine whether the combination of two modalities of immunotherapy, targeting two different tumor antigens, may be feasible and non-toxic, yet enhance the killing of a human breast cancer cell line. The first modality was tumor growth factor α-Pseudomonas exotoxin 38 (TGFα-PE38), which specifically targets and kills tumor cells that express the epidermal growth factor receptor. The second modality was mucin-1 (MUC1)-specific cytotoxic T lymphocytes (CTLs), generated by MUC1 stimulation of peripheral blood mononuclear cells, to target the human breast cancer cell line, MCF7. TGFα-PE38 exhibited specific lysis of the MCF7 cells in a concentration- and time-dependent manner. TGFα-PE38 did not kill the normal hematopoietic stem cells or CTLs. Furthermore, TGFα-PE38 was not inhibitory for the growth or differentiation of the normal human hematopoietic stem cells into erythroid and myeloid colonies. In addition, TGFα-PE38 did not inhibit the killing function of CTLs, either when preincubated or co-incubated with CTLs. Finally, therapeutic enhancement was observed, in that TGFα-PE38 and CTLs were additive in the specific lysis of the MCF7 cells. These two modalities of immunotherapy may be beneficial for humans with breast cancer with or without other therapies, including autologous hematopoietic stem cell transplantation, specifically for purging cancer cells from hematopoietic stem cells prior to transplantation.

Tucaresol down-modulation of MUC1-stimulated human mononuclear cells.

Interaction between antigen presenting cells and T lymphocytes, through receptors and co-stimulatory molecules present on the surface of these cells, is one of the key means to modulate the adaptive immune system. Tucaresol, a Schiff-base-forming chemical, can be used as a substitute for the physiological donor of carbonyl groups of antigen presenting cells, which can interact with the amine groups of T lymphocytes to modulate the adaptive immune system. This study was done to determine whether tucaresol can enhance killing of cancer cells in vitro as well as protect non-obese diabetic severe combined immunodeficient mice from tumor development by mucin 1 stimulated human mononuclear cells through the adaptive immune system. The expected hypothesis was not supported. Percent specific lysis of MCF-7 tumor cells by mucin 1 stimulated human mononuclear cells was reduced by tucaresol. Furthermore, tucaresol abolished the protective effect of mucin 1 stimulated human mononuclear cells against MCF-7 breast cancer cell growth in non-obese diabetic severe combined immunodeficient mice. This study implies that tucaresol may be of use as an immunosuppressive agent.

Olopatadine versus levocetirizine in chronic urticaria: an observer-blind, randomized, controlled trial of effectiveness and safety.

OBJECTIVES: Chronic urticaria (CU) is characterized by frequent appearance of wheals for ≥ 6 weeks. This study was undertaken to compare effectiveness and safety of olopatadine, a newer antihistamine with additional anti-inflammatory properties, in treating CU in comparison to the established second-generation antihistamine levocetirizine. METHODS: A single center, assessor-blind, randomized (1:1), active-controlled, parallel group, Phase IV trial (CTRI/2011/08/001965) was conducted with 120 adult CU patients of either sex. Subjects received either olopatadine (5 mg b.i.d.) or levocetirizine (5 mg/day) for 9 weeks, continuously for first 4 weeks and then on demand basis for last 5 weeks. Primary outcome measures were urticaria activity score (UAS) and urticaria total severity score (TSS). Routine hematological and biochemical tests and treatment-emergent adverse events were monitored for safety. RESULTS: Data from 54 subjects on olopatadine and 51 on levocetirizine were analyzed for effectiveness. UAS and TSS values declined significantly with both drugs over the treatment period but the reduction was greater with olopatadine. Adverse event profiles were comparable with sedation being the commonest complaint. CONCLUSIONS: Olopatadine is a safe and more effective alternative to levocetirizine in the treatment of CU.

A study to evaluate the price control of antifungal medicines and its practical applicability.

BACKGROUND: Superficial fungal infections are common and treatment imposes economic burden on the patients. Government of India had introduced price control over griseofulvin and tolnaftate in 1995; however, this measure can only benefit the needy if the policy is harmonized with the health-care service provider, that is, dermatologists. The aim of this study was to evaluate the existing Government mechanisms over price control of antifungal medications and its reach to the people-in-need. MATERIALS AND METHODS: A questionnaire-based, cross-sectional study was carried out over a period of 6 months. Questionnaire was mailed to members of a state branch of Indian Association of Dermatologists, Venereologists, and Leprologists. Responses reaching investigators within 2 months from the date of mailing were finally analyzed. RESULTS: Among 93 (41.33%) respondents, only 6 (6.5%) were aware of existing price control over griseofulvin but none about tolnaftate. Thirty-nine (41.9%) respondents were in favor of introducing price control on terbinafine and 42 (45.2%) for itraconazole. The topically preferred antifungals were primarily azoles and terbinafine, while among systemic antifungals, dermatologists mostly preferred fluconazole and terbinafine. The choice of antifungals by the dermatologists matched with the evidence-based dermatology data. CONCLUSION: Currently, price-controlled antifungal drugs are less commonly used by practitioners. Although the dermatologists favor price control, the initiative undertaken by the Government has not reached them. This shows the need to bridge the gap between policy makers and health-care service providers to help the ailing population.

Prevention of human adenocarcinoma with CpG-ODN in a mouse model.

CpG-ODNs activate various immune cell subsets and induce the production of numerous cytokines. To determine whether a CpG-ODN-activated innate immune system, without the adaptive immune system, was capable of protecting against cancer cell growth, NOD/SCID mice, which do not have T or B cell function but have a functional innate immune system, were used as a model system. NOD/SCID mice were injected subcutaneously with human prostate cancer cells followed by subcutaneous injection of incremental doses of CpG-ODNs. CpG-ODNs displayed a dose-related antitumoral effect leading to the prevention of tumor growth. These results indicate that ODNs are capable of activating the innate immune system and destroying human cancer cells in the absence of the adaptive immune system.