<Emphasis Type="Italic">N</Emphasis>-(2-Hydroxyphenyl)acetamide: a Novel Suppressor of RANK/RANKL Pathway in Collagen-Induced Arthritis Model in Rats

RANKL and RANK are potential contributors of inflammatory cascade in human and animal model of arthritis. The current study aims to investigate the effect of N-(2-hydroxyphenyl)acetamide (NA-2) on regulation of RANKL pathway in collagen-induced arthritis (CIA) model in rats. CIA was induced using bovine type II collagen in female Wistar rats. The clinical parameters, level of pro-inflammatory and oxidative stress markers were measured to determine the progression of the disease. The mRNA level of RANKL and RANK and downstream mediators of inflammation i.e. c-fos, c-jun, NF-κB and Akt were analysed in spleen tissue using real-time PCR. Immunohistochemical analysis of iNOS, pAkt and c-Fos was also done in spleen tissue. Treatment with NA-2 and indomethacin showed increase in body weight and significant reduction in paw volume and arthritic score (p < 0.0001). Marked reduction in the level of oxidative stress markers, NO, PO and GSH (p < 0.0001), and pro-inflammatory markers, IL-1β (p < 0.0001) and TNF-α (p < 0.01), was also observed. Likewise, NA-2 and indomethacin treatment also significantly suppressed the mRNA expression of RANKL, RANK, c-fos, c-jun, NF-κB (p < 0.0001) and Akt (p < 0.01) and protein expression of iNOS, pAkt and c-Fos (p < 0.0001) compared to the arthritic control group. Our findings suggest that NA-2 is an antiarthritic agent acting in a pleiotropic manner in CIA rats by not only reducing the clinical signs of arthritis, inflammatory cytokines and free radical production but also attenuating the RANK/RANKL signaling pathway.     

Latent activity of curcumin against leishmaniasis in vitro

In this study the anti-proliferative effect of curcumin (curcuma longa) that is the active ingredient of ground dried rhizome has been studied against three local and three reference leishmanial strains, Leishmania major, Leishmania tropica and Leishmania infantum (Pakistani isolate). Curcumin has shown an average IC50 of 5.3 microM against promastigotes of various leishmanial strains which is much lower as compared with pentamidine that is one of the basic treatments against leishmaniasis. The main draw back attributed to these assays performed on promastigotes is the heterogeneity of results compared with those obtained with intracellular amastigotes or with in vivo effect. We also tested activity of curcumin against axenic amastigote like cells (AALC) of L. major strain (MHOM/PK/88/DESTO). Curcumin proves to be far more potent then pentamidine against AALC which further strengthens the fact about its leishmaniacidal activity.     

Comorbid personality disorder predicts suicide after major depression: a 10-year follow-up

OBJECTIVE: To identify psychopathological predictors for suicide in a population of major depressed Diagnostic Statistical Manual-III (DSM-III) in-patients. METHOD: A total of 210 previous participants in multicentre antidepressant drug trials, carried out in a randomized double-blind design, were followed prospectively through a maximum of 10 years. Patients with a drug or alcohol abuse were excluded. The association between suicide and the pretreatment psychopathological profile was analysed using survival statistics. RESULTS: The suicide rate for non-melancholic depressed patients was significantly higher than for melancholic depressed patients. Comorbid personality disorder was independently associated with an increased suicide rate [relative hazard 3.41(CI: 1.15-10.10)]. CONCLUSION: The study indicates that the non-melancholic aspect of depression, and especially comorbid personality disorder, is associated with an increased suicidal vulnerability.     

Preirradiation endocrinopathies in pediatric brain tumor patients determined by dynamic tests of endocrine function

PURPOSE: To prospectively evaluate pediatric patients with localized primary brain tumors for evidence of endocrinopathy before radiotherapy (RT). METHODS AND MATERIALS: Seventy-five pediatric patients were evaluated with the arginine tolerance test and L-dopa test for growth hormone secretory capacity and activity; thyroid-stimulating hormone surge and thyrotropin-releasing hormone stimulation test for the hypothalamic-thyroid axis; the 1-microg adrenocorticotropin hormone (ACTH) and metyrapone test for ACTH reserve; and, depending on age, a gonadotropin-releasing hormone stimulation test to determine gonadotropin response. The study included 38 male and 37 female patients, age 1-21 years with ependymoma (n = 35), World Health Organization (WHO) Grade I-II astrocytoma (n = 18), WHO Grade III-IV astrocytoma (n = 10), craniopharyngioma (n = 7), optic pathway tumor (n = 4), and germinoma (n = 1). Seven patients receiving dexamethasone at the time of the evaluation were excluded from the final analysis. RESULTS: Of 68 assessable patient, 45 (66%) had evidence of endocrinopathy before RT, including 15 of 32 patients (47%) with posterior fossa tumors. Of the 45 patients, 38% had growth hormone deficiency, 43% had thyroid-stimulating hormone secretion abnormality, 22% had an abnormality in ACTH reserve, and 13% had an abnormality in age-dependent gonadotropin secretion. CONCLUSION: The incidence of pre-RT endocrinopathy in pediatric brain tumor patients is high, including patients with tumors not adjacent to the hypothalamic-pituitary unit. These data suggest an overestimation in the incidence of radiation-induced endocrinopathy. Baseline endocrine function should be determined for brain tumor patients before therapy. The potential for radiation-induced endocrinopathy alone cannot be used as an argument for alternatives to RT for most patients. Pre-RT endocrinopathy may be an early indicator of central nervous system damage that will influence the functional outcome unrelated to RT.     

Age-related adverse drug reactions to clomipramine

OBJECTIVE: The aim of this study was to determine whether age itself is a significant factor in predicting adverse drug reactions in depressed inpatients treated with clomipramine. METHOD: The study involved 150 hospitalized, depressed patients treated with 150 mg clomipramine per day. Changes in orthostatic blood pressure during treatment as well as the patients' complaint about side-effects was examined with regard to age. The sample was divided into younger (<56) and older (56-70) groups. RESULTS: No significant differences between younger and older subjects were found on any of the 44 side-effects recorded. However, older depressed patients suffer from more pronounced orthostatic hypotension than younger patients. CONCLUSION: Older depressed patients who have been treated with clomipramine suffer from more severe orthostatic hypotension than younger patients. However, with the right precautions it is safe to treat older patient up to the age of 70 years with a tricyclic antidepressant.     

Hypertension and renovascular disease: follow-up on 100 renal vein renin samplings

The clinical value of renal vein renin sampling (RVRS) as a prognostic tool in the treatment of renovascular hypertension was evaluated. One hundred consecutive patients were included over a 4-year period of time. About half of the patients (49%) were treated interventionally by PTRA (21%), nephrectomy (20%), or vascular surgery (8%). Seven patients (15%) were cured and 15 (32%) had improved (reduction in antihypertensive medicine) after 6 months follow-up, whereas three patients (6%) were cured and 12 (26%) improved after 3-4 years follow-up. Thus, the number of patients cured or improved is comparable with the results from our department reported 20 years ago. However, in the present report, more than twice as many patients were enrolled, leading to double costs. Different indices of lateralisation of the renin generation were calculated for the use in cases of a shrunken kidney (functional share < or =15%). None of the indices clearly discriminated between the patients who did benefit from intervention, and those who did not. The only positive finding was that a peripheral renin concentration lower than 8 mlU/l predicted no effect of intervention, which might lead to the exclusion of 11% of the patients before entering the diagnostic programme. We conclude that the RVRS demands a very restrictive referral pattern if it should be of prognostic value for the blood pressure outcome after intervention. No indices of lateralised renin concentrations proved high predictive value. However, a peripheral renin concentration low in the normal range seems useful as an indicator of no benefit from intervention.     

Plasma osteopontin, hypoxia, and response to the hypoxia sensitiser nimorazole in radiotherapy of head and neck cancer: results from the DAHANCA 5 randomised double-blind placebo-controlled trial

BACKGROUND: The concentration of osteopontin (SPP1) in plasma is associated with tumour hypoxia. The DAHANCA 5 trial found that the hypoxia radiosensitiser nimorazole significantly improved the outcome of radiotherapy for patients with head and neck cancer compared with placebo. However, whether all patients benefit from such modification of hypoxia is unclear. We aimed to assess whether the concentration of plasma osteopontin could predict response to the hypoxia radiosensitiser. METHODS: Plasma concentrations of osteopontin were measured by use of ELISA from stored samples of 320 patients randomised in the DAHANCA 5 trial. Samples were grouped into tertiles according to high (167-1382 microg/L), intermediate (69-166 microg/L), or low (0-68 microg/L) concentrations of plasma osteopontin, and analysed for locoregional tumour control and disease-specific survival at 5 years. FINDINGS: Overall, locoregional tumour failure and disease-specific mortality were more frequent in patients assigned placebo than in those assigned nimorazole (relative risk [RR] 0.51 [95% CI 0.32-0.79] and 0.54 [0.35-0.85], respectively). Locoregional tumour failure was more frequent in patients with high concentrations of osteopontin assigned placebo than in those with high concentrations assigned nimorazole (0.19 [0.08-0.44]), as was disease-specific mortality (0.25 [0.11-0.59]). However, neither locoregional tumour failure nor disease-specific mortality differed between groups for patients with low concentrations of plasma osteopontin (0.79 [0.26-1.70]) and (0.69 [0.31-1.51]) or for those with intermediate concentrations (0.90 [0.41-1.98] and 0.89 [0.41-1.96], respectively). INTERPRETATION: High plasma concentrations of osteopontin are associated with a poor outlook after radiotherapy for patients with head and neck cancer, but can be improved by use of nimorazole. High concentrations of osteopontin can predict clinically relevant hypoxia, and might identify patients who will benefit from modification of hypoxia during radiotherapy.     

Capsular flap for correction of contour deformities of the breast

We describe a technique in which the breast implant capsule is used to fill localized depressions in the breast, including those under the nipple-areola complex. Capsules have been reported to persist long-term and their high vascularity renders them suitable for use as flaps.