Treatment for primary HIV infection: projecting outcomes of immediate,interrupted, or delayed therapy

With limited data available on the optimal treatment of primary HIV infection, disease modeling can be used to project clinical outcomes and inform decision makers. The authors developed a simulation model to evaluate the clinical outcomes and life expectancy projections for three primary HIV infection treatment strategies: 1) continuous antiretroviral therapy (ART) initiated at CD4 count <350 cells/mm(3); 2) continuous ART initiated immediately on diagnosis of primary HIV infection; and 3) ART initiated on diagnosis followed by structured treatment interruption. Projected life expectancies for the three strategies were 23.92, 24.46, and 26.07 years, respectively. The impact of key variables was assessed in sensitivity analysis, with the structured treatment interruption strategy remaining the most effective over a broad range of inputs. The immunologic benefit associated with immediate therapy and the potential for antiretroviral resistance due to structured treatment interruption have the most important impact on the optimal strategy. Based on current data, immediate treatment on diagnosis of primary HIV infection followed by structured treatment interruption will likely yield the best outcome. These results can assist decision makers and those planning clinical trials in defining evidence-based performance measures for primary HIV infection treatment and future trials.     

Late asthmatic reactions induced by inhalation of allergen-derived T cell peptides

In individuals with atopy and asthma, allergen-derived T cell peptides injected intradermally induce isolated late asthmatic reactions (LARs) followed by bronchial hyporesponsiveness to peptide, inhibition of the allergen-induced cutaneous late-phase reaction, and altered T cell function in vitro. Laboratory animal data indicate that "activation" and "tolerance" also occur if peptides are inhaled. In this study, we show that inhalation of Fel d 1-derived peptides induced isolated LAR in individuals with asthma sensitive to cat allergen comparable with that previously demonstrated using intradermal injection. LARs were accompanied by eosinophilia and nonsignificant elevations of total cysteinyl leukotrienes in the sputum. Unlike the intradermal route, repeated inhalation of peptides was not associated with abrogation of the LAR and produced a sputum eosinophilia comparable with the first exposure. In addition, there was no inhibition of the cutaneous late-phase reaction to whole cat dander. Thus, isolated LAR induced by inhaled, allergen-derived peptides represent a novel model of provoked asthma and are not associated with the induction of hyporesponsiveness ("tolerance") in the skin or lung.     

Repetitive transcranial magnetic stimulation as add-on antidepressant treatment. The applicability of the method in a clinical setting

Recent research indicates that repetitive transcranial magnetic stimulation (rTMS) over the frontal cortex has an antidepressant effect. The aim of the present pilot study was to assess the antidepressant effect, side-effects and the applicability in daily clinical practice of left prefrontal high-frequency rTMS. Fifteen inpatients with major depression (ICD-10 and DSM-IV) were randomized to receive 15 days of real left prefrontal high-frequency rTMS (20 trains of 10 s, 60-s interval, 10 Hz, 90% of motor threshold) or sham rTMS as add on to conventional antidepressant treatment. Depressive symptoms and side-effects were evaluated blindly during the treatment period. Five out of eight patients receiving real rTMS suffered from local discomfort during treatment. Three of them dropped out and the project was closed for that reason. Real rTMS did not add efficacy to standard antidepressant medication. This pilot study did not confirm the antidepressant effect of left frontal high-frequency rTMS. Unwanted effects led to considerable patient drop-out and premature termination of the study. The result suggests that alternative treatment delivery technology should be considered.     

131I-meta-iodobenzylguanidine scintigraphy of neuroblastomas

Sixteen neuroblastoma patients have been studied by 131I-meta-iodobenzylguanidine (MIBG) scintigraphy. Three patients were possibly cured, and their scintigraphy results were normal. Thirteen patients had tumors and metastases demonstrated by 131I-MIBG, two of these patients had a normal vanillylmandelic acid (VMA) excretion level. One patient has been treated by 131I-MIBG, but died. 131I-MIBG was concentrated in other cells too, eg, in erythrocytes and platelets.     

Developmental programming of aortic and renal structure in offspring of rats fed fat-rich diets in pregnancy

Evidence from human and animal studies suggests that maternal nutrition can induce developmental programming of adult hypertension in offspring. We have previously described a model of maternal dietary imbalance in Sprague-Dawley rats whereby administration of a maternal diet rich in animal lard programmes the development of increased blood pressure, insulin resistance, dyslipidaemia, obesity and mesenteric artery endothelial dysfunction in adult offspring. To further characterize the mechanism of hypertension in this model we have examined vascular and renal structure in adult offspring of Sprague-Dawley rats fed a control diet (OC) or lard-rich diet (OHF) during pregnancy and suckling followed by a control diet post-weaning. To gain further insight, we assessed aortic reactivity and elasticity in an organ bath preparation and renal renin and Na⁺,K⁺-ATPase activity. Plasma aldosterone concentration was also measured. Stereological examination of the aorta in OHF demonstrated reduced endothelial cell volume and smooth muscle cell number compared with OC. Adult OHF animals showed increased aortic stiffness and reduced endothelium-dependent relaxation. Renal stereology showed no differences in kidney weight, glomerular number or volume in OHF compared with OC, but renin and Na⁺,K⁺-ATPase activity were significantly reduced in OHF compared with controls. Programmed alterations to aortic structure and function are consistent with previous observations that exposure to maternal high fat diets produces systemic vascular changes in the offspring. Despite normal renal stereology, altered renal Na⁺,K⁺-ATPase and renin activity offers further insight into the mechanism underlying the increased blood pressure characteristic of this model.     

Effect of Z-360, a novel orally active CCK-2/gastrin receptor antagonist on tumor growth in human pancreatic adenocarcinoma cell lines in vivo and mode of action determinations in vitro

Purpose Gastrin is known to enhance the growth of pancreatic carcinoma via the cholecystokinin (CCK)-2/gastrin receptor. We investigated the anti-tumor effect of Z-360 (calcium bis [(R)-(−)-3-[3-{5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl}ureido]benzoate]), a novel orally active CCK-2 receptor antagonist alone or combined with the chemotherapeutic agent, gemcitabine in human pancreatic adenocarcinoma cell lines. Results Z-360 potently inhibited specific binding of [³H]CCK-8 to the human CCK-2 receptor, with a K _i value of 0.47 nmol/l, and showed antagonistic activity for this receptor. The anti-tumor effect of Z-360 alone or combined with gemcitabine was assessed using subcutaneous xenografts of MiaPaCa2 and PANC-1 and an orthotopic xenograft model (PANC-1). Oral administration of Z-360 significantly inhibited the growth of MiaPaCa2 (41.7% inhibition at 100 mg/kg, P < 0.01). Combined administration of Z-360 and gemcitabine significantly inhibited subcutaneous PANC-1 tumor growth compared with either agent alone (27.1% inhibition compared to effect with gemcitabine, P < 0.05), and significantly prolonged survival compared with the vehicle control (median survival of 49 days in vehicle compared to 57 days in the combination group, P < 0.05). In vitro studies showed that Z-360 significantly inhibited gastrin-induced proliferation of human CCK-2 receptor-expressing cells, and also significantly reduced gastrin-induced PKB/Akt phosphorylation to the level of untreated controls. Conclusion In the present study, we have shown that Z-360 combined with gemcitabine can inhibit pancreatic tumor growth and prolong survival in a pancreatic carcinoma xenograft model, on a possible mode of action being the inhibition of gastrin-induced PKB/Akt phosphorylation through blockade of the CCK-2 receptor. Our results suggest that Z-360 may be a useful adjunct to gemcitabine for the treatment of pancreatic carcinoma and a therapeutic option for patients with advanced pancreatic cancer.     

Women's experiences and attitudes towards expectant management and induction of labor for post-term pregnancy

BACKGROUND: Clinical guidelines for post-term management differ, and studies on women's attitudes are lacking. We aimed to assess the experiences and attitudes among women managed with serial antenatal monitoring or induction of labor, and the effects of post-term pregnancy on self-reports of quality of life. METHODS: Women were randomized at 41 weeks to immediate induction of labor or antenatal fetal surveillance every third day. At inclusion women answered a questionnaire about their attitudes towards post-term pregnancy and health-related quality of life. This was repeated in a follow-up phone interview 6 months later, including questions about their experiences of labor and perspective on future deliveries. RESULTS: A total of 508 women entered the study. At 41 weeks 74% of all women preferred to be induced. Women reported good general and mental health, but physical health and vitality scores were low. In the induction group, 74% of women said they would prefer the same management in future pregnancies; only 38% of women who had serial antenatal monitoring would prefer this option again (p<0.001). In the induction group, contractions were reported as more intense (n=157 versus n=118, p<0.01) and frequent (n=116 versus n=87, p<0.01) compared to the monitored group. The majority (84%) reported a positive labor induction experience. CONCLUSION: Women preferred induction of labor to serial antenatal monitoring beyond 41 weeks. Labors were shorter and contractions were reported to be more frequent and intense in the induction group compared with the monitored group. However, their experience with labor induction was positive.     

Avenanthramides,polyphenols from oats,exhibit anti-inflammatory and anti-itch activity

Oatmeal has been used for centuries as a soothing agent to relieve itch and irritation associated with various xerotic dermatoses; however few studies have sought to identify the active phytochemical(s) in oat that mediate this anti-inflammatory activity. Avenanthramides are phenolic compounds present in oats at approximately 300 parts per million (ppm) and have been reported to exhibit anti-oxidant activity in various cell-types. In the current study we investigated whether these compounds exert anti-inflammatory activity in the skin. We found that avenanthramides at concentrations as low as 1 parts per billion inhibited the degradation of inhibitor of nuclear factor kappa B-α (IκB-α) in keratinocytes which correlated with decreased phosphorylation of p65 subunit of nuclear factor kappa B (NF-κB). Furthermore, cells treated with avenanthramides showed a significant inhibition of tumor necrosis factor-α (TNF-α) induced NF-κB luciferase activity and subsequent reduction of interleukin-8 (IL-8) release. Additionally, topical application of 1–3 ppm avenanthramides mitigated inflammation in murine models of contact hypersensitivity and neurogenic inflammation and reduced pruritogen-induced scratching in a murine itch model. Taken together these results demonstrate that avenanthramides are potent anti-inflammatory agents that appear to mediate the anti-irritant effects of oats.     

Hsp27 regulates pro-inflammatory mediator release in keratinocytes by modulating NF-kappaB signaling

Heat-shock protein 27 (Hsp27) is a member of the small Hsp family that functions as molecular chaperones and protects cells against environmental stress. Hsp27 is expressed in the upper epidermal layers of normal human skin and has been reported to play a role in keratinocyte differentiation and apoptosis. In this investigation, we show an additional role of Hsp27 in the regulation of inflammatory pathways in keratinocytes. Downregulation of Hsp27 using Hsp27-specific small interfering RNA increased prostaglandin E(2) (PGE(2)) production in both unstimulated and tumor necrosis factor-alpha (TNF-alpha)-stimulated keratinocytes. Moreover, downregulation of Hsp27 increased the release of the pro-inflammatory cytokine IL-8 from TNF-alpha-stimulated and UV-irradiated keratinocytes, and this increase was inhibited by pretreatment with the NF-kappaB inhibitor BAY11-7082. Further studies showed that downregulation of Hsp27 resulted in induction of NF-kappaB reporter activity in keratinocytes. This correlated with enhanced degradation of IkappaB-alpha protein and accumulation of phosphorylated IkappaB-alpha in Hsp27 knockdown cells. Moreover, Hsp27 associated with the IkappaB kinase (IKK) complex. As synthesis of the pro-inflammatory cytokine IL-8 and the prostanoid PGE(2) are regulated by NF-kappaB, this could be a probable mechanism by which Hsp27 modulates the production of these inflammatory cytokines. Thus, Hsp27 plays a protective role in regulating inflammatory responses in skin.