Ionic imbalance and lack of effect of adjuvant treatment with methylene blue in the hamster model of leptospirosis

Leptospirosis in humans usually involves hypokalaemia and hypomagnesaemia and the putative mechanism underlying such ionic imbalances may be related to nitric oxide (NO) production. We previously demonstrated the correlation between serum levels of NO and the severity of renal disease in patients with severe leptospirosis. Methylene blue inhibits soluble guanylyl cyclase (downstream of the action of any NO synthase isoforms) and was recently reported to have beneficial effects on clinical and experimental sepsis. We investigated the occurrence of serum ionic changes in experimental leptospirosis at various time points (4, 8, 16 and 28 days) in a hamster model. We also determined the effect of methylene blue treatment when administered as an adjuvant therapy, combined with late initiation of standard antibiotic (ampicillin) treatment. Hypokalaemia was not reproduced in this model: all of the groups developed increased levels of serum potassium (K). Furthermore, hypermagnesaemia, rather than magnesium (Mg) depletion, was observed in this hamster model of acute infection. These findings may be associated with an accelerated progression to acute renal failure. Adjuvant treatment with methylene blue had no effect on survival or serum Mg and K levels during acute-phase leptospirosis in hamsters.

Effect of treatment with cyclophosphamide in low doses upon the onset of delayed type hypersensitivity in mice chronically infected with Trypanosoma cruzi: involvement of heart interstitial dendritic cells

Acute infection with Trypanosoma cruzi results in intense myocarditis, which progresses to a chronic, asymptomatic indeterminate form. The evolution toward this chronic cardiac form occurs in approximately 30% of all cases of T. cruzi infection. Suppression of delayed type hypersensitivity (DTH) has been proposed as a potential explanation of the indeterminate form. We investigated the effect of cyclophosphamide (CYCL) treatment on the regulatory mechanism of DTH and the participation of heart interstitial dendritic cells (IDCs) in this process using BALB/c mice chronically infected with T. cruzi. One group was treated with CYCL (20 mg/kg body weight) for one month. A DTH skin test was performed by intradermal injection of T. cruzi antigen (3 mg/mL) in the hind-footpad and measured the skin thickness after 24 h, 48 h and 72 h. The skin test revealed increased thickness in antigen-injected footpads, which was more evident in the mice treated with CYCL than in those mice that did not receive treatment. The thickened regions were characterised by perivascular infiltrates and areas of necrosis. Intense lesions of the myocardium were present in three/16 cases and included large areas of necrosis. Morphometric evaluation of lymphocytes showed a predominance of TCD8 cells. Heart IDCs were immunolabelled with specific antibodies (CD11b and CD11c) and T. cruzi antigens were detected using a specific anti-T. cruzi antibody. Identification of T. cruzi antigens, sequestered in these cells using specific anti-T. cruzi antibodies was done, showing a significant increase in the number of these cells in treated mice. These results indicate that IDCs participate in the regulatory mechanisms of DTH response to T. cruzi infection.

The Effect of Valsartan versus Non-RAAS Treatment on Autoregulation of Cerebral Blood Flow.

Background: Cerebral autoregulation (CA) is a protective mechanism which maintains the steadiness of the cerebral blood flow (CBF) through a broad range of systemic blood pressure (BP). Acute hypertension has been shown to reduce the cerebrovascular adaptation to BP variations. However, it is still unknown whether CA is impaired in chronic hypertension. This study evaluated whether a strict control of BP affects the CA in patients with chronic hypertension, and compared a valsartan-based regimen to a regimen not inhibiting the renin-angiotensin-aldosterone system (non-RAAS). Methods: Eighty untreated patients with isolated systolic hypertension were randomized to valsartan 320 mg or to a non-RAAS regimen during 6 months. The medication was upgraded to obtain BP <140/90 mm Hg. Continuous recordings of arterial BP and CBF velocity (transcranial Doppler) were performed during periods of 5 minutes, at rest, and at different levels of alveolar CO(2) pressure provided by respiratory maneuvers. The dominant frequency of CBF oscillations was determined for each patient. Dynamic CA was measured as the mean phase shift between BP and CBF by cross-spectral analysis in the medium frequency and in the dominant CBF frequency. Results: Mean ambulatory 24-hour BP fell from 144/87 to 127/79 mm Hg in the valsartan group and from 144/87 to 134/81 mm Hg in the non-RAAS group (p = 0.13). Both groups had a similar reduction in the central BP and in the carotido-femoral pulse wave velocity. The average phase shift between BP fluctuations and CBF response at rest was normal at randomization (1.82 ± 0.08 s), which is considered a preserved autoregulation and increased to 1.91 ± 0.12 s at the end of study (p = 0.45). The comparison of both treatments showed no significant difference (-0.01 ± 0.17 s vs. 0.16 ± 0.16 s, p = 0.45) for valsartan versus non-RAAS groups. The plasmatic level of glycosylated hemoglobin decreased in the valsartan arm compared to the non-RAAS arm (-0.23 ± 0.06 vs. -0.08 ± 0.07%, p = 0.07). Conclusions: In elderly hypertensive men with isolated chronic systolic hypertension, CA seems efficient at baseline and is not significantly affected by 6 months of BP-lowering treatment. This suggests that the preventive effects of BP medication against stroke are not mediated through a restoration of the CA.

The effect of antiretroviral treatment of different durations in primary HIV infection.

OBJECTIVES: To compare immunological, virological and clinical outcomes in persons initiating combination antiretroviral therapy (cART of different durations within 6 months of seroconversion (early treated) with those who deferred therapy (deferred group). DESIGN: CD4 cell and HIV-RNA measurements for 'early treated' individuals following treatment cessation were compared with the corresponding ART-free period for the 'deferred' group using piecewise linear mixed models. Individuals identified during primary HIV infection were included if they seroconverted from 1st January 1996 and were at least 15 years of age at seroconversion. Those with at least 2 CD4 less than 350 cells/microl or AIDS within the first 6 months following seroconversion were excluded. RESULTS: Of 348 'early treated' patients, 147 stopped cART following treatment for at least 6 (n = 38), more than 6-12 (n = 40) or more than 12 months (n = 69). CD4 cell loss was steeper for the first 6 months following cART cessation, but subsequent loss rate was similar to the 'deferred' group (n = 675, P = 0.26). Although those treated for more than 12 months appeared to maintain higher CD4 cell counts following cART cessation, those treated for 12 months or less had CD4 cell counts 6 months after cessation comparable to those in the 'deferred' group. There was no difference in HIV-RNA set points between the 'early' and 'deferred' groups (P = 0.57). AIDS rates were similar but death rates, mainly due to non-AIDS causes, were higher in the 'deferred' group (P = 0.05). CONCLUSION: Transient cART, initiated within 6 months of seroconversion, seems to have no effect on viral load set point and limited beneficial effect on CD4 cell levels in individuals treated for more than 12 months. Its long-term effects remain inconclusive and need further investigation.

Effect of biomagnetic therapy versus physiotherapy for treatment of knee osteoarthritis: a randomized controlled trial.

OBJECTIVE: To assess the effectiveness of pulsed signal therapy in the treatment of knee osteoarthritis (Kellgren II or III). METHODS: A randomized, double-blind controlled clinical trial. The first 95 patients sent to the clinic with knee osteo-arthritis were selected and randomized into treatment with pulsed signal therapy or conventional physiotherapy. Assessment included recording of usual demographic data, pertinent history, baseline medication and radiographs. Clinical evaluation was made at baseline, 6 weeks and 6 months after the end of treatment by the same blinded doctor. At each follow-up time, the patient was asked to complete a visual analogue pain scale and a Lequesne score. The doctor recorded the degree of pain on motion and the ability to move the affected knee. RESULTS: Both treatments resulted in significant improvements in pain and physical function. A statistical difference was observed only for activities of daily living, where the physiotherapy was more efficient (p<0.03). The cost of treatment with pulsed signal therapy was significantly higher, double the treatment cost of conventional physiotherapy. CONCLUSION: Like physiotherapy, pulsed signal therapy has improved the clinical state of treated patients but with no significant statistical difference. Pulsed signal therapy is, however, more expensive.

The effect of treatment with calcitonin on vertebral fracture rate in osteoporosis.

The efficacy of treatments for osteoporosis does not become evident when evaluated by fracture incidence (FI). Vertebral FI decreased in all controlled studies on calcitonin, but not significantly. Small sample sizes and short periods of treatment may have masked a possible therapeutic benefit, but longer, controlled studies with sodium fluoride or etidronate in larger groups of patients also failed to show a decrease in FI. The present analysis of nine published, therapeutic studies which indicate the FI per year and the initial prevalence of vertebral fractures, examines the question of whether the initial prevalence of fractures has an effect on the subsequent incidence of new fractures and whether the therapeutic effects have to be evaluated as a function of the initial prevalence of fractures. Bearing in mind the differences in roentgenological evaluation and in the size and quality of the various studies, the analysis revealed (1) that in the control groups there was a higher FI in patients with more than three vertebral fractures at baseline (estimated odds ratio (OR) = 49, p = 0.011); (2) that a similar trend, although not statistically significant, was observed in treated patients; (3) that the groups of control patients treated for more than 1 year showed in general an increase in FI beyond the first year and that the reverse was true in treated patients. In conclusion, failure to allow for the initial prevalence of vertebral fractures at the individual level in therapeutic trials of calcitonin to treat osteoporosis and prevent new fractures might have contributed to the absence of a demonstrable benefit of the treatment in those studies.

Adverse events to antiretrovirals in the Swiss HIV Cohort Study: effect on mortality and treatment modification.

BACKGROUND: Antiretroviral therapy (ART) decreases morbidity and mortality in HIV-infected patients but is associated with considerable adverse events (AEs). METHODS: We examined the effect of AEs to ART on mortality, treatment modifications and drop-out in the Swiss HIV Cohort Study. A cross-sectional evaluation of prevalence of 13 clinical and 11 laboratory parameters was performed in 1999 in 1,078 patients on ART. AEs were defined as abnormalities probably or certainly related to ART. A score including the number and severity of AEs was defined. The subsequent progression to death, drop-out and treatment modification due to intolerance were evaluated according to the baseline AE score and characteristics of individual AEs. RESULTS: Of the 1,078 patients, laboratory AEs were reported in 23% and clinical AEs in 45%. During a median follow up of 5.9 years, laboratory AEs were associated with higher mortality with an adjusted hazard ratio (HR) of 1.3 (95% confidence interval [CI] 1.2-1.5; P < 0.001) per score point. For clinical AEs no significant association with increased mortality was found. In contrast, an increasing score for clinical AEs (HR 1.11,95% CI 1.04-1.18; P = 0.002), but not for laboratory AEs (HR 1.07, 95% CI 0.97-1.17; P = 0.17), was associated with antiretroviral treatment modification. AEs were not associated with a higher drop-out rate. CONCLUSIONS: The burden of laboratory AEs to antiretroviral drugs is associated with a higher mortality. Physicians seem to change treatments to relieve clinical symptoms, while accepting laboratory AEs. Minimizing laboratory drug toxicity seems warranted and its influence on survival should be further evaluated.

Immunodensity and mRNA expression of A2A adenosine, D2 dopamine, and CB1 cannabinoid receptors in postmortem frontal cortex of subjects with schizophrenia: effect of antipsychotic treatment.

RATIONALE: Dopamine D2 receptors are the main target of antipsychotic drugs. In the brain, D2 receptors coexpress with adenosine A2A and CB1 cannabinoid receptors, leading to functional interactions. OBJECTIVES: The protein and messenger RNA (mRNA) contents of A2A, D2, and CB1 receptors were quantified in postmortem prefrontal cortex of subjects with schizophrenia. MATERIALS AND METHODS: The study was performed in subjects suffering schizophrenia (n=31) who mainly died by suicide, matched with non-schizophrenia suicide victims (n=13) and non-suicide controls (n=33). The density of receptor proteins was evaluated by immunodetection techniques, and their relative mRNA expression was quantified by quantitative real-time polymerase chain reaction. RESULTS: In schizophrenia, the densities of A2A (90+/-6%, n=24) and D2-like receptors (95+/-5%, n=22) did not differ from those in controls (100%). Antipsychotic treatment did not induce changes in the protein expression. In contrast, the immunodensity of CB1 receptors was significantly decreased (71+/-7%, n=11; p<0.05) in antipsychotic-treated subjects with schizophrenia but not in drug-free subjects (104+/-13%, n=11). The relative mRNA amounts encoding for A2A, D2, and CB1 receptors were similar in brains of drug-free, antipsychotic-treated subjects with schizophrenia and controls. CONCLUSIONS: The findings suggest that antipsychotics induce down-regulation of CB1 receptors in brain. Since A2A, D2, and CB1 receptors coexpress on brain GABAergic neurons and reductions in markers of GABA neurotransmission have been identified in schizophrenia, a lower density of CB1 receptor induced by antipsychotics could represent an adaptative mechanism that reduces the endocannabinoid-mediated suppression of GABA release, contributing to the normalization of cognitive functions in the disorder.

Effect of fertilizer treatment on the biomass production and nutrient uptake of short-rotation willow on cut-away peatlands

Summary

The effect of cognitive behavioral treatment on the positive symptoms of schizophrenia spectrum disorders: a meta-analysis

(from the journal abstract) Background: Despite the effectiveness of anti-psychotic pharmacotherapy, residual hallucinations and delusions do not completely resolve in some medicated patients. Additional cognitive behavioral therapy (CBT) seems to improve the management of positive symptoms. Despite promising results, the efficacy of CBT is still unclear. The present study addresses this issue taking into account a number of newly published controlled studies. Method: Fourteen studies including 1484 patients, published between 1990 and 2004 were identified and a meta-analysis of their results performed. Results: Compared to other adjunctive measures, CBT showed significant reduction in positive symptoms and there was a higher benefit of CBT for patients suffering an acute psychotic episode versus the chronic condition (effect size of 0.57 vs. 0.27). Discussion: CBT is a promising adjunctive treatment for positive symptoms in schizophrenia spectrum disorders. However, a number of potentially modifying variables have not yet been examined, such as therapeutic alliance and neuropsychological deficits. (PsycINFO Database Record (c) 2005 APA, all rights reserved)

Effect of boric acid treatment on mechanical properties of laminated beech veneer lumber

Abstract

Up-regulated 14-3-3β and 14-3-3ζ proteins in prefrontal cortex of subjects with schizophrenia: effect of psychotropic treatment.

14-3-3 is a family of conserved regulatory proteins that bind to a multitude of functionally diverse signalling proteins. Various genetic studies and gene expression and proteomic analyses have involved 14-3-3 proteins in schizophrenia (SZ). On the other hand, studies about the status of these proteins in major depressive disorder (MD) are still missing. Immunoreactivity values of cytosolic 14-3-3β and 14-3-3ζ proteins were evaluated by Western blot in prefrontal cortex (PFC) of subjects with schizophrenia (SZ; n=22), subjects with major depressive disorder (MD; n=21) and age-, gender- and postmortem delay-matched control subjects (n=52). The modulation of 14-3-3β and 14-3-3ζ proteins by psychotropic medication was also assessed. The analysis of both proteins in SZ subjects with respect to matched control subjects showed increased 14-3-3β (Δ=33±10%, p<0.05) and 14-3-3ζ (Δ=29±6%, p<0.05) immunoreactivity in antipsychotic-free but not in antipsychotic-treated SZ subjects. Immunoreactivity values of 14-3-3β and 14-3-3ζ were not altered in MD subjects. These results show the specific up-regulation of 14-3-3β and 14-3-3ζ proteins in PFC of SZ subjects and suggest a possible down-regulation of both proteins by antipsychotic treatment.

Eligibility to treatment and economic effect of the implementation of the new U.S. or European Society of Hypertension/European Society of Cardiology hypertension guidelines.

OBJECTIVE: To evaluate the population and economic impact of implementing the new Joint National Committee (JNC) or European Society of Hypertension (ESH)/European Society of Cardiology (ESC) hypertension guidelines in the Swiss population. METHODS: Cross-sectional, population-based sample (6708 participants) collected between 2003 and 2006 in the city of Lausanne, Switzerland. Blood pressure categories were defined according to both the JNC (JNC-7 and JNC-8) and the ESH/ESC (2007 and 2013) guidelines. RESULTS: The proportion of participants aged 35-60 years eligible for drug treatment was 25.6% [95% confidence interval (CI) 24.4-26.9%] and 24.8% (95% CI 23.6-26.0%) for the JNC-7 and the JNC-8 guidelines, respectively; for participants aged 60-75 years, the values were 62.3% (95% CI 60.1-64.5%) and 46.8% (95% CI 44.5-49.0%), respectively. Shifting from the JNC-7 to the JNC-8 guidelines would lead to an annual saving of 163.6 million Swiss francs (187.7 million US dollars or 134.5 million European euro). The proportion of participants aged 35-75 years without chronic kidney disease, diabetes mellitus or reported history of cardiovascular disease and eligible for treatment was 30.2% (95% CI 29.0-31.4%) for the ESH/ESC 2007 and 2013 guidelines. For participants with chronic kidney disease, diabetes mellitus or reported history of cardiovascular disease, the values were 73.6% (95% CI 70.8-76.3%) and 55.6% (95% CI 52.5-58.8%), respectively. Shifting from the ESH/ESC 2007 to the ESH/ESC 2013 guidelines would lead to an annual saving of 86.9 million Swiss francs (99.5 million US dollars or 71.4 million European euro). CONCLUSION: In Switzerland, shifting from the JNC-7 to the JNC-8 guidelines or from the ESH/ESC 2007 to the ESH/ESC 2013 guidelines would decrease the prevalence of patients eligible for treatment and increase the percentage of treated patients within blood pressure goals. Both strategies lead to potential savings in antihypertensive drug treatment.