Double-blind Controlled Clinical Trials Research Articles

Efficacy and safety of roxadustat for the treatment of anemia in non-dialysis chronic kidney disease patients: A systematic review and meta-analysis of randomized double-blind controlled clinical trials

To evaluate the efficacy and safety of roxadustat in the treatment of anemia in non-dialysis-dependent chronic kidney disease (NDD-CKD) patients. For this systematic review and meta-analysis, we searched for randomized controlled trials (RCTs) of anemia in NDD-CKD patients to assess the efficacy and safety of roxadustat. The primary efficacy endpoint was the proportion of patients who achieved a hemoglobin (Hb) response. Secondary efficacy endpoints were hepcidin, serum iron, serum ferritin (SF), total iron-binding capacity (TIBC), transferrin saturation (TAST), and low-density lipoprotein (LDL). In addition, adverse events (AEs) were compared. Meta-analyses were performed using Revman 5.4 software. The quality of the evidence was assessed using the Cochrane risk of bias tool. This study was conducted under a pre-established protocol registered with PROSPERO (registration number: CRD42021252331). Seven studies enrolled 4,764 patients, of whom 2,730 received roxadustat and 2,034 received placebo. The results of this meta-analysis showed that roxadustat increased Hb levels [weighted mean difference (WMD) = 1.43, 95% CI: 1.17 to 1.68, P < 0.001, I 2 = 95%], and Hb response [relative ratio (RR) = 8.12, 95% CI: 5.80 to 11.37, P < 0.001, I 2 = 61%]. In addition, roxadustat significantly increased transferrin TAST. During the treatment period in patients with anemia, the AEs of roxadustat compared with placebo was not statistically significant. Roxadustat can improve anemia in NDD-CKD patients by increasing Hb levels and regulating iron metabolism, but does not increase the incidence of AEs. [https://www.crd.york.ac.uk/prospero/], identifier [CRD42021252331].

EFFECT OF BRAZIL NUT (BERTHOLLETIA EXCELSA) SUPPLEMENTATION ON HUMAN HEALTH: A SYSTEMATIC REVIEW

Previous studies suggest that Brazil nut can improve the nutritional status of selenium, reduce oxidative stress, modify lipid profile, and alter inflammatory markers. A systematic review was performed to evaluate and synthesize the results of studies on the effect of Brazil nut supplementation on human health. The review was conducted according to the recommendations of the Preferred Reporting Items for reviews and was based on searches of the databases BIREME, BMC Proceedings, The British Library, The Cochrane Library, and PubMed up to December 2019. The searches also included at the databases Google Scholar and Web of Sciences. The descriptors were identified using the Health Science Descriptors system and the search strategy included the following combination of keywords: Bertholletia, protein, lipid, nutritive value, and selenium; in English and Portuguese. A total of 510 potential studies were screened, of which 25 studies were considered for this review. All studies showed that supplementation with Brazil nut in the amounts evaluated improved the selenium status in the body and had positive effects without reports of adverse effects. This systematic review indicates that Brazil nut has a beneficial effect on human health, but further studies with double-blind controlled clinical trials and larger sample sizes are needed for the validation of these effects.

The relation between thyroid dysregulation and impaired cognition/behaviour: An integrative review.

Despite decades of research on the relation between thyroid diseases and cognition, the nature of this relationship remains elusive. An increasing prevalence of cognitive impairment and thyroid dysfunction has been consistently observed with ageing. Also, there appears to be an association between thyroid disorders and cognitive decline. Given the increasing global burden of dementia, elucidating the relationship between thyroid disorders as a potentially modifiable risk factor of cognitive impairment was the main goal of this review. We summarise the current literature examining the relationship between thyroid hormonal dysregulation and cognition or behaviour. We present the available imaging and pathological findings related to structural and functional brain changes related to thyroid hormonal dysregulation. We also propose potential mechanisms of interaction between thyroid hormones, autoantibodies and cognition/behaviour. Effects of gender, ethnicity and environmental factors are also briefly discussed. This review highlights the need for long-term prospective studies to capture the course of brain functional changes associated with the incidence and progression of thyroid dysregulations along with the confounding effects of non-modifiable risk factors such as gender and ethnicity. Moreover, double-blind controlled clinical trials are necessary to devise appropriate treatment plans to prevent cognitive consequences of over or undertreatment of thyroid disorders.

Obeticholic acid-a new therapy in PBC and NASH.

Obeticholic acid (OCA) is a semi-synthetic hydrophobic bile acid (BA) analogue that is highly selective agonist of farnesoid X receptor (FXR), a key nuclear BA receptor, which induces expression of gut-derived hormones, in particular fibroblast growth factor 19. The resulting beneficial effects of OCA on glucose and lipid metabolism and particularly hepatic inflammation make it a candidate for the treatment of a variety of conditions including primary biliary cholangitis (PBC) and nonalcoholic steatohepatitis (NASH). In PBC patients who have not initially responded to ursodeoxycholic acid, OCA has been shown in double-blind controlled clinical trials to significantly reduce serum alkaline phosphatase. To date, OCA is the only therapy licensed by the FDA, EMA and endorsed by NICE as second line therapy for PBC.No medications are currently approved in Europe or the USA for the treatment of NASH.In recent clinical trials, OCA has been shown encouraging results by improving liver blood tests and reducing liver fibrosis with no worsening of NASH. OCA is the established second line therapy for PBC in those patients who fail to adequately respond to ursodeoxycholic acid. The main side effects of OCA treatment in both PBC and NASH is that of dose-dependent pruritis which can lead to treatment discontinuation in ~1-10% of patients. In addition, OCA-treated patients may also exhibit (reversible) alterations in serum lipid levels; most notably a small decrease in high density lipoprotein cholesterol. It is not yet known whether these changes carry a long-term cardiovascular risk in NASH.In addition, the relatively high cost of OCA may limit its use in cash-limited health systems. Additional clinical trials are in progress to ascertain the long-term effects of OCA on survival in PBC and NASH. New FXR agonists with a lower rate of side effects are being developed and trialed. Combination therapy with other agents may offer increased efficacy.

Specific composition of polyphenolic compounds with fatty acids as an approach in helping to reduce spirochete burden in Lyme disease: in vivo and human observational study.

Background:Lyme disease (LD) is a tick-borne infection caused by Borrelia burgdorferi sensu lato. The current therapeutic approach to this disease is limited to antibiotics. However, after their administration, about 20% of patients experience delayed onset of this illness manifesting as lingering persistent symptoms.Methods:To determine a suitable approach that would help reduce this number, we examined the efficacy of a composition of polyphenolic compounds (baicalein, luteolin, and rosmarinic acid) with fatty acids (monolaurin and cis-2-decenoic acid), and iodine/kelp in a Lyme disease animal model and volunteers.Results:The results showed that 4 weeks of dietary intake of this composition reduced the spirochete burden in animal tissues by about 75%. Basic and differential blood parameters did not show significant differences between control animals and the animals fed with this composition. Also, hepatic and renal toxicity markers were not changed and apoptosis was not observed. Relevant inflammatory cytokines such as IL-6, IL-17, TNF-α, and INF-γ, were elevated in infected animals but normalized in infected and treated animals. A small observational study revealed that after administration of this composition to 17 volunteers three times per day for 6 months, 67.4% of the volunteers with late or persistent LD, and not receptive to previous antibiotic application, responded positively, in terms of energy status as well as physical and psychological wellbeing to supplementation with this composition, while 17.7% had slight improvement, and 17.7% were none responsive.Conclusion:We concluded that this specific composition revealed feasible benefits in late or persistent LD management, although double-blind controlled clinical trials are warranted.

Standard versus biofilm antimicrobial susceptibility testing to guide antibiotic therapy in cystic fibrosis

The antibiotics used to treat pulmonary infections in people with cystic fibrosis are typically chosen based on the results of antimicrobial susceptibility testing performed on bacteria traditionally grown in a planktonic mode (grown in a liquid). However, there is considerable evidence to suggest that Pseudomonas aeruginosa actually grows in a biofilm (or slime layer) in the airways of people with cystic fibrosis with chronic pulmonary infections. Therefore, choosing antibiotics based on biofilm rather than conventional antimicrobial susceptibility testing could potentially improve response to treatment of Pseudomonas aeruginosa in people with cystic fibrosis. This is an update of a previously published Cochrane Review. To compare biofilm antimicrobial susceptibility testing-driven therapy to conventional antimicrobial susceptibility testing-driven therapy in the treatment of Pseudomonas aeruginosa infection in people with cystic fibrosis. We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. Most recent search: 19 June 2017.We also searched two ongoing trials registries and the reference lists of relevant articles and reviews. Most recent searches: 24 August 2017 and 05 September 2017. Randomized controlled trials of antibiotic therapy based on biofilm antimicrobial susceptibility testing compared to antibiotic therapy based on conventional antimicrobial susceptibility testing in the treatment of Pseudomonas aeruginosa pulmonary infection in people with cystic fibrosis. Both authors independently selected trials, assessed their risk of bias and extracted data from eligible trials. Additionally, the review authors contacted the trial investigators to obtain further information. The quality of the evidence was assessed using the GRADE criteria. The searches identified two multicentre, randomized, double-blind controlled clinical trials eligible for inclusion in the review with a total of 78 participants (adults and children); one trial was done in people who were clinically stable, the other in people experiencing pulmonary exacerbations. These trials prospectively assessed whether the use of biofilm antimicrobial susceptibility testing improved microbiological and clinical outcomes in participants with cystic fibrosis who were infected with Pseudomonas aeruginosa. The primary outcome was the change in sputum Pseudomonas aeruginosa density from the beginning to the end of antibiotic therapy.Although the intervention was shown to be safe, the data from these two trials did not provide evidence that biofilm susceptibility testing was superior to conventional susceptibility testing either in terms of microbiological or lung function outcomes. One of the trials also measured risk and time to subsequent exacerbation as well as quality of life measures and did not demonstrate any difference between groups in these outcomes. Both trials had an overall low risk of bias and the quality of the evidence using GRADE criteria was deemed to be moderate to high for the outcomes selected. The current evidence is insufficient to recommend choosing antibiotics based on biofilm antimicrobial susceptibility testing rather than conventional antimicrobial susceptibility testing in the treatment of Pseudomonas aeruginosa pulmonary infections in people with cystic fibrosis. Biofilm antimicrobial susceptibility testing may be more appropriate in the development of newer, more effective formulations of drugs which can then be tested in clinical trials.

GLP-1 Agonists and Blood Pressure: A Review of the Evidence.

Type 2 diabetes mellitus (T2DM) is a major risk factor for cardiovascular disease. The presence of concomitant hypertension in diabetics is a major driver of excess cardiovascular risk. Glucagon-like peptide-1 receptor agonists (GLP-1a) act on numerous pathways that intersect glycemic, weight, and blood pressure (BP) control. BP-lowering effects have been observed in mouse models of hypertension with a variety of GLP-1a. Acute administration of GLP-1a in humans has been shown to no effects and sometimes increased BP in humans. Chronic administration of GLP-1a, however, reduces clinic systolic BP (≈2mmHg) at least when evaluated as a secondary end point in glycemia-lowering studies while simultaneously increasing heart rate. BP lowering has not been consistently observed in two recent double-blind controlled clinical trials evaluating ambulatory BP as the primary end point. While a number of mechanisms including vascular, myocardial, renal, and central nervous system pathways have been suggested in animal studies, these mechanistic pathways have not been sufficiently detailed in humans and it is unclear if the same pathways are operational. Further studies need to be conducted to unravel the full spectrum of effects of this drug class. An understanding of their effects on BP may help provide an explanation for the ability of GLP-1a to influence cardiovascular (CV) events in ongoing event-driven CV trials.

Standard versus biofilm antimicrobial susceptibility testing to guide antibiotic therapy in cystic fibrosis.

The antibiotics used to treat pulmonary infections in people with cystic fibrosis are typically chosen based on the results of antimicrobial susceptibility testing performed on bacteria traditionally grown in a planktonic mode (grown in a liquid). However, there is considerable evidence to suggest that Pseudomonas aeruginosa actually grows in a biofilm (or slime layer) in the airways of people with cystic fibrosis with chronic pulmonary infections. Therefore, choosing antibiotics based on biofilm rather than conventional antimicrobial susceptibility testing could potentially improve response to treatment of Pseudomonas aeruginosa in people with cystic fibrosis. This is an update of a previously published Cochrane Review. To compare biofilm antimicrobial susceptibility testing-driven therapy to conventional antimicrobial susceptibility testing-driven therapy in the treatment of Pseudomonas aeruginosa infection in people with cystic fibrosis. We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched a registry of ongoing trials and the reference lists of relevant articles and reviews.Most recent search: 19 November 2014. Randomized controlled trials of antibiotic therapy based on biofilm antimicrobial susceptibility testing compared to antibiotic therapy based on conventional antimicrobial susceptibility testing in the treatment of Pseudomonas aeruginosa pulmonary infection in people with cystic fibrosis. Both authors independently selected trials, assessed their risk of bias and extracted data from eligible trials. Additionally, the review authors contacted the trial investigators to obtain further information. The searches identified two multicentre, randomized, double-blind controlled clinical trials eligible for inclusion in the review with a total of 78 participants; one trial was done in people who were clinically stable, the other in people experiencing pulmonary exacerbations. These trials prospectively assessed whether the use of biofilm antimicrobial susceptibility testing improved microbiological and clinical outcomes in participants with cystic fibrosis who were infected with Pseudomonas aeruginosa. The primary outcome was the change in sputum Pseudomonas aeruginosa density from the beginning to the end of antibiotic therapy.Although the intervention was shown to be safe, the data from these two trials did not provide evidence that biofilm susceptibility testing was superior to conventional susceptibility testing either in terms of microbiological or lung function outcomes. One of the trials also measured risk and time to subsequent exacerbation as well as quality of life measures and did not demonstrate any difference between groups in these outcomes. Both trials had an overall low risk of bias. The current evidence is insufficient to recommend choosing antibiotics based on biofilm antimicrobial susceptibility testing rather than conventional antimicrobial susceptibility testing in the treatment of Pseudomonas aeruginosa pulmonary infections in people with cystic fibrosis. Biofilm antimicrobial susceptibility testing may be more appropriate in the development of newer, more effective formulations of drugs which can then be tested in clinical trials.

Phototherapy effect on the muscular activity of regular physical activity practitioners

Clinical investigations have demonstrated the effectiveness of phototherapy on the muscle activity. The aim of this study was to investigate the effect of low-level laser therapy (LLLT) on the tibialis anterior muscle of regular physical activity practitioners by electromyographic, biomechanical, and biochemical (lactate) analysis. Double-blind controlled clinical trials were conducted with 12 healthy females, regular physical activity practitioners, between 18 and 30 years. The LLLT application (780 nm, 30 mW, 0.81 J/point, beam area of 0.2 cm(2), 27 s, ≈ 29 points) in the tibialis anterior muscle occurred after the delimitation of the points on every 4 cm(2) was held. It was observed that (a) a significant torque increase (p < 0.05) post-LLLT compared to the values after placebo therapy at the beginning of resistance exercise, (b) both muscle torque (isokinetic) and median frequency (EMG) showed a faster decay of the signals collected after placebo and laser treatment when compared to control values, (c) no significant change in torque in the strength test of five repetitions, (d) a significant muscle activity decrease (p < 0.05) after laser therapy compared to control values, and (e) an increase in lactate levels post-LLLT (p < 0.05) after 30 min of exercise. It is concluded that the LLLT increased the muscle torque at the beginning of the exercise and maintained the levels of lactate after resistance exercise. Therefore, the LLLT with the parameters used in this study can be utilized in rehabilitation to improve muscle performance in elite athletes.

Transcutaneous laser treatment of leg veins

Leg telangiectasias and reticular veins are a common complaint affecting more than 80% of the population to some extent. To date, the gold standard remains sclerotherapy for most patients. However, there may be some specific situations, where sclerotherapy is contraindicated such as needle phobia, allergy to certain sclerosing agents, and the presence of vessels smaller than the diameter of a 30-gauge needle (including telangiectatic matting). In these cases, transcutaneous laser therapy is a valuable alternative. Currently, different laser modalities have been proposed for the management of leg veins. The aim of this article is to present an overview of the basic principles of transcutaneous laser therapy of leg veins and to review the existing literature on this subject, including the most recent developments. The 532-nm potassium titanyl phosphate (KTP) laser, the 585-600-nm pulsed dye laser, the 755-nm alexandrite laser, various 800-983-nm diode lasers, and the 1,064-nm neodymium yttrium-aluminum-garnet (Nd:YAG) laser and various intense pulsed light sources have been investigated for this indication. The KTP and pulsed dye laser are an effective treatment option for small vessels (<1 mm). The side effect profile is usually favorable to that of longer wavelength modalities. For larger veins, the use of a longer wavelength is required. According to the scarce evidence available, the Nd:YAG laser produces better clinical results than the alexandrite and diode laser. Penetration depth is high, whereas absorption by melanin is low, making the Nd:YAG laser suitable for the treatment of larger and deeply located veins and for the treatment of patients with dark skin types. Clinical outcome of Nd:YAG laser therapy approximates that of sclerotherapy, although the latter is associated with less pain. New developments include (1) the use of a nonuniform pulse sequence or a dual-wavelength modality, inducing methemoglobin formation and enhancing the optical absorption properties of the target structure, (2) pulse stacking and multiple pass laser treatment, (3) combination of laser therapy with sclerotherapy or radiofrequency, and (4) indocyanin green enhanced laser therapy. Future studies will have to confirm the role of these developments in the treatment of leg veins. The literature still lacks double-blind controlled clinical trials comparing the different laser modalities with each other and with sclerotherapy. Such trials should be the focus of future research.

Laser treatment of recurrent herpes labialis: a literature review

Recurrent herpes labialis is a worldwide life-long oral health problem that remains unsolved. It affects approximately one third of the world population and causes frequent pain and discomfort episodes, as well as social restriction due to its compromise of esthetic features. In addition, the available antiviral drugs have not been successful in completely eliminating the virus and its recurrence. Currently, different kinds of laser treatment and different protocols have been proposed for the management of recurrent herpes labialis. Therefore, the aim of the present article was to review the literature regarding the effects of laser irradiation on recurrent herpes labialis and to identify the indications and most successful clinical protocols. The literature was searched with the aim of identifying the effects on healing time, pain relief, duration of viral shedding, viral inactivation, and interval of recurrence. According to the literature, none of the laser treatment modalities is able to completely eliminate the virus and its recurrence. However, laser phototherapy appears to strongly decrease pain and the interval of recurrences without causing any side effects. Photodynamic therapy can be helpful in reducing viral titer in the vesicle phase, and high-power lasers may be useful to drain vesicles. The main advantages of the laser treatment appear to be the absence of side effects and drug interactions, which are especially helpful for older and immunocompromised patients. Although these results indicate a potential beneficial use for lasers in the management of recurrent herpes labialis, they are based on limited published clinical trials and case reports. The literature still lacks double-blind controlled clinical trials verifying these effects and such trials should be the focus of future research.

Efficacy and Adverse Effects of Venlafaxine in Children and Adolescents with ADHD: A Systematic Review of Non-controlled and Controlled Trials

Attention deficit hyperactivity disorder (ADHD) is a common psychiatric disorder in children and adolescents. Stimulants are commonly prescribed for ADHD management. There is clinical trial evidence that some medications with noradrenergic properties such as atomoxetine are effective. It is of theoretical and practical importance if other agents with noradrenergic properties display a comparable pattern of efficacy. This paper is a systematic review of the efficacy and safety of venlafaxine for treating children and adolescents with ADHD. MEDLINE, Google scholar, Scopus, and Web of science (ISI) databases were electronically searched in July 2012, updated on November 2012. Time and language of publication were not exclusion criteria. Efficacy outcomes were assessed by a valid and reliable parent- and/or teacher-reported instrument to evaluate clinical symptoms. Adverse effects were also evaluated. There were three uncontrolled trials and only two double blind controlled clinical trials. Venlafaxine appeared effective for treating ADHD. The rates of some adverse effects of venlafaxine were less than those documented for methylphenidate. While one of the two small controlled trials did not find difference between venlafaxine ad methylphenidate, the other trial reported lower efficacy for venlafaxine. Headache, insomnia, and nausea were among the most common adverse effects. This systematic review provides preliminary support that venlafaxine may have short term utility in treating ADHD in children and adolescents. However, before recommending venlafaxine for treatment, more robust and larger clinical trials, in particular providing evidence of its long-term efficacy, safety and tolerability are required.

Endometrial Morphology After Treatment of Uterine Fibroids With the Selective Progesterone Receptor Modulator, Ulipristal Acetate

Selective progesterone receptor modulators (SPRMs) have beneficial effects in reducing the size of uterine fibroids and the amount of bleeding, but their endometrial effects have not been seen with other agents. This report describes the morphology of the endometrium after 3 mo of treatment with the SPRM, ulipristal acetate (UPA). In 2 Phase III randomized double-blind controlled clinical trials, 546 patients with uterine myomas were treated with 5 or 10 mg of UPA daily for 13 wk or placebo or gonadotropin-releasing hormone agonist. Endometrial biopsies were taken at screening, end of treatment (13 wk), and after treatment-free follow-up (38 wk). Biopsies were assessed independently by 3 pathologists according to a preset morphologic scheme. After 13 wk, the UPA-treated endometrium showed altered architectural glandular features including extensive cystic dilatation. The glandular epithelium appeared inactive or contained abortive subnuclear vacuolization, occasional mitoses, and apoptosis. Abnormal stromal vessels were commonly seen. There was a high level of agreement between pathologists on the presence or the absence of nonphysiological changes. One case of hyperplasia without atypia and 4 polyps were seen at 13 wk of UPA treatment. Six months after treatment, the endometrium returned to normal histology in the majority of the patients, with 1 polyp and no cases of hyperplasia in the UPA-treated groups, and 2 hyperplasias (1 with and 1 without atypia) in the placebo or the gonadotropin-releasing hormone-agonist groups. Mild reversible thickening of the endometrium occurs in a minority of cases. It is important that pathologists are aware of the spectrum of changes induced by SPRMs to avoid misdiagnoses of endometrial hyperplasia or polyps.

Geographic location of antineoplastic agent clinical trials conducted in developed and developing countries

For the past 30 years, clinical trials have been increasingly conducted in developing countries. These trials allow results to be generalizable to similar populations, offer access to treatment for patients in need, and examine diseases with differing patterns than developed countries. However, the characteristics of antineoplastic clinical trials and recent trends in study location in developing countries are unknown. The primary objective was to evaluate the location, study phase, results, funding source, and ethics board approval of randomized double-blind controlled clinical trials evaluating antineoplastic agents by geographic location. This is a retrospective evaluation of studies indexed in the PubMed/Medline database published in 2007-2011. Clinical trials were identified with the search terms "drug therapy", "antineoplastic agents" and "double blind method" and limited to English language, human, and randomized controlled trial. We assessed frequencies of characteristics of antineoplastic clinical trials. A total of 116 trials evaluating antineoplastic drug therapy were identified. The highest frequency of clinical trials were published in 2009 (27.6 %), followed by 2011 (23.3 %), 2010 (20.7 %), 2007 (14.6 %), and 2008 (13.8 %). According to geographic region, 33.8 % were conducted in North America, followed by Europe (31.5 %) and Asia (16.2 %). Based on economic status, the majority (77.8 %) of clinical trial locations were in developed countries and 22.2 % were in developing countries. No significant difference was found between study locations in developed countries and developing countries from 2007 to 2011. When comparing studies conducted in developing and developed countries, there was no difference in the year published, study phase, results, funding source, or investigational review board approval and informed consent. Studies conducted in developed countries were significantly more likely to be single country studies (p = 0.02) and published in a journal with an impact factor greater than 10 (p = 0.013) when compared to studies conducted in developing countries. Based on economic status, there was no significant location change of antineoplastic clinical trials from 2007 to 2011. Clinical trials conducted in developing countries were more often multi-country studies and published in journals with lower impact factors.

Ascorbic Acid Has Superior Ex Vivo Antiproliferative, Cell Death-Inducing and Immunomodulatory Effects over IFN-α in HTLV-1-Associated Myelopathy

BackgroundClear therapeutic guidelines for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) are missing due to the lack of randomized double-blind controlled clinical trials. Moderate yet similar clinical benefit has been demonstrated for IFN-α and high-dose ascorbic acid (AA) monotherapy in a large open clinical trial. However, there is a lack of in vivo and in vitro studies exploring and comparing the effects of high-dose AA and IFN-α treatment in the context of HAM/TSP. Therefore, we performed the first comparative analysis of the ex vivo and in vitro molecular and cellular mechanisms of action of IFN-α and high-dose AA in HAM/TSP.Principal FindingsThrough thymidine incorporation and quantification of Th1/Th2/Th17 cytokines, we demonstrate that high-dose AA displays differential and superior antiproliferative and immunomodulatory effects over IFN-α in HAM/TSP PBMCs ex vivo. In addition, high-dose AA, but not IFN-α, induced cell death in both HAM/TSP PBMCs and HTLV-1-infected T-cell lines MT-2 and MT-4. Microarray data combined with pathway analysis of MT-2 cells revealed AA-induced regulation of genes associated with cell death, including miR-155. Since miR-155 has recently been demonstrated to up-regulate IFN-γ, this microRNA might represent a novel therapeutic target in HAM/TSP, as recently demonstrated in multiple sclerosis, another neuroinflammatory disease. On the other hand, IFN-α selectively up-regulated antiviral and immune-related genes.ConclusionsIn comparison to IFN-α, high-dose AA treatment has superior ex vivo and in vitro cell death-inducing, antiproliferative and immunomodulatory anti-HTLV-1 effects. Differential pathway activation by both drugs opens up avenues for targeted treatment in specific patient subsets.

Ameliorating Attention Problems in Children With Sickle Cell Disease

This pilot study examined whether methylphenidate (MPH) was effective in enhancing cognitive performance and attention for children with sickle cell disease (SCD) with cerebrovascular complications who evidence attention problems. In this multisite, pilot study, we evaluated 2 separate double-blind controlled clinical trials, including a laboratory trial of the short-term efficacy of MPH, with the second study a 3-week home/school crossover trial evaluating the efficacy of MPH. The laboratory trial included 14 participants between the age of 7 and 16 years. Assessments included measures of sustained attention, reaction time, executive functions, and verbal memory. The home/school trial included 20 participants. The outcome measures were parent and teacher ratings of attention. The first study compared MPH with placebo, while the second trial compared placebo, low-dose (LD) MPH, and moderate-dose MPH. In the laboratory trial, significant effects were revealed for measures of memory and inhibitory control. Parent and teacher reports from the home/school trial indicate that moderate-dose MPH produced superior improvement in attention relative to the placebo and LD MPH. Stimulant medication positively impacted select measures of memory and inhibitory control in some children with SCD. Attention, as rated by parent and teachers, was improved for a greater number of children and adolescents on higher doses of MPH relative to LD MPH and placebo. Stimulant medication may provide an effective intervention for some children with SCD and cerebrovascular complications who demonstrate attention problems.

A quantitative review of the profile and time course of symptom change in schizophrenia treated with clozapine

Contemporary analyses demonstrate an early response to antipsychotic treatment in non-refractory schizophrenia. The profile of response to clozapine is unknown. We used meta-analytic and statistical procedures to examine the response profile to clozapine. We identified 19 unique, randomized, double-blind controlled clinical trials with suitable time course data, representing 1745 subjects. Individual subject data were available for 419 subjects, obtained from two industry-sponsored trials. Symptom severity scores from the BPRS or the PANSS were entered into regression analyses to estimate linear and quadratic coefficients of the rate of change of symptom severity over 4 weeks. Both linear and quadratic regression coefficients for clozapine, and for comparator antipsychotics differed significantly from zero (p ≤ 0.001), indicating early response profiles. Compared with other antipsychotic arms, for clozapine the treatment response was greater (d = -0.578, p = 0.021), and the linear coefficient was steeper (d = -0.502, p = 0.042); the quadratic coefficients indicating attenuation did not differ. Analyses of 6-week data and individual subject data from non-refractory and refractory trials were consistent with the primary findings. Somewhat surprisingly, clozapine shows an early response profile, similar in pattern but somewhat larger in magnitude than other antipsychotic drugs.

Monovalent type 1 oral poliovirus vaccine among infants in India: Report of two randomized double-blind controlled clinical trials

Background To provide the polio eradication initiative with more immunogenic oral poliovirus vaccines (OPVs), we evaluated newly developed monovalent type 1 OPV (mOPV1) among infants in India. Methods Two double-blind randomized controlled clinical trials compared two mOPV1s (mOPV1 A and mOPV1 B) versus trivalent OPV (tOPV X) given at birth (trial I), or assessed two products of higher-potency mOPV1 (mOPV1 C and mOPV1 D) versus regular-potency mOPV1 (mOPV1 B) or tOPV Y given at birth and at 30 days (trial II). Results In trial I, 597 newborns were enrolled, 66 withdrawn or excluded, leaving 531 (88.9%) subjects for analysis. Seroconversion to poliovirus type 1 was 10.4% for mOPV1 A, 15.6% for mOPV1 B and 10.2% for tOPV X. In trial II, 718 newborns were enrolled, 135 withdrawn or excluded, leaving 583 (81.2%) subjects for analysis. Seroconversion to poliovirus type 1 following a birth dose was 15.1%, 19.7%, 18.0% and 10.6%, following the 30-day dose 87.1%, 89.2%, 84.4%, or 55.9%, and cumulative for both doses 90.4%, 90.3%, 89.5% and 61.9% for mOPV1s B, C, and D and tOPV Y, respectively. Conclusions In both studies, seronconversion rates were unexpectedly low to poliovirus type 1 after mOPV1 or tOPV given at birth but high for all formulations of mOPV1 given at age 30 days. The cause for low immunogenicity of OPV at birth in India is not known.

Fighting against acquired immunodeficiency syndrome with Chinese medicine: A perspective from China

Continuing expansion of the human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) pandemic has been recognized as an exceptional challenge to global health. Taking highly active antiretroviral treatment (HAART), a confirmed effective treatment, has its limitations. While a much cheaper and potential treatment-the Chinese medicine (CM) has not been paid enough attention from the worldwide. We explained the CM viewpoints about pathology and etiology to answer some questions about whether and how CM can treat AIDS. Some herbal formulae and their targeted patterns and common symptoms were also introduced. Chinese government has realized the important role of CM as an independent therapy for early management, bolstering immune-system functions depressed by HIV, and has funded large randomized double-blind controlled clinical trials to more accurately assess the benefits, and valued the fundamental research to establish a quantitative standardization of pattern diagnosis. Researchers of CM are looking for cooperation with all the world's top experts in the areas of AIDS and immunity to strive for victories in the fight against AIDS.

Hump nosed viper bite in Sri Lanka-descriptive observational study of 1543 cases

Objective: To identify the clinical manifestations of hump nosed viper envenomation and to recognize the available treatment methods to prevent complications. Methods: Descriptive observational study involving a series of 1543 patients admitted with hump nosed viper bite to 5 major hospitals in Sri Lanka was conducted. Data collection was done consecutively during February 1990 and February 2008. Except Hypnale, identification of the biting snake was made by the corresponding author after visual examination of the dead or live snakes, which were brought to hospital. Results: Sixty seven (4.34%) patients developed systemic effects and two (0.1%) patients died due to effects of envenomation or complications of treatment. Systemic effects varied from coagulopathy, nephropathy to some neurological manifestations. Fifty nine (3.8%) patients had only coagulopathy and they received either, intravenous isotonic saline to ensure adequate urine out put i.e. 0.5 mL/kg /hour or 15 mL/kg of fresh frozen plasma (FFP). None of the patients that had coagulopathy developed renal failure. Contamination of the sample by mildly venomous species of Hypnale may have contributed to the low incidence of systemic complications. Conclusions: It is likely that early hydration with normal saline or FFP can prevent acute renal failure. FFP showed a tendency for early correction of coagulopathy. Role of FFP in hump nosed viper envenomation is worth studying in randomized double blind controlled clinical trials.