Serum pentraxin 3 levels in term neonates with persistent pulmonary hypertension.

BACKGROUND: Persistent pulmonary hypertension of the neonate (PPHN) is a serious disorder. The long pentraxin 3 (PTX3) plays an important role in angiogenesis, cell proliferation, tissue repair and cell regulation. The present study aims to assess the diagnostic and clinical value of PTX3 in PPHN. METHODS: The present case-control 60 full-term neonates diagnosed with PPHN by echocardiography within 72 hours of birth. In addition, there were 30 age and sex-matched healthy neonates who served as controls. All participants were subjected to careful history taking and complete clinical examination, Laboratory investigations included complete blood count, C-reactive protein (CRP), blood culture and PTX3 level. Radiological investigations included plain X- ray and two-dimensional transthoracic echocardiography (TTE). RESULTS: Comparison between patients and controls revealed that patients had significantly higher CRP (6.12±2.18 versus 3.69±1.25 mg/dl, p < 0.001) and PTX3 levels (2.07±0.67 versus 0.96±0.21, p < 0.001) when compared with controls. Patients with associated PDA had significantly higher PTX3 levels when compared with patients without (2.58±0.5 versus 2.02±0.51 ng/ml, p = 0.002). Also, patients with associated PFO had significantly higher PTX3 levels when compared with patients without (2.12±1.05 versus 2.05±0.46, p = 0.002). ROC curve analysis identified good performance of CRP and PTX3 levels in diagnosis of PPHN with PTX3 showing better performance. CONCLUSIONS: There is a significant association between serum PTX3 levels and PPHN particularly those with associated PDA or PFO.

Macrophage polarization and signaling in diabetic kidney disease: a catalyst for disease progression.

Diabetic kidney disease (DKD) is a serious complication of diabetes affecting millions of people worldwide. Macrophages, a critical immune cell type, are central players in the development and progression of DKD. In this comprehensive review, we delve into the intricate role of macrophages in DKD, examining how they can become polarized into proinflammatory M1 or anti-inflammatory M2 phenotypes. We explore the signaling pathways involved in macrophage recruitment and polarization in the kidneys, including the key cytokines and transcription factors that promote M1 and M2 polarization. In addition, we discuss the latest clinical studies investigating macrophages in DKD and explore the potential of hypoglycemic drugs for modulating macrophage polarization. By gaining a deeper understanding of the mechanisms that regulate macrophage polarization in DKD, we may identify novel therapeutic targets for this debilitating complication of diabetes. This review provides valuable insights into the complex interplay between macrophages and DKD, shedding light on the latest developments in this important area of research. This review aims to enhance understanding of the role that macrophages play in the pathogenesis of DKD.

Magic shotgun approach to anti-inflammatory pharmacotherapy: Synthesis of novel thienopyrimidine monomers/heterodimer as dual COX-2 and 15-LOX inhibitors endowed with potent antioxidant activity.

Emerging evidence points to the intertwining framework of inflammation and oxidative stress in various ailments. We speculate on the potential impact of the magic shotgun approach in these ailments as an attempt to mitigate the drawbacks of current NSAIDs. Hence, we rationally designed and synthesized new tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine monomers/heterodimer as dual selective COX-2/15-LOX inhibitors with potent antioxidant activity. The synthesized compounds were challenged with diverse in vitro biological assays. Regarding the monomeric series, compound 5k exerted the highest COX-2 inhibitory activity (IC50 = 0.068 µM, SI = 160.441), while compound 5i showed the highest 15-LOX inhibitory activity (IC50 = 1.97 µM). Surpassing the most active monomeric members, the heterodimer 11 stemmed as the most potent and selective one in the whole study (COX-2 IC50 = 0.065 µM, SI = 173.846, 15-LOX IC50 = 1.86 µM). Heterodimer design was inspired by the cross-talk between the partner monomers of the COX-2 isoform. Moreover, some of our synthesized compounds could significantly reverse the LPS-enhanced production of ROS and proinflammatory cytokines (IL-6, TNF-α, and NO) in RAW 264.7 macrophages. Again, the heterodimer showed the strongest suppressor activity against ROS (IC50 = 18.79 µM) and IL-6 (IC50 = 4.15 µM) production outperforming the two references, celecoxib and diclofenac. Regarding NO suppressor activity, compound 5j (IC50 = 18.62 µM) surpassed the two references. Only compound 5a significantly suppressed TNF-α production (IC50 = 19.68 µM). Finally, molecular modeling simulated the possible binding scenarios of our synthesized thienopyrimidines within the active sites of COX-2 and 15-LOX. These findings suggest that those novel thienopyrimidines are promising leads showing pharmacodynamics synergy against the selected targets.

SGLT2 Inhibitor-Dapagliflozin Attenuates Diabetes-Induced Renal Injury by Regulating Inflammation through a CYP4A/20-HETE Signaling Mechanism.

Diabetic kidney disease (DKD) is a serious complication of diabetes, affecting millions of people worldwide. Inflammation and oxidative stress are key contributors to the development and progression of DKD, making them potential targets for therapeutic interventions. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a promising class of drugs, with evidence demonstrating that they can improve renal outcomes in people with diabetes. However, the exact mechanism by which SGLT2i exert their renoprotective effects is not yet fully understood. This study demonstrates that dapagliflozin treatment attenuates renal injury observed in type 2 diabetic mice. This is evidenced by the reduction in renal hypertrophy and proteinuria. Furthermore, dapagliflozin decreases tubulointerstitial fibrosis and glomerulosclerosis by mitigating the generation of reactive oxygen species and inflammation, which are activated through the production of CYP4A-induced 20-HETE. Our findings provide insights onto a novel mechanistic pathway by which SGLT2i exerts their renoprotective effects. Overall, and to our knowledge, the study provides critical insights into the pathophysiology of DKD and represents an important step towards improving outcomes for people with this devastating condition.

Hybrid N-Acylcysteines as Dual-Acting Matrix Disruptive and Anti-Quorum Sensing Agents Fighting Pseudomonas aeruginosa Biofilms: Design, Synthesis, Molecular Docking Studies, and In Vitro Assays.

Biofilms facilitate the pathogenesis of life-threatening Pseudomonas aeruginosa infections by coating mucosal surfaces or invasive devices and offer protection from antimicrobial therapy and the host immune response, thus increasing mortality rates and financial burden. Herein, new hybrid N-acylcysteines (NAC) incorporating selected acyl groups from organic acids and their derivatives, which are capable of quenching pathogen quorum sensing (QS) systems, were designed and their antibiofilm activity and anti-QS were evaluated. N-acylcysteines (4a-h) were synthesized and characterized by 1H NMR and 13C NMR, and their purity was confirmed by elemental analyses. N-(4-Hydroxy-3,5-dimethoxybenzoyl)-l-cysteine (4d) and N-(4-methoxybenzoyl)-l-cysteine (4h) showed a higher antibiofilm activity against PAO1 biofilms than the rest of the targets and the standard NAC. They showed 83 and 82% inhibition of biofilms at 5 mM and eradicated mature biofilms at 20 mM concentrations (NAC biofilm inhibition = 66% at 10 mM and minimum biofilm eradication concentration = 40 mM). This was confirmed via visualizing adherent biofilm cells on catheter pieces using scanning electron microscopy. In the same vein, both 4d and 4h showed the highest docking score with the QS signal receptor protein LasR (-7.8), which was much higher than that of NAC (-5) but less than the score of the natural agonist N-(3-oxododecanoyl)-l-homoserine (OdDHL) (-8.5). Target 4h (5 mM) decreased the expression of quorum sensing encoding genes in P. aeruginosa PAO1 strain by 53% for pslA, 47% for lasI and lasR, and 29% for filC, lowered PAO1 pyocyanin production by 76.43%, completely blocked the proteolytic activity of PAO1, and did not affect PAO1 cell viability. Targets 4d and 4h may find applications for the prevention and treatment of biofilm-mediated P. aeruginosa local infections of the skin, eye, and wounds. N-(4-Methoxybenzoyl)-l-cysteine 4h is a promising dual-acting matrix disruptive and anti-QS antibiofilm agent for further investigation and optimization.

Influence of intermittent fasting on prediabetes-induced neuropathy: Insights on a novel mechanistic pathway.

Aims: Peripheral neuropathy (PN) is correlated with obesity and metabolic syndrome. Intermittent fasting (IF) has been described as the cornerstone in the management of obesity; however, its role in prediabetic complications is not well elucidated. Cytochromes P450 Monooxygenases (CYP450) are major sources of Reactive Oxygen Species (ROS) that orchestrate the onset and development of diabetic complications. One of the CYP-metabolites, Expoxyecosatetraenoic Acids (EETs), are considered to be negative regulators of ROS production. In this study, we elucidated the role of IF on ROS production and investigated its influence on prediabetes-induced PN. Methods: C57/BL6 control mice, prediabetic, prediabetic that underwent alternate day fasting with different diet composition, and prediabetic mice treated with EET-metabolizing sEH-inhibitor, AUDA. Body mass composition, metabolic, behavioral, and molecular tests were performed. Results: High-fat diet (HFD) led to an increase in NADPH-induced ROS production; that was due to an alteration in the epoxygenase pathway assessed by the decrease in CYP1a1/1a2 expression. IF reinstated the homeostatic levels of EETs in HFD-fed mice. Moreover, treatment with AUDA mimicked the beneficial effect observed with IF. Conclusion: IF and EETs bioavailability have a protective role in prediabetes-induced PN, suggesting a novel interventional strategy in the management of prediabetes and its associated complications.

Vitis Methods to Understand and Develop Strategies for Diagnosis and Sustainable Control of Grapevine Trunk Diseases.

Vitis vinifera is affected by many diseases every year, depending on causal agents, susceptibility of cultivars, and climate region. Some are caused by a single agent, such as gray mold caused by Botrytis cinerea or powdery mildew caused by Erysiphe necator. Others result from the actions of a complex of pathogens such as grapevine trunk diseases (GTDs). GTDs are presently among the most devastating diseases in viticulture worldwide because both the economic losses and the long-term sustainability of vineyards are strongly affected. The complexity of GTDs results from the diversity of associated fungi, the undetermined period of latency within the vine (asymptomatic status), the erratic foliar symptom expression from one year to the next, and, probably correlated with all of these points, the lack of efficient strategies to control them. Distinct methods can be beneficial to improve our knowledge of GTDs. In vitro bioassays with cell suspensions, calli, foliar discs, full leaves, or plantlets, and in vivo natural bioassays with cuttings, grafted plants in the greenhouse, or artificially infected ones in the vineyard, can be applied by using progressive integrative levels of in vitro and in vivo, depending on the information searched. In this review, the methods available to understand GTDs are described in terms of experimental procedures, main obtained results, and deliverable prospects. The advantages and disadvantages of each model are also discussed.

Successful oral desensitization in sesame allergy in ana adult woman

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Thoracic disc herniation: Surgical treatment.

Thoracic disc herniation is rare and mainly occurs between T8 and L1. The herniation is calcified in 40% of cases and is labeled as giant when it occupies more than 40% of the spinal canal. A surgical procedure is indicated when the patient has severe back pain, stubborn intercostal neuralgia or neurological deficits. Selection of the surgical approach is essential. Mid-line calcified hernias are approached from a transthoracic incision, while lateralized soft hernias can be approached from a posterolateral incision. The complication rate for transthoracic approaches is higher than that of posterolateral approaches; however, the former are performed in more complex herniation cases. The thoracoscopic approach is less invasive but has a lengthy learning curve. Retropleural mini-thoracotomy is a potential compromise solution. Fusion is recommended in cases of multilevel herniation, herniation in the context of Scheuermann's disease, when more than 50% bone is resected from the vertebral body, in patients with preoperative back pain or herniation at the thoracolumbar junction. Along with complications specific to the surgical approach, the surgical risks are neurological worsening, dural breach and subarachnoid-pleural fistulas. Giant calcified herniated discs are the largest contributor to myelopathy, intradural extension and postoperative complications. Some of the technical means that can be used to prevent complications are explored, along with how to address these complications.

A podoscopic and descriptive study of foot deformities in patients with Down syndrome.

INTRODUCTION: Subjects with Down syndrome (DS) are known to be affected by various foot deformities. Despite the fact that some of these deformities have been reported in the literature, a more comprehensive description would be of benefit. The aim of this study is to investigate the prevalence of known foot deformities in patients with DS and of other previously non-described foot anomalies in this population. HYPOTHESIS: Subjects with DS have an increased prevalence of foot deformities compared to control subjects. METHODS: Fifty-five subjects with DS (age: 14.6±7.4 years) had undergone podiatric clinical and podoscopic examinations to study their main foot deformities and their footprints, respectively. The results of these examinations were compared to those of an age-matched asymptomatic control group of fifty-three subjects (age: 13.4±11.2 years). RESULTS: Significantly more prevalent foot deformities were found in the DS group: hallux valgus (36.4%), syndactyly between the 2nd and 3rd toes (9.1%), grade II pes planus (39.1%) and grade III pes planus (30%). Moreover, joint laxity (43.6%) was significantly more prevalent in the DS group. Furthermore, the presence of an increased space between the 1st and 2nd toes in patients with DS and its prevalence (73.6%) were described for the first time. A multivariate analysis revealed a significant relationship between the presence of joint laxity and flatfoot in only the control but not the DS group. Other foot deformities were found to be consistently more frequent in the DS population but not significantly higher than the control group. DISCUSSION: Although subjects with DS had significantly greater joint laxity and BMI compared to the control group, neither of these factors was found to be related to the increased prevalence of flatfoot in DS patients. LEVEL OF EVIDENCE: IV-retrospective study.

A cross-sectional assessment of quality of life of breast cancer patients in Saudi Arabia.

OBJECTIVE: This aim of this study was to assess the quality of life of Saudi female breast cancer patients and determine the effects of the sociodemographic and clinical characteristics on the quality of life of those patients. STUDY DESIGN: This study was designed as a cross-sectional study. METHODS: The data were collected from 145 female cancer patients who were recruited from outpatient units in different clinical settings in Riyadh, Saudi Arabia, from September 2014 to February 2015. Questionnaires were distributed to the patients during their visits to the outpatient clinics after obtaining informed consent. Quality of life was assessed using a validated Arabic version of the European Organisation for Research and Treatment of Cancer (EORTC) quality of life. RESULTS: Among functional scales, emotional functioning scored the highest (83.25 [95% CI 79.53-86.98]). The most distressing symptom on the symptom scale was insomnia (mean 84.14 [95% CI 79.95-88.32]), followed by appetite loss (mean 80.92 [95% CI 76.51-85.33]) and dyspnoea (mean 80.00 [95% CI 75.51-84.49]). Poor functioning was found in sexual enjoyment (mean 22.52 [95% CI 17.97-27.08]) while future perspective scored the highest (mean 76.32 [95% CI 70.52-82.12]). CONCLUSION: This study shows breast cancer survivors in Saudi had a low overall global quality of life. Saudi women showed average scores on all the functional scales but the emotional ones scored the highest. Insomnia, appetite loss, and dyspnoea were the distressing symptoms on symptom scales while future perspective domain scored the highest in item of QLQ-BR23.

The novel elicitor AsES triggers a defense response against Botrytis cinerea in Arabidopsis thaliana.

AsES (Acremonium strictum Elicitor and Subtilisin) is a novel extracellular elicitor protein produced by the avirulent isolate SS71 of the opportunist strawberry fungal pathogen A. strictum. Here we describe the activity of AsES in the plant-pathogen system Arabidopsis thaliana-Botrytis cinerea. We show that AsES renders A. thaliana plants resistant to the necrotrophic pathogen B. cinerea, both locally and systemically and the defense response observed is dose-dependent. Systemic, but not local resistance is dependent on the length of exposure to AsES. The germination of the spores in vitro was not inhibited by AsES, implying that protection to B. cinerea is due to the induction of the plant defenses. These results were further supported by the findings that AsES differentially affects mutants impaired in the response to salicylic acid, jasmonic acid and ethylene, suggesting that AsES triggers the defense response through these three signaling pathways.

Time to surgical review: an assessment of the traditional model of emergency surgical care.

BACKGROUND: The traditional model for emergency surgical care consists of an on-call team providing service to the emergency department, while simultaneously balancing the demands of elective work. Various newer models, such as the "surgeon of the week" aim to reduce the conflict between elective and emergency duties. Despite the recent focus on newer models, there remains no data on the effectiveness of the traditional model. We aim to assess the efficacy of the traditional model in a large regional hospital. METHODS: A retrospective study between July 2009 and March 2010 was performed. Primarily, we assessed the initial time to surgical consultation after emergency department referral. Secondarily, we evaluated the impact of time periods, days of week, and case-mix etiology on this consultation time. RESULTS: The overall median time to surgical consultation after emergency department referral was 30 min (N = 860, P = 0.709). However, the median time to consultation was 60, 30, and 20 min for daytime, evening and night time, respectively (*P < 0.001). Trauma cases had a median time of 15 min, vascular had 45 min, neoplasm had 120 min, while other categories (upper and lower gastroenterology, and skin related) were 30 min (*P = 0.025). DISCUSSION: Newer models of acute surgical care have desirable outcomes in consultation times. However, regional and economical implications have a substantial impact on which model is feasible at local levels. We demonstrated that the traditional model still remains effective in a large sized tertiary referral unit.

Assessment of health implications related to processing and use of natural wool insulation products.

This paper discusses possible health implications related to dust particles released during the manufacture of sheep's wool-based non-woven insulation material. Such insulation may replace traditional synthetic insulation products used in roofs, wall cavities, etc. A review of the literature concerning organic dusts in general and sheep's wool fiber summarizes dust exposure patterns, toxicological pathways and the hazards imposed by inhalation and explosion risk. This paper highlights a need for more research in order to refrain from overgeneralizing potential pulmonary and carcinogenic risks across the industries. Variables existing between industries such as the use of different wool types, processes, and additives are shown to have varying health effects. Within the final section of the paper, the health issues raised are compared with those that have been extensively documented for the rock and glass wool industries.

Extracellular compounds produced by fungi associated with Botryosphaeria dieback induce differential defence gene expression patterns and necrosis in Vitis vinifera cv. Chardonnay cells.

Three major grapevine trunk diseases, esca, botryosphaeria dieback and eutypa dieback, pose important economic problems for vineyards worldwide, and currently, no efficient treatment is available to control these diseases. The different fungi associated with grapevine trunk diseases can be isolated in the necrotic wood, but not in the symptomatic leaves. Other factors seem to be responsible for the foliar symptoms and may represent the link between wood and foliar symptoms. One hypothesis is that the extracellular compounds produced by the fungi associated with grapevine trunk diseases are responsible for pathogenicity.In the present work, we used Vitis vinifera cv. Chardonnay cells to test the aggressiveness of total extracellular compounds produced by Diplodia seriata and Neofusicoccum parvum, two causal agents associated with botryosphaeria dieback. Additionally, the toxicity of purified mellein, a characteristic toxin present in the extracellular compounds of Botryosphaeriaceae, was assessed.Our results show that the total extracellular compounds produced by N. parvum induce more necrosis on Chardonnay calli and induce a different defence gene expression pattern than those of D. seriata. Mellein was produced by both fungi in amounts proportional to its aggressiveness. However, when purified mellein was added to the culture medium of calli, only a delayed necrosis and a lower-level expression of defence genes were observed. Extracellular compounds seem to be involved in the pathogenicity of the fungi associated with botryosphaeria dieback. However, the doses of mellein used in this study are 100 times higher than those found in the liquid fungal cultures: therefore, the possible function of this toxin is discussed.

Developing and implementing a plan for large-scale burn disaster response in New Jersey.

For the first time in modern history burn centers must face the reality of having to potentially care for a staggering number of injured patients. Factors such as staffing, patient acuity and bed availability compel medical professionals to regularly examine various aspects of their respective healthcare delivery systems, especially with regards to how these systems should function for mass casualty response. The majority of burn care in New Jersey is provided by one designated burn treatment facility. A planning group was formed to identify additional hospital support systems capable of providing short-term patient care during a disaster. Focus was on three key areas: identifying actual versus potential nonburn center resources, ascertaining the number and level of burn expertise at these facilities, and assessing the capacities of any available resources and personnel. Retrospective review of discharge data highlighted which of the more than seventy New Jersey hospitals besides The Burn Center were treating and releasing burn injures. In a disaster The Burn Center designates these hospitals as Tier Facilities to serve as additional resources until patients may be transferred to other recognized regional and national burn centers. Triage is conducted in accordance with the American Burn Association Benefit-to-Ratio Triage grid, matching patient acuity with each hospital's tier designation. A secondary triage, conducted 24 hours after the initial incident, identifies which patients require transport for more specialized burn care. Twenty-seven burn centers from Maine through Maryland and the District of Columbia, who have joined together as a Consortium, agree to support one another for optimal patient distribution and management in accordance with accepted national standards of care. State Medical Coordination Centers equipped to coordinate and track transport of large numbers of injured personnel are able to facilitate this collaborative, multiagency response throughout the northeast region. Burn centers share many issues common to emergency preparedness. Paramount among them is an ability to provide quality burn care for the greatest number of patients at a time when staff and resources will be severely limited. It is incumbent upon burn centers to explore opportunities extending beyond individual state and regional resources in order for centers to continually maintain this standard of care, particularly in a disaster.

True-FISP MRI in diagnosis of postoperative hernia recurrence: a brief report.

BACKGROUND: A 24-year-old man underwent laparoscopic mesh repair of a right direct inguinal hernia which had recurred after previous surgery 3 months previously. A large swelling was noted in the right groin 4 h postoperatively, which was reduced initially but recurred within 24 h. A differential diagnosis of postoperative recurrence versus hematoma was considered, and patient was referred for imaging. METHODS: The patient was imaged using different modalities including B-mode ultrasonography, computed tomography (CT) of the pelvis, and True-FISP magnetic resonance imaging (true imaging with steady-state precession MRI). RESULTS: Initial focused ultrasound (US) [corrected] was suggestive of but equivocal for recurrence. Subsequent non-contrast CT of the region followed by rapid sequence (true-FISP) MRI confirmed the presence of bowel in the inguinal canal. CONCLUSION: Imaging has a role in the diagnosis of postoperative hernia recurrence in cases where there is a clinical diagnostic dilemma, especially MRI using true-FISP sequence, which is acquired in seconds, is a non-ionising radiation modality and does not have inter operator variability.

Design, synthesis and in vitro anticancer evaluation of 4,6-diamino-1,3,5-triazine-2-carbohydrazides and -carboxamides.

Series of substituted 4,6-diamino-1,3,5-triazine-2-carbohydrazides and -carboxamides have been synthesised, based on molecular modelling of candidate structures related to the previously reported Rad6B-inhibitory diamino-triazinylmethyl benzoate anticancer agents TZ8 and TZ9. Synthesis of the target compounds was readily accomplished in two steps from aryl biguanides via reaction of phenylhydrazine or benzylamines with key 4-amino-6-(arylamino)-1,3,5-triazine-2-carboxylate intermediates. These new triazine derivatives were tested for in vitro anticancer activity against the Rad6B expressing human breast cancer cell lines MDA-MB-231 and MCF-7. Active compounds, such as the triazinyl-carbohydrazides 3a-e, were found to exhibit low micromolar IC50 values particularly in the Rad6B-overexpressing MDA-MB-231 cell line.

Randomized clinical trial of the benefit of laparoscopy with closure of loop ileostomy.

BACKGROUND: The aim was to compare reversal and laparoscopy with standard reversal of loop ileostomy in terms of hospital stay and morbidity in a randomized study. METHODS: Patients having reversal of a loop ileostomy were randomized to either standard reversal of ileostomy or reversal and laparoscopy. Strict discharge criteria were applied: toleration of two meals without nausea and vomiting, passing a bowel motion, and attaining adequate pain control with oral analgesia. Morbidity and cost were also compared between the two groups. RESULTS: A total of 74 patients (reversal and laparoscopy 40, standard reversal 34) with a median age of 61 years underwent loop ileostomy reversal; there were 45 men (61 per cent). Ileostomy was most commonly carried out after laparoscopic low anterior resection (36 patients). Median length of stay, based on discharge criteria, was significantly shorter in the reversal and laparoscopy group than in the standard group: 4 (interquartile range 3-4) versus 5 (4-6) days (P = 0·003). The overall morbidity rate was also lower in patients who had ileostomy reversal and laparoscopy: 10 versus 32 per cent (P = 0·023). The median cost per patient was lower in the reversal and laparoscopy group: €3450 (interquartile range 2766-3450) versus €4527 (3843-7263) (P = 0·015). There was no statistically significant difference in American Society of Anesthesiologists fitness grade or time to reversal between the two groups. CONCLUSION: Reversal of loop ileostomy with laparoscopy was associated with a shorter hospital stay, lower morbidity and reduced cost compared with the standard technique. REGISTRATION NUMBER: ISRCTN46101203 (http://www.controlled-trials.com).