Randomized Phase 3 trial demonstrating high efficacy, favourable safety and convenience of a novel calcipotriol and betamethasone dipropionate cream for the treatment of psoriasis.

BACKGROUND: The fixed dose combination of calcipotriene (CAL) and betamethasone dipropionate (BDP) is a well-established topical treatment option for psoriasis based on strong scientific rationale for the single agents having complementary efficacy and safety. CAL/BDP PAD-cream is an easily spreadable cream based on PAD Technology™, an innovative formulation and drug delivery system. OBJECTIVES AND METHODS: A Phase 3, multicentre, randomized, investigator-blind, active and vehicle-controlled trial enrolling 490 patients with mild to moderate psoriasis according to the Physician Global Assessment (PGA) scale was conducted in three European countries. Products were applied once daily for 8 weeks. The aim of the trial was to evaluate the efficacy and safety of CAL/BDP PAD-cream as well as treatment acceptability compared to CAL/BDP gel and PAD-cream vehicle. Primary endpoint was percentage change in modified Psoriasis Area and Severity Index (mPASI) from baseline to Week 8. RESULTS: The percentage mean change from baseline to Week 8 in mPASI for CAL/BDP PAD-cream (67.5%) was superior compared to PAD-cream vehicle (11.7%; p < 0.0001) and non-inferior to CAL/BDP gel (63.5%). The proportion of patients achieving PGA treatment success (at least two-step improvement to clear or almost clear) after 8 weeks was superior for CAL/BDP PAD-cream (50.7%) compared to PAD-cream vehicle (6.1%, p < 0.0001) and statistically significantly greater than CAL/BDP gel (42.7%, p = 0.0442). Patient-reported psoriasis treatment convenience score (PTCS) for CAL/BDP PAD-cream was rated superior to CAL/BDP gel at Week 8 (p < 0.0001) and the mean change in DLQI from baseline to Week 8 improved statistically significantly more in the CAL/BDP PAD-cream group compared to both PAD-cream vehicle (p < 0.0001) and CAL/BDP gel (p = 0.0110). Safety assessments during the trial demonstrated that CAL/BDP PAD-cream was well-tolerated. CONCLUSION: CAL/BDP PAD-cream is a novel topical treatment of psoriasis that has a high efficacy and a favourable safety profile combined with a superior patient-reported treatment convenience.

Calcipotriol/betamethasone dipropionate foam demonstrates comparable efficacy to clinical trial data in the real world, improves patient satisfaction and is cost-effective.

Real-world evidence studies are becoming increasingly important in providing insight into clinical effectiveness and safety, economic outcomes, patient-reported outcomes and health-related quality of life of treatments in the clinical setting. These studies also help to complement data reported in clinical studies. Fixed-dose combination calcipotriol 50 µg/g plus betamethasone dipropionate 0.5 mg/g cutaneous foam (Cal/BD foam) is a topical agent used for the treatment of psoriasis vulgaris. In clinical studies, Cal/BD foam has demonstrated a significantly greater efficacy and rapid onset of action compared with both single and combination formulations such as ointments and gels. To date, three observational studies have examined the real-world efficacy and safety of Cal/BD foam in clinical practice in the United States, Germany and Spain. Data gathered from these studies reinforce the positive findings reported in clinical studies assessing Cal/BD foam for the treatment of psoriasis and demonstrate improved patient satisfaction with Cal/BD foam. Using Cal/BD foam has been shown to be cost-effective based on results from randomised clinical trials and cost-effective analysis. As such, Cal/BD foam has the potential to lower treatment costs by reducing the need for some patients to progress to more expensive treatments, such as phototherapy and biologics. Cal/BD foam is therefore a cost-effective solution for the treatment of psoriasis vulgaris that should be considered when prescribing topicals.

Androgen receptor variant-driven prostate cancer: clinical implications and therapeutic targeting.

While there are myriad mechanisms of primary and acquired resistance to conventional and next-generation hormonal therapies in prostate cancer, the potential role of androgen receptor splice variants (AR-Vs) has recently gained momentum. AR-Vs are abnormally truncated isoforms of the androgen receptor (AR) protein that lack the COOH-terminal domain but retain the NH2-terminal domain and DNA-binding domain and are thus constitutively active even in the absence of ligands. Although multiple preclinical studies have previously implicated AR-Vs in the development of castration resistance as well as resistance to abiraterone and enzalutamide, recent technological advances have made it possible to reliably detect and quantify AR-Vs from human clinical tumor specimens including blood samples. Initial clinical studies have now shown that certain AR-Vs, in particular AR-V7, may be associated with resistance to abiraterone and enzalutamide but not taxane chemotherapies when detected in circulating tumor cells. Efforts are now underway to clinically validate AR-V7 as a relevant treatment-selection biomarker in the context of other key genomic aberrations in men with metastatic castration-resistant prostate cancer. Additional efforts are underway to therapeutically target both AR and AR-Vs either directly or indirectly. Whether AR-Vs represent drivers of castration-resistant prostate cancer, or whether they are simply passenger events associated with aggressive disease or clonal heterogeneity, will ultimately be answered only through these types of clinical trials.

Evaluation of an epithelial plasticity biomarker panel in men with localized prostate cancer.

BACKGROUND: Given the potential importance of epithelial plasticity (EP) to cancer metastasis, we sought to investigate biomarkers related to EP in men with localized prostate cancer (PC) for the association with time to PSA recurrence and other clinical outcomes after surgery. METHODS: Men with localized PC treated with radical prostatectomy at the Durham VA Medical Center and whose prostatectomy tissues were included in a tissue microarray (TMA) linked to long-term outcomes. We performed immunohistochemical studies using validated antibodies against E-cadherin and Ki-67 and mesenchymal biomarkers including N-cadherin, vimentin, SNAIL, ZEB1 and TWIST. Association studies were conducted for each biomarker with baseline clinical/pathologic characteristics an risk of PSA recurrence over time. RESULTS: Two hundred and five men contributed TMA tissue and had long-term follow-up (median 11 years). Forty-three percent had PSA recurrence; three died of PC. The majority had high E-cadherin expression (86%); 14% had low/absent E-cadherin expression. N-cadherin was rarely expressed (<4%) and we were unable to identify an E-to-N-cadherin switch as independently prognostic. No associations with clinical risk group, PSA recurrence or Gleason sum were noted for SNAIL, ZEB1, vimentin or TWIST, despite heterogeneous expression between patients. We observed an association of higher Ki-67 expression with Gleason sum (P=0.043), National Comprehensive Cancer Network risk (P=0.013) and PSA recurrence (hazard ratio 1.07, P=0.016). CONCLUSIONS: The expression of EP biomarkers in this cohort of men with a low risk of PC-specific mortality was not associated with aggressive features or PSA relapse after surgery.

Prebiotics and probiotics: the prevention and reduction in severity of atopic dermatitis in children.

The purpose of this review was to identify whether supplementation with prebiotics and/or probiotics help prevent the development or reduce the severity of atopic dermatitis in children less than three years of age. Since 1997, immunostimulatory supplements, such as prebiotics and probiotics, have been investigated. Various supplementations include probiotics (single strain or mix), probiotics with formula, probiotics mix with prebiotics, and prebiotics. In this narrative review, we examined 13 key articles on prebiotics and/or probiotics, and their effects on infant atopic dermatitis. Among the selected studies, a total of 3,023 participants received supplements or placebo. Eight out of the 13 (61.5%) studies reported a significant effect on the prevention of atopic dermatitis after supplementation with probiotics and/or prebiotics. Five out of the 13 (38.5%) studies indicated significant reduction in the severity of atopic dermatitis after supplementation. Based on the available studies, supplementation with certain probiotics (Lactobacillus rhamnosus GG) appears to be an effective approach for the prevention and reduction in severity of atopic dermatitis. A mix of specific probiotic strains prevented atopic dermatitis among infants. Based on studies with prebiotics, there was a long-term reduction in the incidence of atopic dermatitis. Supplementation with prebiotics and probiotics appears useful for the reduction in the severity of atopic dermatitis. Additional interventional studies exploring prebiotics and probiotics are imperative before recommendations can be made.

Effects of a 5-HT(3) antagonist, ondansetron, on fasting and postprandial small bowel water content assessed by magnetic resonance imaging.

BACKGROUND: 5-HT(3) antagonists have been shown to be effective in relieving the symptoms of irritable bowel syndrome with diarrhoea (IBS-D). Using a recently validated magnetic resonance imaging (MRI) method, we have demonstrated reduced fasting small bowel water content (SBWC) in IBS-D associated with accelerated small bowel transit. We hypothesized that slowing of transit with ondansetron would lead to an increase in SBWC by inhibiting fasting motility. AIM: To assess the effects of ondansetron compared with placebo in healthy volunteers on SBWC and motility in two different groups of subjects, one studied using MRI and another using manometry. METHODS: Healthy volunteers were given either a placebo or ondansetron on the day prior to and on the study day. Sixteen volunteers underwent baseline fasting and postprandial MRI scans for 270 min. In a second study, a separate group of n = 18 volunteers were intubated and overnight migrating motor complex (MMC) recorded. Baseline MRI scans were carried out after the tube was removed. RESULTS: Fasting SBWC was markedly increased by ondansetron (P < 0.0007). Ondansetron reduced the overall antroduodenal Motility Index (P < 0.04). The subjects who were intubated had significantly lower fasting SBWC (P < 0.0002) compared with the group of subjects who were not intubated. CONCLUSIONS: The 5-HT(3) receptor antagonism increased fasting small bowel water. This was associated with reduced fasting antroduodenal Motility Index which may explain the clinical benefit of such drugs.

Patient satisfaction with Trilucent breast implants.

We report our findings in a retrospective study of patient satisfaction with soybean oil-filled mammary implants. Sixty-two women who had breast augmentation with Trilucent breast implants were sent a questionnaire to assess their satisfaction with implant placement; 19 of the 62 attended for clinical examination. Overall satisfaction with triglyceride implant placement was high: very pleased 45% (18/40), pleased 32.5% (13/40), content 12.5% (5/40). The majority of women felt that it had enhanced their body image and lifestyle (82.5%).

Randomised trial of magnesium in in-hospital cardiac arrest. Duke Internal Medicine Housestaff.

BACKGROUND: The apparent benefit of magnesium in acute myocardial infarction, and the persistently poor outcome after cardiac arrest, have led to use of magnesium in cardiopulmonary resuscitation. Because few data on its use in cardiac arrest were available, we undertook a randomised placebo-controlled trial (MAGIC trial). METHODS: Patients treated for cardiac arrest by the Duke Hospital code team were randomly assigned intravenous magnesium (2 g [8 mmoles] bolus, followed by 8 g [32 mmoles] over 24 h; 76 patients) or placebo (80 patients). Only patients in intensive care or general wards were eligible; those whose cardiac arrest occurred in emergency, operating, or recovery rooms were excluded. The primary endpoint was return of spontaneous circulation, defined as attainment of any measurable blood pressure or palpable pulse for at least 1 h after cardiac arrest. The secondary endpoints were survival to 24 h, survival to hospital discharge, and neurological outcome. Analysis was by intention to treat. FINDINGS: There were no significant differences between the magnesium and placebo groups in the proportion with return of spontaneous circulation (41 [54%] vs 48 [60%], p = 0.44), survival to 24 h (33 [43%] vs 40 [50%], p = 0.41), survival to hospital discharge (16 [21%] vs 17 [21%], p = 0.98), or Glasgow coma score (median 15 in both). INTERPRETATION: Empirical magnesium supplementation did not improve the rate of successful resuscitation, survival to 24 h, or survival to hospital discharge overall or in any subpopulation of patients with in-hospital cardiac arrest.

Characterization and solubility measurements of uranium-contaminated soils to support risk assessment.

Remediation of uranium-contaminated soils is considered a high priority by the U.S. Department of Energy because these soils, if left untreated, represent a hazard to the environment and human health. Because the risk to human health is a function of the solubility of uranium in the soils, the objectives of this work are to measure the uranium solubility of two contaminated soils, before and after remedial treatment, and determine the health risk associated with these soils. Two carbonate-rich, uranium-contaminated soils from the U.S. Department of Energy Fernald Environmental Management Project facility near Cincinnati, Ohio, as well as two nearby background soils were characterized and their uranium solubility measured in a 75-d solubility experiment using acid rain, groundwater, lung serum, and stomach acid simulants. Results show that the soluble uranium levels of each soil by each simulant are greatly influenced by their contamination source term. Risk calculations and biokinetic modeling based on the solubility data show that the risks from the soil ingestion and groundwater ingestion pathways are the predominant contributors to the total carcinogenic risk, whereas the risk from the soil inhalation pathway is the smallest contributor to this risk. However, kidney toxicity was the greater health concern of the Fernald Environmental Management Project soils, primarily from undiluted ingestion of the groundwater solution following contact with the contaminated soils. Sensitivity analyses indicate that uranium solubility is a key parameter in defining kidney toxicity; therefore, without proper consideration of the solubility of radionuclides/metals in untreated and treated soils, important factors may be overlooked which may result in soil cleanup goals or limits which are not protective of human health and the environment. We recommend that characterization and measurement of target radionuclides/metals solubilities should also be required by the regulatory community to support the establishment of scientifically-sound, site-specific, soil cleanup goals or limits.

Indicators of abuse or neglect in preschool children's drawings.

1. Research designed to examine the systematic ability of children's drawings to disclose abuse or neglect has been equivocal. 2. The use of art to understand preschool-aged children is particularly advantageous because very young children usually are not able to communicate their feelings clearly. 3. The study shows that the family drawings of abused or neglected preschool children can be differentiated from those of children not identified as abused or neglected.

The epidemiology of hip fractures and methods of prevention.

Hip fractures are common in the elderly, affecting 1 in 4 women by the age of 90 years and 1 in 8 men. These fractures have caused an "epidemic" during the last 20 years because the age specific rate for such fractures has doubled, and there has been a significant increase in the size of the elderly population in Europe. Hip fracture patients occupy a quarter of all orthopedic beds, the treatment is costly and the rehabilitation slow. Fifteen percent die in hospital; 33% are dead by one year. Of survivors only 2/3 return to their own home. There is now a move to prevent such fractures. Hip fractures arise in the elderly for two reasons: deteriorating bone stock and increasing falls. Hip fracture prevention needs to address both issues, but most work has looked at bone stock. Predictions of hip fracture risk even if based on bone density are poor, so preventive measures need to target the whole population. Bone density rises to a peak at 35 to 40 years in both sexes; men have a higher bone density at all times than women. Thereafter there is a steady loss of 1-2% per year. Women have 10 years of accelerated loss after the menopause. Hip fracture prevention starts by ensuring that peak bone mass is reached. This is under genetic influence but may be maximized by adequate dietary calcium and physical activity in adolescence. Smoking, alcohol and steroid use reduce bone density and their use should be moderated. In women amenorrhea reduces bone density. For women, estrogen may stop menopausal loss and maintain bone density for at least 15 years and in retrospective studies can reduce the fracture risk by 50%. Calcitonin may be an alternative. Five years beyond the menopause primary or secondary prevention may be started. Estrogen is still the best therapy but may be less popular because of the return of menstrual periods. Calcitonin or oral calcium supplements may also be of benefit. Drugs in combination may be more effective than alone. Over age 70, when calcium absorption diminishes, vitamin D, calcium and calcitonin may be effective. For men, treatment options are calcium, calcitonin or, later on, vitamin D. The role of exercise in bone density protection is unclear but should be encouraged for general health reasons. Bisphosphonates are new drugs that may be useful. Falls become increasingly common in the elderly such that up to 80% of all 80-year-olds may sustain at least one fall per year.(ABSTRACT TRUNCATED AT 400 WORDS)

Sigmoid stricture at colonoscopy--an indication for surgery.

Strictures of the sigmoid colon continue to pose a diagnostic dilemma. They commonly appear to be due to diverticular disease but carcinoma must always be excluded. In some cases diverticula may be present but in others there is no obvious cause for the stricture. In a series of 1039 consecutive colonoscopies performed between 1984 and 1986, 19 cases of sigmoid stricture that could not be negotiated with the colonoscope were encountered. In each case the cause of the stricture could not be demonstrated. Fifteen patients (79%) underwent laparotomy primarily on clinical grounds or with barium enema findings suggestive of carcinoma. A final diagnosis of diverticular disease was made in nine cases and adenocarcinoma is six cases. Barium enema was a poor predictor of malignancy in a stricture. Four patients were treated conservatively and two of these patients continued to have significant symptoms due to diverticular disease. This experience suggests that sigmoid strictures that prevent the passage of a colonoscope should be resected when the cause of the stricture is not apparent.

Immunohistochemical localization of a spectrin-like protein (fodrin) in nerve cells in culture.

The distribution of fodrin in neurones in culture was demonstrated by immunohistochemistry with anti-spectrin antibodies. There was strong staining of the plasma membrane and cell extensions and also labelling of a cytoskeletal network throughout the cytoplasm.

Characterization and partial purification of a 5,700 dalton form of substance P-like immunoreactivity from the rat hypothalamus.

Analysis of rat hypothalamic extracts by gel filtration and HPLC revealed the presence of a form of substance P-like immunoreactivity with a molecular weight of approximately 5,700 (6k-SP). 6k-SP is probably an N-terminally extended form of substance P; the peptide may be an intermediate in SP biosynthesis, or may function as a biologically active peptide in its own right.