Gremlin – a putative pathogenic player in progressive renal disease

Progressive renal fibrosis is the end process of renal injury leading to kidney failure. Current therapies for chronic renal failure aim to slow this process but fail to halt its progression. As the mechanisms involved in glomerulosclerosis and tubulointerstitial fibrosis are unravelled, potential treatments for this growing clinical problem should emerge. Gremlin, a developmental regulator of bone morphogenetic proteins (BMPs), has recently been implicated in processes such as glomerulosclerosis, tubulointerstitial fibrosis and cellular hypertrophy, and may represent a novel therapeutic target in progressive renal diseases.     

Is exposure to an effective contingency management intervention associated with more positive provider beliefs?

This study empirically examined opinions of treatment providers regarding contingency management (CM) programs while controlling for experience with a specific efficacious CM program. In addition to empirically describing provider opinions, we examined whether the opinions of providers at the sites that implemented the CM program were more positive than those of matched providers at sites that did not implement it. Participants from 7 CM treatment sites (n = 76) and 7 matched nonparticipating sites (n = 69) within the same nodes of the National Institute of Drug Abuse Clinical Trials Network completed the Provider Survey of Incentives (PSI), which assesses positive and negative beliefs about incentive programs. An intent-to-treat analysis found no differences in the PSI summary scores of providers in CM program versus matched sites, but correcting for experience with tangible incentives showed significant differences, with providers from CM sites reporting more positive opinions than those from matched sites. Some differences were found in opinions regarding costs of incentives, and these generally indicated that participants from CM sites were more likely to see the costs as worthwhile. The results from the study suggest that exposing community treatment providers to incentive programs may itself be an effective strategy in prompting the dissemination of CM interventions.     

Programmed cell death in human pathogenic fungi – a possible therapeutic target

ABSTRACT

Introduction: Diseases caused by pathogenic fungi are increasing because of antibiotic overuse, the rise of immunosuppressive therapies, and climate change. The limited variety of antimycotics and the rapid adaptation of pathogenic fungi to antifungal agents serve to exacerbate this issue. Unfortunately, about 1.6 million people are killed by fungal infections annually.

Areas covered: The discovery of the small antimicrobial proteins produced by microorganisms, animals, humans, and plants will hopefully overcome challenges in the treatment of fungal infections. These small proteins are highly stable and any resistance to them rarely evolves; therefore, they are potentially good candidates for the treatment and prevention of infections caused by pathogenic fungi. Some of these proteins target the programmed cell death machinery of pathogenic fungi; this is potentially a novel approach in antimycotic therapies. In this review, we highlight the elements of apoptosis in human pathogenic fungi and related model organisms and discuss the possible therapeutic potential of the apoptosis-inducing, small, antifungal proteins.

Expert opinion: Small antimicrobial proteins may establish a new class of antimycotics in the future. The rarity of resistance and their synergistic effects with other frequently used antifungal agents may help pave the way for their use in the clinic.     

Genes associated with epithelial-mesenchymal transition: possible therapeutic targets in ductal pancreatic adenocarcinoma?

Epithelial to mesenchymal transition (EMT) is a biological process that allows well-differentiated, polarized epithelial cells to undergo a conversion to motile, unpolarized mesenchymal cells. EMT plays crucial roles during implantation, embryogenesis, and organ development (Type 1 EMT), is associated with tissue regeneration and organ fibrosis (Type 2 EMT), and involved in cancer invasion, metastasis, and drug resistance (Type 3 EMT). Since aggressiveness and drug resistance are hallmarks of ductal pancreatic cancer, significant effort has been undertaken in recent years to elucidate molecular EMT mechanisms in this dismal malignancy. This represents a formidable challenge for several reasons: EMT is a dynamic process, both with regard to spatial and temporal heterogeneity. Moreover, EMT is induced and regulated by a complex network of traditional signaling pathways and new players like microRNAs. Interestingly, similar molecular characteristics link EMT-type cells also to the concept of cancer stem cells. This review tries to integrate the current knowledge regarding EMT and pancreatic cancer; furthermore to outline not only the perspective on novel EMT-associated therapeutic targets, but also on overcoming drug resistance by interfering with EMT.     

Is weight loss possible in patients treated with thiazolidinediones? Experience with a low-calorie diet

SUMMARY

Background: Weight gain is a frequent side-effect of thiazolidinediones, possibly related to fluid retention and stimulation of pre-adipocyte differentiation.

Methods: We report our experience with a low-calorie diet (800cal, sodium content 1500?mmol?day^?1) combined with behavior modification on eight patients treated with thiazolidinediones (six pioglitazone and two rosiglitazone).

Results: All patients had reported previous weight gain following treatment with thiazolidinediones. All patients lost weight over 12 weeks in the program with their mean?±?SD body weight falling from 270?±?54?lbs (123?±?25?kg) to 244?±?61 lbs (111?±?28?kg) (p?<?0.01). The weight loss observed was no different from that observed

in 16 age- and gender-matched patients with type 2 diabetes not treated with thiazolidinediones (from 263?±?54?lbs (120?±?25?kg) to 239?±?52?lbs (109?±?24?kg); p?<?0.01). Glycemic control improved while reducing insulin treatment. Blood pressure control also improved and antihypertensive medications were decreased. The degree and time course of weight loss is no different from that in patients treated with other diabetic therapies and is associated with improved glycemic and blood pressure control.

Conclusions: We conclude that a program of caloric restriction and behavior modification is effective in leading to weight loss in patients treated with thiazolidinediones. This effect is reassuring, since thiazolidinediones stimulate adipogenesis.     

Is weight loss possible in patients treated with thiazolidinediones? Experience with a low-calorie diet

BACKGROUND: Weight gain is a frequent side-effect of thiazolidinediones, possibly related to fluid retention and stimulation of pre-adipocyte differentiation. METHODS: We report our experience with a low-calorie diet (800 cal, sodium content 1500 mmol/day) combined with behavior modification on eight patients treated with thiazolidinediones (six pioglitazone and two rosiglitazone). RESULTS: All patients had reported previous weight gain following treatment with thiazolidinediones. All patients lost weight over 12 weeks in the program with their mean +/- SD body weight falling from 270 +/- 54 lbs (123 +/- 25 kg) to 244 +/- 61 lbs (111 +/- 28 kg) (p < 0.01). The weight loss observed was no different from that observed in 16 age- and gender-matched patients with type 2 diabetes not treated with thiazolidinediones (from 263 +/- 54 lbs (120 +/- 25 kg) to 239 +/- 52 lbs (109 +/- 24 kg); p < 0.01). Glycemic control improved while reducing insulin treatment. Blood pressure control also improved and antihypertensive medications were decreased. The degree and time course of weight loss is no different from that in patients treated with other diabetic therapies and is associated with improved glycemic and blood pressure control. CONCLUSIONS: We conclude that a program of caloric restriction and behavior modification is effective in leading to weight loss in patients treated with thiazolidinediones. This effect is reassuring, since thiazolidinediones stimulate adipogenesis.     

Role of thrombin in CNS damage associated with intracerebral haemorrhage: opportunity for pharmacological intervention?

Intracerebral haemorrhage (ICH) results in high mortality and morbidity. The most important causes of neurological deterioration after ICH are progression of oedema and injury to nerve cells and axons surrounding the haematoma, as well as haematoma enlargement. Recent studies have indicated that thrombin, formed upon clotting of the haematoma, plays an important role in these processes. As opposed to conventional therapeutic approaches, administration of a thrombin inhibitor could effectively limit oedema formation and neuronal damage, improving survival and functional outcome. A small, preliminary clinical trial has suggested that antithrombin therapy with intravenously administered argatroban may be useful in treatment of ICH. Randomised, controlled studies are needed to confirm these initial findings.     

Is behavioral sensitization to ethanol associated with contextual conditioning in mice?

Behavioral sensitization to drugs of abuse seems to involve learning processes. In mice, ethanol-induced locomotor sensitization is potentiated by repeated pairing of ethanol (EtOH) injections and the testing chamber. The present study aimed to test: (1). the association between the performance in a contextual conditioning task and the development of behavioral sensitization to EtOH in mice; (2). whether EtOH sensitization would be expressed in a different testing environment. Male albino Swiss mice (n=72) were initially submitted to a contextual fear conditioning task. After 2 weeks without manipulation, the animals received daily i.p. injections of 2.2 g/kg EtOH (n=52) or saline (n=20), for 21 days. They were tested weekly for locomotor activity in activity cages. After 1 week of withdrawal, all mice received 2.2 g/kg EtOH and had their locomotor activity recorded in an open-field. According to the locomotor behavior displayed along the 21-day treatment, EtOH-treated mice were classified as sensitized (n=15) or non-sensitized (n=15). When these subgroups and saline-treated mice were compared for the freezing response in the conditioning test, sensitized mice displayed a greater freezing time than non-sensitized mice. When challenged with EtOH in the open-field, none of the EtOH-treated subgroups expressed behavioral sensitization. These results suggest that the development of EtOH sensitization seems to be positively associated with contextual learning, and further confirms that the expression of sensitization is highly dependent on contextual cues.     

Chronic renal failure as a complication of hemorrhagic fever with renal syndrome in 17 years’ old boy

Hemorrhagic fever with renal syndrome (HFRS) is an acute infective multisystemic disease that commonly presents with fever, hemorrhage and acute renal failure. A 17-year-old boy presented with thrombocytopenia, profuse subconjunctival hemorrhage and anuric renal failure with fluid overload. The patient required continuous ambulatory peritoneal dialysis. He developed diuresis but did not recover renal function during reconvalescent period. Hantaan, Puumala, Seoul, Belgrade virus infection with haemorrhagic fever with renal syndrome was confirmed by serologic test.     

Is it possible to predict treatment response to a proton pump inhibitor in functional dyspepsia?

BACKGROUND: The efficacy of proton pump inhibitors in functional dyspepsia is modest and the prognostic factors are almost unknown. METHODS: Data were pooled on patients (n = 826) with a diagnosis of functional dyspepsia from two placebo-controlled trials who were treated with omeprazole, 10 or 20 mg once daily, for 4 weeks. Self-administered questionnaires for the assessment of symptoms and health-related quality of life were completed before entry, and epigastric pain/discomfort was recorded on diary cards. Treatment success was defined as the complete absence of epigastric pain/discomfort on each of the last 3 days of week 4. Prognostic factors were identified by multiple logistic regression analysis. RESULTS: The most discriminating predictor of treatment success (P < 0.0001) was the number of days with epigastric pain/discomfort during the first week of treatment. Fewer days with symptoms during the first week led to higher response rates at 4 weeks. In addition, age > 40 years, bothersome heartburn, low scores for bloating, epigastric pain and diarrhoea, history of symptoms for < 3 months and low impairment of vitality at baseline were identified as positive predictors of outcome. CONCLUSIONS: Early response to treatment with a proton pump inhibitor, during the first week, seems to predict the outcome after 4 weeks in patients with functional dyspepsia.     

Peaks in substance use prior to treatment presentation – a re-evaluation

Background: Presentation to substance misuse treatment is believed to coincide with extremes of behaviour or function, leading some to suggest that such extreme behaviours can improve over time, in the absence of appropriate, evidence-based treatment. In challenging times for services, it is essential that available evidence on this potential explanation of the treatment effect is summarised and disseminated to policy makers. We combined an analysis of existing data with a rapid literature review.

Methods: We used the UK Drug Treatment Outcomes Research Study (DTORS) baseline cohort (N?=?1,794) to examine levels of substance use and offending at treatment presentation, in relation to self-defined norms. A rapid review identified 7 studies (US, 5; UK, 2) examining change in substance use, and 6 studies (Australia, 1; Norway, 3; US, 2) examining change in function, ahead of treatment.

Results: In our sample, users were unlikely (9%) to be using more drugs than self-defined norms at treatment entry, and more likely (39%) to be using less than self-defined norms. A minority (24%) offended at higher levels than self-defined norms; 43% at lower levels. Among studies in the review, none identified increased substance use; 3 identified reduced function (employment, court appearances, and mental health admissions).

Conclusion: Available evidence fails to support the belief that presentation to treatment commonly occurs at extreme points of behaviour. An increase in substance use ahead of treatment was not evident; data on reduced function was ambiguous.     

Modafinil combined with cognitive training is associated with improved learning in healthy volunteers – A randomised controlled trial

Improving cognition in people with neuropsychiatric disorders remains a major clinical target. By themselves pharmacological and non-pharmacological approaches have shown only modest effects in improving cognition. In the present study we tested a recently-proposed methodology to combine CT with a ‘cognitive-enhancing’ drug to improve cognitive test scores and expanded on previous approaches by delivering combination drug and CT, over a long intervention of repeated sessions, and used multiple tasks to reveal the cognitive processes being enhanced. We also aimed to determine whether gains from this combination approach generalised to untrained tests. In this proof of principle randomised-controlled trial thirty-three healthy volunteers were randomised to receive either modafinil or placebo combined with daily cognitive training over two weeks. Volunteers were trained on tasks of new-language learning, working memory and verbal learning following 200 mg modafinil or placebo for ten days. Improvements in trained and untrained tasks were measured. Rate of new-language learning was significantly enhanced with modafinil, and effects were greatest over the first five sessions. Modafinil improved within-day learning rather than between-day retention. No enhancement of gains with modafinil was observed in working memory nor rate of verbal learning. Gains in all tasks were retained post drug-administration, but transfer effects to broad cognitive abilities were not seen. This study shows that combining CT with modafinil specifically elevates learning over early training sessions compared to CT with placebo and provides a proof of principle experimental paradigm for pharmacological enhancement of cognitive remediation.     

Evaluation of potential health effects associated with occupational and environmental exposure to styrene – an update

The potential chronic health risks of occupational and environmental exposure to styrene were evaluated to update health hazard and exposure information developed since the Harvard Center for Risk Analysis risk assessment for styrene was performed in 2002. The updated hazard assessment of styrene’s health effects indicates human cancers and ototoxicity remain potential concerns. However, mechanistic research on mouse lung tumors demonstrates these tumors are mouse-specific and of low relevance to human cancer risk. The updated toxicity database supports toxicity reference levels of 20 ppm (equates to 400 mg urinary metabolites mandelic acid + phenylglyoxylic acid/g creatinine) for worker inhalation exposure and 3.7 ppm and 2.5 mg/kg bw/day, respectively, for general population inhalation and oral exposure. No cancer risk value estimates are proposed given the established lack of relevance of mouse lung tumors and inconsistent epidemiology evidence. The updated exposure assessment supports inhalation and ingestion routes as important. The updated risk assessment found estimated risks within acceptable ranges for all age groups of the general population and workers with occupational exposures in non-fiber-reinforced polymer composites industries and fiber-reinforced polymer composites (FRP) workers using closed-mold operations or open-mold operations with respiratory protection. Only FRP workers using open-mold operations not using respiratory protection have risk exceedances for styrene and should be considered for risk management measures. In addition, given the reported interaction of styrene exposure with noise, noise reduction to sustain levels below 85 dB(A) needs be in place.