Management of AIDS-related Kaposi's sarcoma

The advent of highly active antiretroviral therapy (HAART) has lead to a substantial reduction in the prevalence, morbidity, and mortality associated with AIDS-related Kaposi's sarcoma. Similarly, concomitant advances in chemotherapy and supportive-care protocols have allowed for Kaposi's sarcoma to be managed more effectively in comparison with the pre-HAART era. Furthermore, developments in our understanding of the pathogenesis of Kaposi's sarcoma have identified several molecular targets that can potentially provide new therapeutic strategies. This Review discusses the role of conventional chemotherapeutic and immunomodulatory agents in the treatment of Kaposi's sarcoma and summarises the current status and future prospects of novel molecularly targeted agents in the treatment of this disease.     

Thalidomide in combination with oral daily cyclophosphamide in patients with pretreated hormone refractory prostate cancer: a phase I clinical trial

AIM: This is a phase I study investigating the toxicity and the potential efficacy of thalidomide and oral cyclophosphamide in patients with hormone refractory prostate cancer (HRPC), previously treated with docetaxel-based regimens. METHODS: Two dose levels of thalidomide (100 and 200 mg every day) were studied. Patients were accrued to each dose level in cohorts of 3 starting from dose 1 level (100 mg). Thalidomide was started on day 1 at the assigned dose and continued for four consecutive weeks; oral cyclophosphamide (50 mg for day) was given for four consecutive weeks (1 cycle) starting on the same day initiating thalidomide. Toxicity was evaluated every two weeks; changes in prostate-specific antigen (PSA) levels were evaluated every cycle. Treatment was planned for four cycles. RESULTS: Sixteen men were treated. Ten patients in cohort 1, and 6 in cohort 2 were enrolled respectively. Grade 1-2 constipation, peripheral neuropathy and fatigue were the most common side effects, noted in 6 (37.5%), 5 (31.25%) and 3 (19%) patients, respectively. Three patients stopped the treatment at level 2, during the first cycle, for toxicity. Those three patients were evaluable only for toxicity. The MTD was 100 mg thalidomide. Thirteen patients completed two cycles. Two patients (15%) had a >50% decrease in PSA, while in one patient (8%) the PSA decrease was less of 50%. Overall PSA decrease was of 23%. CONCLUSIONS: The oral combination of thalidomide and cyclophosphamide is well tolerated and appears to be associated with biochemical response in this population. Future phase II trials, in pre-treated and untreated patients, are needed to evaluate clinical efficacy of this regimen in HRPC.     

14-methoxymetopon,a highly potent μ opioid agonist,biphasically affects ethanol intake in Sardinian alcohol-preferring rats

Rationale Increased opioidergic activity is thought to increase the propensity to consume ethanol. However, the dose monotonicity and receptor subtype for this effect remain uncertain. 14-methoxymetopon is a centrally acting, selective μ opioid receptor agonist with greater systemic antinociceptive potency than morphine and a putatively improved therapeutic index. Objective To determine whether 14-methoxymetopon influenced voluntary ethanol intake in Sardinian alcohol-preferring (sP) rats. Methods Male sP rats with continuous 2-bottle choice access to ethanol (10% v/v) or water were subjects. The effects of systemic 14-methoxymetopon administration (2, 5, 12.25, 30 μg/kg, s.c.) on 4-h ethanol intake were determined. The ability of naltrexone (50 μg/kg, s.c.), an opioid antagonist, to block actions of 14-methoxymetopon (12.25, 30 μg/kg, s.c.) was examined as were the effects of 14-methoxymetopon (12.25 μg/kg, s.c.) on self-administered blood alcohol levels (BALs) and clearance of a passive ethanol bolus (1 g/kg). Finally, the effects of central 14-methoxymetopon administration (0.0003–100 ng, i.c.v.) on 4-h ethanol intake were evaluated. Results Systemic 14-methoxymetopon very potently and dose-dependently suppressed ethanol and food intake for 30 min, followed by a greater, longer-lasting, and behaviorally specific increase in ethanol intake. The increased ethanol intake led to threefold higher BALs, was naltrexone-reversible, and not due to altered ethanol clearance. Intracerebroventricular 14-methoxymetopon administration rapidly altered ethanol intake per an inverted U-shaped dose-response function, increasing it at a 10 pg dose, while suppressing it at a 10,000-fold higher dose. Conclusions The novel μ analgesic increases ethanol intake, a potential therapeutic liability, and results suggest a non-monotonic influence of brain μ opioid receptor stimulation on ethanol intake. Valentina Sabino and Pietro Cottone contributed equally to this work.     

A novel neural network-based survival analysis model.

A feedforward neural network architecture aimed at survival probability estimation is presented which generalizes the standard, usually linear, models described in literature. The network builds an approximation to the survival probability of a system at a given time, conditional on the system features. The resulting model is described in a hierarchical Bayesian framework. Experiments with synthetic and real world data compare the performance of this model with the commonly used standard ones.     

Intra-arrest hypothermia during cardiac arrest: a systematic review

ABSTRACT: INTRODUCTION: Therapeutic hypothermia is largely used to protect the brain following return of spontaneous circulation (ROSC) after cardiac arrest (CA), but it is unclear whether we should start therapeutic hypothermia earlier, that is, before ROSC. METHODS: We performed a systematic search of PubMed, EMBASE, CINAHL, the Cochrane Library and Ovid/Medline databases using "arrest" OR "cardiac arrest" OR "heart arrest" AND "hypothermia" OR "therapeutic hypothermia" OR "cooling" as keywords. Only studies using intra-arrest therapeutic hypothermia (IATH) were selected for this review. Three authors independently assessed the validity of included studies and extracted data regarding characteristics of the studied cohort (animal or human) and the main outcomes related to the use of IATH: Mortality, neurological status and cardiac function (particularly, rate of ROSC). RESULTS: A total of 23 animal studies (level of evidence (LOE) 5) and five human studies, including one randomized controlled trial (LOE 1), one retrospective and one prospective controlled study (LOE 3), and two prospective studies without a control group (LOE 4), were identified. IATH improved survival and neurological outcomes when compared to normothermia and/or hypothermia after ROSC. IATH was also associated with improved ROSC rates and with improved cardiac function, including better left ventricular function, and reduced myocardial infarct size, when compared to normothermia. CONCLUSIONS: IATH improves survival and neurological outcome when compared to normothermia and/or conventional hypothermia in experimental models of CA. Clinical data on the efficacy of IATH remain limited.     

Clinical significance of elevated alanine aminotransferase in blood donors: a follow-up study.

Alanine aminotransferase (ALT) elevation in blood donors can be related to many variables such as viral hepatitis, overweight and ethanol consumption. BACKGROUND/AIMS: This study aims to define factors associated with ALT elevation in candidates for blood donation, to evaluate ALT levels during follow-up, and to establish a histological diagnosis of hepatic disease. METHODS: Alcoholism, obesity, drug-induced liver disease, diabetes, hemochromatosis and alpha 1-anti-trypsin deficiency were investigated in 119 subjects (113 males, six females, aged 33.4+/-8.4 years) who were hepatitis B surface antigen/anti-hepatitis C virus negative and had been rejected as blood donors as a result of elevated ALT (>1.5 times the upper normal limit (UNL) in two determinations). During follow-up, ALT was determined every 8 weeks and liver biopsy recommended in cases with persistently elevated ALT levels. RESULTS: Obesity (30.2%) and alcoholism (28.6%) were most frequently associated with ALT elevation and in 9.2% of cases no association was found. ALT levels decreased significantly, regardless of the associated factor. Liver histology in 40 patients showed steatosis (35%), steatohepatitis (30%), non-specific reactive hepatitis (12.5% of cases), normal liver (15% of cases) and alcoholic cirrhosis, hemochromatosis and non-specific portal fibrosis in three cases. CONCLUSION: ALT levels usually dropped during follow-up and although severe hepatic lesions can be found in asymptomatic blood donors, mild hepatic damage is the rule.     

Clinical and Genetic Predictors of Priapism in Sickle Cell Disease: Results from the Recipient Epidemiology and Donor Evaluation Study III Brazil Cohort Study

IntroductionPriapism is the persistent and painful erection of the penis and is a common sickle cell disease (SCD) complication.AimThe goal of this study was to characterize clinical and genetic factors associated with priapism within a large multi-center SCD cohort in Brazil.MethodsCases with priapism were compared to SCD type-matched controls within defined age strata to identify clinical outcomes associated with priapism. Whole blood single nucleotide polymorphism genotyping was performed using a customized array, and a genome-wide association study (GWAS) was conducted to identify single nucleotide polymorphisms associated with priapism.Main Outcome MeasureOf the 1,314 male patients in the cohort, 188 experienced priapism (14.3%).ResultsPriapism was more common among older patients (P = .006) and more severe SCD genotypes such as homozygous SS (P < .0001). In the genotype- and age-matched analyses, associations with priapism were found for pulmonary hypertension (P = .05) and avascular necrosis (P = .01). The GWAS suggested replication of a previously reported candidate gene association of priapism for the gene transforming growth factor beta receptor 3 (TGFBR3) (P = 2 × 10^?4).Clinical ImplicationsOlder patients with more severe genotypes are at higher risk of priapism, and there is a lack of consensus on standard treatment strategies for priapism in SCD.Strengths & LimitationsThis study characterizes SCD patients with any history of priapism from a large multi-center cohort. Replication of the GWAS in an independent cohort is required to validate the results.ConclusionThese findings extend the understanding of risk factors associated with priapism in SCD and identify genetic markers to be investigated in future studies to further elucidate priapism pathophysiology.Ozahata M, Page GP, Guo Y, et al. Clinical and Genetic Predictors of Priapism in Sickle Cell Disease: Results from the Recipient Epidemiology and Donor Evaluation Study III Brazil Cohort Study. J Sex Med 2019;16:1988–1999.     

Feeding microstructure in diet-induced obesity susceptible versus resistant rats: central effects of urocortin 2

With one billion people overweight worldwide, the need to identify risk factors and treatments for obesity is urgent. The present study determined whether rats genetically prone to diet-induced obesity (DIO) show preexisting differences in meal microstructure and are sensitive to central anorectic effects of corticotropin-releasing factor type 2 (CRF₂) receptor stimulation. Male, selectively bred DIO rats and their diet resistant (DR) counterparts ( n = 9/genotype) were weaned onto low-fat chow and compared as young adults for spontaneous or intracerebroventricular urocortin 2 administration-induced (0, 0.3, 1, 3 μg) differences in ingestion. DIO rats were hyperphagic selectively at the dark cycle onset, showing shorter latencies to initiate feeding, faster returns to eating following meal completion, and a lower satiety ratio than DR rats. At other times, DIO rats had briefer postmeal intervals, but ate smaller and briefer meals, resulting in normal intake. DIO rats also ate faster than DR rats. Urocortin 2 was less potent in DIO rats, ineffective at the 0.3 μg dose, but produced CRF₂ antagonist-reversible anorexia at higher doses. Though heavier, chow-maintained DIO rats were proportionately as or more lean than DR rats. Thus, DIO rats showed signs of a preexisting, heritable deficit in the maintenance of postmeal satiety and a reduced sensitivity to anorectic CRF₂ agonist stimulation. The meal patterns of DIO rats temporally resemble human 'snacking' behaviour, which predicts adult obesity. Because central CRF₂ stimulation retains full anorectic efficacy at higher doses in the DIO model, manipulating this neuropeptidergic system might yield new therapeutic approaches for diet-induced obesity.