GW190521 Mass Gap Event and the Primordial Black Hole Scenario.

The LIGO/Virgo Collaboration has recently observed GW190521, the first binary black hole merger with at least the primary component mass in the mass gap predicted by the pair-instability supernova theory. This observation disfavors the standard stellar-origin formation scenario for the heavier black hole, motivating alternative hypotheses. We show that GW190521 cannot be explained within the primordial black hole (PBH) scenario if PBHs do not accrete during their cosmological evolution, since this would require an abundance which is already in tension with current constraints. On the other hand, GW190521 may have a primordial origin if PBHs accrete efficiently before the reionization epoch.

The influence of Generalized Anxiety Disorder on Executive Functions in children with ADHD.

The present study was aimed at verifying whether the presence of generalized anxiety disorder (GAD) affects executive functions in children with attention-deficit hyperactivity disorder (ADHD). Two groups of children with ADHD were selected for the study according to the presence or absence of GAD. The first group of 28 children with ADHD with GAD (mean age: 9 ± 1.2; males/females: 24/4) was matched for gender, age, IQ, psychiatric comorbidity with a second group of 29 children with ADHD without GAD (mean age: 8.8 ± 0.7; males/females: 26/3). The two groups with ADHD were compared to 28 typically developing children (mean age: 8.3 ± 1.3; males/females: 23/5) on different measures involving processes especially important in inhibitory control such as rule maintenance, stimulus detection, action selection and action execution. Our results indicated that, differently from children with ADHD with GAD, only the group with ADHD without GAD showed a deficit in inhibitory control. Comorbid subgroups should be differentiated, especially, to develop specific and efficient therapeutic interventions in ADHD.

Indian summer heat wave of 2015: a biometeorological analysis using half hourly automatic weather station data with special reference to Andhra Pradesh.

Heat wave is a hazardous weather-related extreme event that affects living beings. The 2015 summer heat wave affected many regions in India and caused the death of 2248 people across the country. An attempt has been made to quantify the intensity and duration of heat wave that resulted in high mortality across the country. Half hourly Physiologically Equivalent Temperature (PET), based on a complete heat budget of human body, was estimated using automatic weather station (AWS) data of four locations in Andhra Pradesh state, where the maximum number of deaths was reported. The heat wave characterization using PET revealed that extreme heat load conditions (PET >41) existed in all the four locations throughout May during 2012-2015, with varying intensity. The intensity and duration of heat waves characterized by "area under the curve" method showed good results for Srikakulam and Undi locations. Variations in PET during each half an hour were estimated. Such studies will help in fixing thresholds for defining heat waves, designing early warning systems, etc.

Factors Predicting Patient's Allocation to Short- and Long-Term Therapeutic Community Treatments in the Italian VOECT Cohort Study.

The Evaluation of Therapeutic Community Treatments and Outcomes (VOECT) study was conducted in 131 Italian Therapeutic Communities (TCs) in 2008/2009. All of the patients entering residential treatment for drug or alcohol dependence were invited to participate. Data regarding patient socio-demographic characteristics, drug and alcohol consumption, health and psychopathological status, prior treatments and outcomes, and their motivation score were collected upon enrolment onto the study. The aim of this work was to identify the factors associated with allocation to short- versus long-term programmes in drug or alcohol dependent patients entering TCs in Italy. Of the 2470 patients included in the analysis, 30.8% were allocated to short-term treatment and 69.2% to long-term treatment. Several factors were significantly associated with the allocation to short- and long-term treatments: unstable living conditions; entering the TC when not detoxified; a high Symptom Checklist-90 somatization score; prior cessation episodes; previous in-patient detoxification treatments; psychosocial treatments; entering the TC by oneself; and a low motivation score.

Different Contribution of the Monkey Prefrontal and Premotor Dorsal Cortex in Decision Making During a Transitive Inference Task.

Several studies have reported similar neural modulations between brain areas of the frontal cortex, such as the dorsolateral prefrontal (DLPFC) and the premotor dorsal (PMd) cortex, in tasks requiring encoding of the abstract rules for selecting the proper action. Here we compared the neuronal modulation of the DLPFC and PMd of monkeys trained to choose the higher rank from a pair of abstract images (target item), selected from an arbitrarily rank-ordered set (A > B > C > D > E > F) in the context of a transitive inference task. Once acquired by trial-and-error, the ordinal relationship between pairs of adjacent images (i.e., A > B; B > C; C > D; D > E; E > F), monkeys were tested in indicating the ordinal relation between items of the list not paired during learning. During these decisions, we observed that the choice accuracy increased and the reaction time decreased as the rank difference between the compared items enhanced. This result is in line with the hypothesis that after learning, the monkeys built an abstract mental representation of the ranked items, where rank comparisons correspond to the items' position comparison on this representation. In both brain areas, we observed higher neuronal activity when the target item appeared in a specific location on the screen with respect to the opposite position and that this difference was particularly enhanced at lower degrees of difficulty. By comparing the time evolution of the activity of the two areas, we observed that the neural encoding of target item spatial position occurred earlier in the DLPFC than in the PMd.

Neural correlates of cognitive control of reaching movements in the dorsal premotor cortex of rhesus monkeys.

Canceling a pending movement is a hallmark of voluntary behavioral control because it allows us to quickly adapt to unattended changes either in the external environment or in our thoughts. The countermanding paradigm allows the study of inhibitory processes of motor acts by requiring the subject to withhold planned movements in response to an infrequent stop-signal. At present the neural processes underlying the inhibitory control of arm movements are mostly unknown. We recorded the activity of single units in the rostral and caudal portion of the dorsal premotor cortex (PMd) of monkeys trained in a countermanding reaching task. We found that among neurons with a movement-preparatory activity, about one-third exhibit a modulation before the behavioral estimate of the time it takes to cancel a planned movement. Hence these neurons exhibit a pattern of activity suggesting that PMd plays a critical role in the brain networks involved in the control of arm movement initiation and suppression.

Anticonvulsants for cocaine dependence.

BACKGROUND: Cocaine dependence is a major public health problem that is characterized by recidivism and a host of medical and psychosocial complications. Although effective pharmacotherapy is available for alcohol and heroin dependence none exists currently for cocaine dependence despite two decades of clinical trials primarily involving antidepressant, anti convulsivant and dopaminergic medications. There has been extensive consideration of optimal pharmacological approaches to the treatment of cocaine dependence with consideration of both dopamine antagonists and agonists. Anticonvulsants have been candidates for the treatment of addiction based on the hypothesis that seizure kindling-like mechanisms contribute to addiction. OBJECTIVES: To evaluate the efficacy and the acceptability of anticonvulsants for cocaine dependence SEARCH STRATEGY: We searched the Cochrane Drugs and Alcohol Groups specialised register (issue 4, 2007), MEDLINE (1966 - march 2007), EMBASE (1988 - march 2007), CINAHL (1982- to march 2007) SELECTION CRITERIA: All randomised controlled trials and controlled clinical trials which focus on the use of anticonvulsants medication for cocaine dependence DATA COLLECTION AND ANALYSIS: Two authors independently evaluated the papers, extracted data, rated methodological quality MAIN RESULTS: Fifteen studies (1066 participants) met the inclusion criteria for this review: the anticonvulsants drugs studied were carbamazepine, gabapentin, lamotrigine, phenytoin, tiagabine, topiramate, valproate. No significant differences were found for any of the efficacy measures comparing any anticonvulsants with placebo. Placebo was found to be superior to gabapentin in diminishing the number of dropouts, two studies, 81 participants, Relative Risk (RR) 3.56 (95% CI 1.07 to 11.82) and superior to phenythoin for side effects, two studies, 56 participants RR 2.12 (95% CI 1.08 to 4.17). All the other single comparisons are not statistically significant. AUTHORS' CONCLUSIONS: Although caution is needed when assessing results from a limited number of small clinical trials at present there is no current evidence supporting the clinical use of anticonvulsants medications in the treatment of cocaine dependence. Aiming to answer the urgent demand of clinicians, patients, families, and the community as a whole for an adequate treatment for cocaine dependence, we need to improve the primary research in the field of addictions in order to make the best possible use out of a single study and to investigate the efficacy of other pharmacological agent.

Antipsychotic medications for cocaine dependence.

BACKGROUND: Cocaine dependence is a public health problem characterized by recidivism and a host of medical and psychosocial complications. Cocaine dependence remains a disorder for which no pharmacological treatment of proven efficacy exists, although considerable advances in the neurobiology of this addiction could guide future medication development OBJECTIVES: To evaluate the efficacy and the acceptability of antipsychotic medications for cocaine dependence SEARCH STRATEGY: We searched the following sources: MEDLINE (1966 to October 2006), EMBASE (1980 to October 2006), CINAHL (1982 to October 2006), Cochrane Drug and Alcohol Group Specialised Register (October 2006). We also searched the reference lists of trials, the main electronic sources of ongoing trials (National Research Register, meta-Register of Controlled Trials; Clinical Trials.gov) and conference proceedings likely to contain trials relevant to the review. All searches included also non-English language literature. SELECTION CRITERIA: All randomised controlled trials and controlled clinical trials with focus on the use of any antipsychotic medication for cocaine dependence DATA COLLECTION AND ANALYSIS: Two authors independently evaluated the papers, extracted data, rated methodological quality MAIN RESULTS: Seven small studies were included (293 participants): the antipsychotic drugs studied were risperidone, olanzapine and haloperidol. No significant differences were found for any of the efficacy measures comparing any antipsychotic with placebo. Risperidone was found to be superior to placebo in diminishing the number of dropouts, four studies, 178 participants, Relative Risk (RR) 0.77 (95% CI 0.77 to 0.98). Most of the included studies did not report useful results on important outcomes such as side effects, use of cocaine during treatment and craving. The results on olanzapine and haloperidol come from studies too small to give conclusive results. AUTHORS' CONCLUSIONS: Although caution is needed when assessing results from a limited number of small clinical trials there is no current evidence, at the present , supporting the clinical use of antipsychotic medications in the treatment of cocaine dependence. Furthermore, most of the included studies did not report useful results on important outcomes such as side effects, use of cocaine during the treatment and craving. Aiming to answer the urgent demand of clinicians, patients, families, and the community as a whole for an adequate treatment for cocaine dependence, larger randomised investigations should be designed investigating relevant outcomes and reporting data to allow comparison of results between studies. Moreover some efforts should be done also to investigate the efficacy of other type medications, like anticonvulsant, currently used in clinical practice.

Gamma-hydroxybutyric acid for treatment of opiate withdrawal syndrome.

In a double-blind placebo-controlled trial, gamma-hydroxybutyric acid (GHB) (25 mg/kg orally) suppressed most of the withdrawal symptomatology in 14 heroin addicts and 13 methadone-maintained subjects. The GHB effect was prompt (within 15 minutes) and persisted for between 2 and 3 hours. Subsequently, the same patients received GHB in an open study every 2 to 4 hours for the first 2 days and 4 to 6 hours for the following 6 days: most abstinence signs and symptoms remained suppressed and patients reported felling well. Urine analysis failed to detect any presence of opiate metabolites. No withdrawal symptomatology recurred after 8 days of treatment when GHB was suspended, and patients were challenged with an intravenous injection of 0.4 mg naloxone. The results indicate that GHB may be useful in the management of opiate withdrawal.

Early exposure to restraint stress enhances chemical carcinogenesis in rat liver.

This study examines the effect of a stress-associated condition on chemical hepatocarcinogenesis in the rat. Rats were given diethylnitrosamine (200 mg/kg. b.w., i.p.), followed, 1 week later, by three cycles of immobilization at room temperature. Two weeks after the last cycle they were treated according to the resistant hepatocyte protocol. At 4 weeks after selection, mean size of glutathione-S-transferase 7-7 positive foci/nodules was increased in the immobilized group (0.82+/-0.22 vs. 0.25+/-0.04 mm(2) in controls). Furthermore, at the end of 1 year 10/13 animals (77%) developed hepatocellular carcinoma in the former group, while only 6/14 (43%) incidence of cancer was found in controls. These results indicate that exposure to restraint stress early during carcinogenesis enhances the development of chemically-induced hepatocellular carcinoma in the rat.

Liver cell proliferation induced by the mitogen ethylene dibromide, unlike compensatory cell proliferation, does not achieve initiation of rat liver carcinogenesis by diethylnitrosamine.

The purpose of this investigation was to determine whether mitogen-induced cell proliferation is as effective as compensatory cell proliferation in achieving initiation of carcinogenesis in rat liver. Male Wistar rats were injected with a single non-necrogenic dose of the hepatocarcinogen diethylnitrosamine (DENA) during the peak of DNA synthesis following the administration of the hepatic mitogen ethylene dibromide (EDB) or a necrogenic dose of CCl4. After subjecting the animals to a promoting procedure, the rats were sacrificed and the initiated hepatocytes were monitored as gamma-glutamyltranspeptidase (gamma-GT) positive foci. The results indicate that while DENA administration during compensatory cell proliferation results in the formation of GT positive foci, no enzyme-altered foci were produced when the carcinogen was given during liver hyperplasia induced by EDB, despite the fact that at the time of carcinogen administration, the extent of cell proliferation, as monitored by thymidine incorporation into DNA, was the same in both the groups.

An earlier proliferative response of hepatocytes in gamma-glutamyl transferase positive foci to partial hepatectomy.

One of the hallmarks of initiated hepatocytes is their resistance to several hepatotoxins. This property forms the basis for their selective growth under conditions which are inhibitory to the non-initiated hepatocytes. Selective growth of initiated hepatocytes also occurs, albeit at a low level, in initiated rat liver without exposure to any known promoting regimen and/or in the absence of any known selective pressure to which initiated hepatocytes can possibly be resistant. This latter phenotypic property of initiated hepatocytes was further characterized by comparing the kinetics of response of hepatocytes in gamma-glutamyl transferase positive foci and in the surrounding liver to 2/3 partial hepatectomy both in the presence and in the absence of a promoting regimen. Male Fischer 344 rats (130-150 g) were initiated with a single dose of diethylnitrosamine and 1 week later they were placed on either a semi-synthetic basal diet or a promoting diet containing 1% orotic acid. Partial hepatectomy was performed 15 weeks after initiation and animals from both groups were killed at 12, 16, 20, 24, 30, 36, 48, 72 or 96 h after operation. Each animal received a pulse of 3H-labelled thymidine 1 h prior to killing. Autoradiographic studies revealed that hepatocytes in gamma-glutamyl transferase positive foci in the livers of rats fed the basal diet were significantly labelled at 16 h post-partial hepatectomy while surrounding hepatocytes were still virtually quiescent (LI 12.7 +/- 4.7 versus 1.2 +/- 0.5%, respectively). Higher labelling index in foci compared to the surrounding liver was also seen at 20 h post-PH (36.9 +/- 2.6 versus 21.5 +/- 2.4). Similar earlier response of hepatocytes in gamma-glutamyl transferase positive foci was also seen in initiated rats exposed to dietary orotic acid. In addition, orotic acid treatment appears to have imposed a slight delay on the entry of hepatocytes in the surrounding liver into 'S' phase and thereby enhancing the differential of growth response between these two populations.

Glucose-6-phosphate dehydrogenase (G6PD) activity in tumoral tissues of G6PD-deficient subjects affected by larynx carcinoma.

The activity of glucose-6-phosphate dehydrogenase (G6PD), the key enzyme of the hexose monophosphate (HMP) shunt pathway, was measured in both normal and tumoral larynx tissues from normal and G6PD deficient subjects. Significant increases of this enzymatic activity were found in tumoral tissues of both normal and G6PD deficient subjects, who were characterized by very low levels of G6PD activity in erythrocytes as well as in larynx tissue.

One-step detection and genotyping of human papillomavirus in cervical samples by reverse hybridization.

This study describes a nonisotopic polymerase chain reaction-reverse hybridization-based method (PCR-RH) for the one-step detection and genotyping of anogenital human papillomavirus (HPV) in a microwell format. HPV DNA was amplified and labeled by PCR using GP5+/GP6+ primers. Labeled amplicons were hybridized to 20 HPV type-specific capture probes anchored to the surface of plastic microwells and detected by an immunoenzymatic assay. Assay sensitivity was <50 pg labeled amplicon, and no cross-reactivity was observed, as determined by hybridizing serial dilutions of labeled PCR products to either matched or mismatched capture probes. The assay was tested on 66 clinical samples (23 specimens with normal histology, I fibropapilloma, 26 cervical intraepithelial neoplasia grade 1 [CIN1], 9 CIN2, and 7 CIN3) and compared with a method based on restriction fragment length polymorphism (RFLP) of PCR products. PCR-RH and PCR-RFLP performed equally well on clinical samples. The overall HPV detection rate was similar: 65.1% (43/66) for PCR-RH and 57.6% (38/66) for PCR-RFLP. HPV DNA was found in all CIN2 and CIN3 samples by both methods; however, PCR-RH detected more positives among normal biopsy samples and CINI cases. Overall, there was good agreement between the two genotyping methods, but RH yielded fewer cases with undetermined HPV genotype.

Total and HDL cholesterol in human hematologic neoplasms.

In this study serum cholesterol was measured in different types of human hematologic malignancies characterized by a wide range of cell proliferation. In all tumoral types a significant decrease of HDL cholesterol was observed, whereas total serum cholesterol generally remained unchanged. Another interesting observation of our study was the apparent inverse correlation between the extent of cell proliferation in these neoplastic disorders and the level of HDL cholesterol. Since a decrease of HDL cholesterol was previously observed, in our laboratory, in different experimental models of normal and neoplastic cell proliferation, we suggest that the decrease of HDL cholesterol may be a generalized phenomenon related to massive cellular growth in normal and malignant processes.

Prohibition of take-home dosages: negative consequences on methadone maintenance treatment.

Patients on methadone maintenance were forewarned that a law prohibiting take-home dosages was to be enforced within 6 months. At the end of the 6-month period preceding the enforcement of the law the effect of the anticipated suppression of the take-home privilege was studied on a cohort of 211 methadone-maintained patients on take-home dosages. The outcome of the treatment of these patients was compared to that of a control group of 220 patients at the end of a 6-month period prior to the announcement of the new law. The outcome of the study suggests that the restrictive regulation is counterproductive for retaining patients in treatment.

Buprenorphine: a controlled clinical trial in the treatment of opioid dependence.

Clinical trials carried out to compare methadone and buprenorphine in the treatment of opioid dependence have generally employed an alcoholic solution of buprenorphine, which has a bioavailability superior to that of the tablets. Since the product available for large scale use is in tablet form, one intended to verify the efficacy of this formulation. In a multicentre randomised controlled double blind study, 72 opioid dependent patients were assigned to treatment with buprenorphine (8 mg/day) or methadone (60 mg/day) for a period of 6 months. The two compounds did not show any significant difference with regard to urinalyses: the average percentage of analyses proving negative was 60.4% for patients assigned to buprenorphine, and 65.5% for those assigned to methadone. With regard to retention, a non-significant trend in favour of methadone was observed. Patients completing the trial improved significantly in terms of psychosocial adjustment and global functioning, as ascertained by the DSM-IV-GAF and symptom checklist-90 (SCL-90) scales, and this was independent of the treatment group. Finally, in the case of buprenorphine, patients who dropped out differed significantly from those who stayed, in terms of a higher level of psychopathological symptoms, and a lower level of psychosocial functioning. The results of the study further support the utility of buprenorphine for the treatment of opioid dependence.

Psychiatric severity and treatment response in a comprehensive methadone maintenance treatment program.

The purpose of this study was to investigate the influence of the severity of concomitant psychiatric symptomatology on some selected measures of methadone maintenance treatment efficacy in a comprehensive methadone maintenance treatment program (MMTP). The cohort studied included 267 patients who entered a maintenance program in the years 1991-92. Two groups of patients differing in the severity of psychiatric symptomatology were obtained on the bases of the referral to the psychiatrist and the ascertainment of a current disorder. These two groups were compared for retention in treatment, urine tests positive for morphine while in treatment and methadone dose during an observation period of 2 years. The outcome of the study suggests that on these outcome parameters, patients on MMTP who are more psychiatrically ill can perform as well as the other patients.

Comparative effects of insulin and refeeding on DNA synthesis, HMP shunt and cholesterogenesis in diabetic and fasted rats.

DNA synthesis, cholesterogenesis and the enzymes of the hexosemonophosphate (HMP) shunt pathway were investigated in liver of diabetic rats treated with insulin and in fasted/re-fed rats. Both insulin and refeeding were found to induce liver cell proliferation, accompanied by a remarkable increase in cholesterogenesis. An enhancement of glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (G6PD) activities was also found in insulin-treated diabetic rats and in re-fed rats, supporting the concept that these two enzymes are involved in the proliferative process. Since insulin did not exert the same biochemical effects in a non replicating cell population, such as in insulin-treated normal rats, these studies provide new evidence of a close correlation between DNA, cholesterol synthesis and HMP shunt enzymes during cell proliferation.

Sexual dimorphism in the regulation of cell turnover during liver hyperplasia.

A sexual dimorphism occurs in liver cell proliferation following partial hepatectomy, female liver regenerating faster than male, while a continuous excess of choline to females shifts their growth pattern toward that of males (L. Tessitore, P. Pani and M.U. Dianzani, Carcinogenesis, 13 (1992) 1929). In this study we have investigated (a) if the same sexual modulation occurs in a different type of liver growth, hyperplasia induced by a direct mitogen and (b) if the pre-administration of choline to females is able to modulate this dimorphism. Liver hyperplasia induced by lead nitrate, a potent mitogen, has also shown a peculiar sexual dimorphism in all phases of the proliferative process. In contrast with liver regeneration after partial hepatectomy, the mitogenic action of lead nitrate was less effective and was delayed in females as compared with males, by evaluating liver weight, protein accumulation, DNA synthesis and mitotic index. These results were also confirmed by the trend of liver regression by apoptosis. The apoptotic index was higher in males than in females. A prolonged administration of an excess of choline has partially filled these sexual differences, since choline has moved, in females, all the observed parameters (liver weight, protein accumulation, DNA synthesis, mitotic and apoptotic indexes) to values closer to those observed in males.