Roles of phosphoinositide-dependent kinase-1 in α1B-adrenoceptor phosphorylation and desensitization

The role of phosphoinositide-dependent protein kinase-1 (PDK-1) activity on α(1B)-adrenoceptor phosphorylation and function was explored using pharmacological inhibitors and expression of a dominant-negative mutant of this enzyme. Noradrenaline-, phorbol myristate acetate-, lysophosphatidic acid- and epidermal growth factor-mediated α(1B)-adrenoceptor phosphorylation were markedly reduced by the two inhibitors used: UCN-01 [(7-hydroxystaurosporine; (3R*,8S*, 9R*, 10R*,12R*)-2,3,9,10,11,12-hexahydro-3-hydroxy-9-methoxy-8-methyl-10-(methylamino)-8,12-epoxy-1H, 8H-2,7b,12a-triazadibenzo[a,g]-cyclonona[cde]triden-1-one)] and OSU-03012 [(2-amino-N-[4-[5-(2-phenanthrenyl)-3-trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-acetamide)]. A similar effect was observed in cells expressing a PDK-1 dominant-negative mutant. Phosphorylated PDK-1 (S241) and protein kinase C α (T497) were associated with cell membranes in the basal state which increased in response to the hormonal stimuli mentioned previously. UCN-01 essentially abolished phospho-PDK-1 membrane-association and markedly attenuated that of protein kinase C α. Consistent with the findings, UCN-01 reduced lysophosphatidic acid- and epidermal growth factor-induced α(1B-)adrenoceptor desensitization. Our data suggest that PDK-1 plays a permissive role in α(1B)-adrenoceptor desensitization and phosphorylation and participates in the formation of signaling complexes, which delicately modulate receptor function and regulation.     

Assessing the future direction of sustainable development in public hospitals: Time-horizon,path and action

PurposeTo assess the future direction of sustainable development in public hospitals, focusing on their short- versus long-term time horizons, top-down versus bottom-up paths, and intra-organizational versus inter-organizational actions.Design/Methodology/approachThe selection of significant health care organizations was based on judgmental sampling. This study applied an inductive approach. The interviewees were identified according to their knowledge of the future direction of their organizations’ sustainable development.FindingsThe sustainable development of the studied public hospitals is aimed at the synchronization of actions with other hospitals in the public healthcare system. The public hospitals studied differ in their interconnected elements of time (short- versus long-time horizons), paths (top-down versus bottom-up) and specific actions (intra-organizational versus inter-organizational).Research limitations/implications Offers insights into how to assess the direction of sustainable development in public hospitals. We stress the importance of time, path and action in conjunction. Furthermore, this study provides a three-dimensional framework to assess the future direction of sustainable development in organizations as well as in industries. Both the former and latter characteristics are shaped by the elements of time, path and action.Managerial ImplicationsProvides a three-dimensional framework of criteria to assess the direction of sustainable development in organizations. The assessment criteria may be used by organizations to assess the direction of other organizations in their industry. Industry associations or authorities may look into the status and future direction of sustainable development in industries or sectors as a whole. The assessment criteria provide an opportunity and foundation to benchmark against others in the same industry and insights to face pandemic as Covid-19.Originality/ValueFirst study to consider a three-dimensional framework based on time, path and action to assess the future direction of sustainable development in an organization.     

Long-term (3-year) neurocognitive effectiveness of antipsychotic medications in first-episode non-affective psychosis: a randomized comparison of haloperidol, olanzapine, and risperidone

Introduction

The initially postulated superior neurocognitive effectiveness of second-generation antipsychotics is currently under debate.

Methods

A prospective, randomized, open-label study was carried out to compare the long-term neurocognitive effectiveness of haloperidol, olanzapine, and risperidone in the first episode of schizophrenia spectrum disorders. A final sample of 79 patients randomized to haloperidol (N?=?28), olanzapine (N?=?23), or risperidone (N?=?28) who completed clinical and cognitive evaluations at baseline and 3-year follow-up was included in the final analysis. Forty-one healthy individuals were also included in the final analysis. The main outcome measure was cognitive changes at 3-year follow-up. Due to the fact that some of the patients had switched their initially prescribed antipsychotic medication during the course of the study (6 out of 28 in haloperidol group, 18 out of 23 in olanzapine group, and 24 out of 28 in risperidone group continued with the initial study drug at 3-year assessment), we have also conducted a per protocol analysis.

Results

Overall, cognitive changes were similar in the three treatment groups and controls, although a greater improvement in Rey Auditory Verbal Learning Test, Digit Symbol, and Iowa Gambling Test was found in the treatment groups. The better performance observed on Rey Auditory Verbal Learning Test and Digit Symbol in olanzapine treatment group was likely explained by the lower prevalence of use of antimuscarinic drugs. These results were essentially similar to those found in the intention-to-treat analysis.

Conclusions

The major conclusion of this study is that haloperidol, olanzapine, and risperidone have not demonstrated substantial neurocognitive effectiveness, improving cognitive deficits present in the early phases of the illness. The study also underscores the importance of exploring new drugs for the treatment of cognitive impairments and associated functional disabilities in schizophrenia.     

The Validity of Truant Youths’ Marijuana Use and Its Impact on Alcohol Use and Sexual Risk Taking

Few studies investigating the validity of marijuana use have used samples of truant youths. In the current study, self-reports of marijuana use are compared with urine test results for marijuana to identify marijuana underreporting among adolescents participating in a longitudinal brief intervention for drug-involved truant youths. It was hypothesized that marijuana underreporting would be associated with alcohol underreporting and engaging in sexual risk behaviors. The results indicated marijuana underreporting was significantly associated with self-denial of alcohol use, but not associated with sexual risk behavior. Also, there was an age effect in marijuana use underreporting such that younger truant youths were more likely to underreport marijuana use, compared to older truant youths. Implications for policy and future research are discussed.     

Evaluation of the anticocaine monoclonal antibody GNC92H2 as an immunotherapy for cocaine overdose

The illicit use of cocaine continues in epidemic proportions and treatment for cocaine overdose remains elusive. Current protein-based technology offers a new therapeutic venue by which antibodies bind the drug in the blood stream, inactivating its toxic effects. The therapeutic potential of the anticocaine antibody GNC92H2 was examined using a model of cocaine overdose. Swiss albino mice prepared with intrajugular catheters were tested in photocell cages after administration of 93 mg/kg (LD50) of cocaine and GNC92H2 infusions ranging from 30 to 190 mg/kg. GNC92H2 was delivered 30 min before, concomitantly or 3 min after cocaine treatment. Significant blockade of cocaine toxicity was observed with the higher dose of GNC92H2 (190 mg/kg), where premorbid behaviors were reduced up to 40%, seizures up to 77% and death by 72%. Importantly, GNC92H2 prevented death even post-cocaine injection. The results support the important potential of GNC92H2 as a therapeutic tool against cocaine overdose.     

Cholinergic modulation of the urethro genital reflex in spinal cord-transected rats

The aim of this study was to determine which of the muscarinic receptor subtypes are involved in the modulation of the urethrogenital reflex (UGR) in male, spinal cord-transected rats. The electromyographic (EMG) responses of the bulbospongiosus muscle (BS) to the topical spinal application of muscarine and the combination of muscarine and the selective muscarine receptor antagonists methoctramine (M2), AFDX (M2), 4DAMP (M3) and tropicamide (M4) were determined before and after the elicitation of UGR by way of the mechanical stimulation of the urethra. When 50- and 100-mug doses of muscarine were applied without urethral stimulation, a rhythmic activity of the BS was observed, similar to the one found when UGR was evoked. The M3 and M4 - but not the M2 - antagonists prevented BS response to muscarine when urethral stimulation was not performed. When UGR was elicited following urethral stimulation muscarine produced an increase in burst duration and a decrease in burst frequency. The M2 antagonist reverted the effects of muscarine on the UGR, while the M3 and M4 antagonists produced a significant increase in the frequency and in the bursts number, when compared to the control muscarine response. The differences observed in BS responses to muscarine and muscarine antagonists before and after UGR elicitation were probably linked to the intrinsic effects of the endogenous acethylcholine (Ach) released after urethral stimulation. The present results suggest a cholinergic modulation of UGR in spinal cord-transected rats mediated by the M2, M3 and M4 muscarinic receptor subtypes.     

Pharmacokinetics of D,L-3-hydroxy-3-ethyl-3-phenylpropionamide (HEPP) in pregnant rats at different stages of gestation and maternal-fetal disposition during late pregnancy

The pharmacokinetics of D,L-3-hydroxy-3-ethyl-3-phenylpropionamide (HEPP), an investigational anticonvulsant drug, was evaluated in nonpregnant and in pregnant rats on gestation day (GD) 7, 12, and 21 after an intraperitoneal (i.p.) dose of 50mg/kg. Maternal-fetal disposition in the GD21 group was also evaluated. In all groups, HEPP was rapidly absorbed and the disposition was well described by an open two-compartment kinetic model. The most pronounced effects of pregnancy on the kinetics of HEPP were observed at GD21 in which significant increases in the first-order hybrid disposition rate constants alpha and beta, with corresponding decreases in half-lives were observed. Gestation also affected the intercompartmental transfer rate constants k(12) and k(21), specially at GD12 and at GD21. These changes could be associated with the physiologic increases in blood flow and cardiac output of pregnancy. There was also a slight decrease in the apparent volume of distribution at GD21, and a progressive decrease in the clearance values normalized by the body weight. No other significant differences in kinetic parameters were observed. On GD21, HEPP rapidly transfers from maternal blood to fetuses, to reach concentrations in the placenta and fetuses slightly higher than those of the maternal plasma (fetal:maternal ratio ranging from 1.07 to 1.45). After equilibrium, the concentrations in maternal, placental, and fetal tissues decreased in parallel.     

Active hexose correlated compound acts as a prebiotic and is antiinflammatory in rats with hapten-induced colitis

Active hexose correlated compound (AHCC) is a product prepared from the mycelium of edible Basidiomycete fungi that contains oligosaccharides. Here we have studied the antiinflammatory effect of AHCC in the trinitrobenzenesulfonic acid (TNBS) model of colitis in rats. Rats received AHCC (100 or 500 mg/kg) daily starting 2 d before (pretreatment) colitis induction and were killed 6 d after the TNBS challenge. The status of the rats was assessed by morphological and biochemical methods. The effect of AHCC on the colonic microflora was also assessed by studying the bacteria profile in feces by standard culture techniques. AHCC administration attenuated colonic inflammation, improving rat weight, food intake, damage score, extension of necrosis, colonic weight, colonic weight-to-length ratio, myeloperoxidase and alkaline phosphatase activities, glutathione concentration, and the expression of proinflammatory cytokines and chemokines (IL-1beta, IL-1 receptor antagonist, TNF, and monocyte chemoattractant protein-1) and of mucins 2-4 and trefoil factor 3. The magnitude of the antiinflammatory effect of AHCC was similar to that of sulfasalazine (200 mg/kg). The study of colonic microflora indicated that rats treated with AHCC had higher aerobic and lactic acid bacteria counts as well as higher bifidobacteria counts, whereas clostridia were reduced when compared with the TNBS group. Therefore, our results indicate that AHCC is antiinflammatory and could be useful as a prebiotic to design functional foods for inflammatory bowel disease patients.     

Análisis comparativo de 3 regímenes de tratamiento en niños con linfoma de Burkitt

Between January 1980 and June 1996, a total of 86 patients with Burkitt’s lymphoma were treated at our institution. The current study is a retrospective review of how these patients evolved comparing the complications, overall and disease-free survival rates using 3 different treatment regimens. Forty-six patients were treated with regimen 1, 26 with regimen 2 and 14 with regimen 3. The following variables were analyzed: age and sex of the population, laboratory and X-ray results (blood chemistry, lactic dehydrogenase, bone marrow aspirate, cerebral spinal fluid, cytology, imaging studies of the primary tumor), the stage of the disease, the chemotherapeutic regimen received, the complications experienced, overall and disease-free survival rates, causes of death and prognostic factors. The patients median age was of 72 months. A total of 63 patients (73%) had advanced stage (III–IV) and the remaining 23 early stages (I–II). There was and overall survival rate of 63.9% for all stages and a overall disease-free survival rate of 54.5%. No statistical difference when overall survival comparison was made between regimens 1 (51%) and 2 (72%) (p=0.13). A difference was observed when regimen 1 was compared to regimen 3 (86%) (p=0.025). The overall survival comparison among the three treatment regimens had a p value of 0.06. All of the patients that remained in full remission beyond 18 months are alive and without evidence of disease regardless of the stage and treatment regimen. Intensive, short chemotherapy regimen appears to be a superior regimen when compared to other regimens. Regimen 3 offers a relatively low morbidity and the highest disease free survival of the three regimens studied.