Cannabis-induced hypodopaminergic anhedonia and cognitive decline in humans: Embracing putative induction of dopamine homeostasis

Over years, the regular use of cannabis has substantially increased among young adults, as indicated by the rise in cannabis use disorder (CUD), with an estimated prevalence of 8. 3% in the United States. Research shows that exposure to cannabis is associated with hypodopaminergic anhedonia (depression), cognitive decline, poor memory, inattention, impaired learning performance, reduced dopamine brain response-associated emotionality, and increased addiction severity in young adults. The addiction medicine community is increasing concern because of the high content of delta-9-tetrahydrocannabinol (THC) currently found in oral and vaping cannabis products, the cognitive effects of cannabis may become more pronounced in young adults who use these cannabis products. Preliminary research suggests that it is possible to induce \u27dopamine homeostasis,\u27 that is, restore dopamine function with dopamine upregulation with the proposed compound and normalize behavior in chronic cannabis users with cannabis-induced hypodopaminergic anhedonia (depression) and cognitive decline. This psychological, neurobiological, anatomical, genetic, and epigenetic research also could provide evidence to use for the development of an appropriate policy regarding the decriminalization of cannabis for recreational use

Chronic methamphetamine effects on brain structure and function in rats

Methamphetamine (MA) addiction is a growing epidemic worldwide. Chronic MA use has been shown to lead to neurotoxicity in rodents and humans. Magnetic resonance imaging (MRI) studies in MA users have shown enlarged striatal volumes and positron emission tomography (PET) studies have shown decreased brain glucose metabolism (BGluM) in the striatum of detoxified MA users. The present study examines structural changes of the brain, observes microglial activation, and assesses changes in brain function, in response to chronic MA treatment. Rats were randomly split into three distinct treatment groups and treated daily for four months, via i.p. injection, with saline (controls), or low dose (LD) MA (4 mg/kg), or high dose (HD) MA (8 mg/kg). Sixteen weeks into the treatment period, rats were injected with a glucose analog, [18F] fluorodeoxyglucose (FDG), and their brains were scanned with micro-PET to assess regional BGluM. At the end of MA treatment, magnetic resonance imaging at 21T was performed on perfused rats to determine regional brain volume and in vitro [3H]PK 11195 autoradiography was performed on fresh-frozen brain tissue to measure microglia activation. When compared with controls, chronic HD MA-treated rats had enlarged striatal volumes and increases in [3H]PK 11195 binding in striatum, the nucleus accumbens, frontal cortical areas, the rhinal cortices, and the cerebellar nuclei. FDG microPET imaging showed that LD MA-treated rats had higher BGluM in insular and somatosensory cortices, face sensory nucleus of the thalamus, and brainstem reticular formation, while HD MA-treated rats had higher BGluM in primary and higher order somatosensory and the retrosplenial cortices, compared with controls. HD and LD MA-treated rats had lower BGluM in the tail of the striatum, rhinal cortex, and subiculum and HD MA also had lower BGluM in hippocampus than controls. These results corroborate clinical findings and help further examine the mechanisms behind MA-induced neurotoxicity

Olaparib maintenance therapy after frontline chemotherapy in patients with BRCA-mutated ovarian cancer: real-world results in expanded access program

Introduction. Olaparib is the only PARP inhibitor approved in Russia for the maintenance therapy for BRCA-positive ovarian cancer after frontline chemotherapy. We conducted a real-world analysis of olaparib efficacy and safety for this indication.Aim. To assess the efficacy of PARP inhibitors in real-world clinical practice.Materials and methods. Patients with stage III-IV BRCA-mutated ovarian cancer who received olaparib maintenance therapy in expanded access program in 03.2019-12.2020 timeframe. Briefly, key inclusion criteria were: serous or endometrioid highgrade ovarian cancer; pathogenic BRCA1/2 mutation; primary or interval debulking; complete or partial response to frontline platinum-based therapy. Olaparib was administered as tablets (300 mg BID) up to 2-years, disease progression or unacceptable toxicity, whichever occurred first. The primary endpoint of the study was progression-free survival (PFS), overall survival (OS) and safety were key secondary endpoints. Statistical analysis was done with R and RStudio software.Results and discussion. 23 patients were enrolled. Median age was 49 years, all patients had high-grade serous adenocarcinoma histology. Complete debulking at primary or interval surgery was achieved in 30% of patients. With median follow-up time equal to 22 months, median PFS and OS were not reached. The 2-year PFS and OS were 65 and 84%, respectively. Grade 3-4 adverse events was detected in 7 (30.4%) patients.Conclusion. Our results supports high efficacy of olaparib in real clinical practice setting reported in the SOLO1 trial

Hallazgos hematológicos en perros y gatos en Lima, Perú

The aim of this study was to conduct a haematological evaluation of dogs and cats in Lima, Peru. A total of 460 blood samples (410 dogs and 50 cats) were collected between December 2017 and May 2018. The smears were stained with Wright and the reticulocytes were stained with Brilliant cresyl blue. Descriptive statistics were performed for quantitative variables in the erythroid, myeloid and lymphoid series, as well as the frequency analysis of qualitative variables between species indicator of type of anaemia and leukaemia, ability of medullary regeneration, abnormal morphological changes, out of physiological range and presence of extra and intracellular microorganisms. The most frequent alterations were normochromic normocytic anaemia (23.2% dog, 10% cat), megaloblastic anaemia (5.1% dog), severe hypochromic microcytic anaemia (4% cat), neutrophilic chronic myeloid leukaemia (7.1% dog, 8% cat), monocytosis with cytoplasmic vacuolization in monocytes (4.9% dog), severe thrombocytosis with platelet aggregates (6% cat), polychromatophilia (6.3% dog), dacrocytes (54.4% dog, 64% cat), acanthocytes (11.7% dog, 40% cat) , macrocytes (14.6% dog, 6% cat), small leukocytes (10% dog, 6% cat), Cytauxzoon felis (20% cat), Anaplasma spp (0.2% dog) and Mycoplasma spp (2% dog, 20% cat). Only significant differences were observed between sexes in total platelets (p=0.0087) and eosinophils (p=0.0260) being greater in male dogs. It is concluded that the prevalence of C. felis in the cats studied is relatively low and there is a risk of zoonosis of Anaplasma spp and Mycoplasma spp in the owners of affected animals in Lima, Perú.El objetivo del estudio fue realizar una evaluación hematológica a perros y gatos en Lima, Perú. Se colectaron 460 muestras de sangre (410 perros y 50 gatos) entre diciembre de 2017 y mayo de 2018. Los frotis se colorearon con Wright y las láminas de reticulocitos con Azul de cresil brillante. Se realizó estadística descriptiva para variables cuantitativas en las series eritroide, mieloide y linfoide, así como el análisis de frecuencias de variables cualitativas entre especies indicadoras de tipo de anemia y leucemia, capacidad de regeneración medular, cambios morfológicos anormales, salida de rango fisiológico y presencia de microorganismos extra e intracelular. Predominaron la anemia normocítica normocrómica (23.2% perro, 10% gato), anemia megaloblástica (5.1% perro), anemia severa microcítica hipocrómica (4% gato), leucemia mieloide crónica de neutrófilos (7.1% perro, 8% gato), monocitosis con vacuolización citoplasmática en monocitos (4.9% perro), trombocitosis severa con agregados plaquetarios (6% gato), policromatofilia (6.3% perro), los dacriocitos (54.4% perro, 64% gato), acantocitos (11.7% perro, 40% gato), macrocitos (14.6% perro, 6% gato), leucocitos pequeños (10% perro, 6% gato), Cytauxzoon felis (20% gato), Anaplasma spp (0.2% perro) y Mycoplasma spp (2% perro, 20% gato). Solo se evidenciaron diferencias significativas entre sexos en las plaquetas totales (p=0.0087) y los eosinófilos (p=0.0260) siendo mayor en perros machos. Se concluye que la prevalencia de C. felis en los gatos estudiados es relativamente baja y existe un riesgo de zoonosis de Anaplasma spp y Mycoplasma spp en los propietarios de animales afectados en Lima, Perú. &nbsp

Primary care nurses: effects on secondary care referrals for diabetes

Background: Primary care nurses play an important role in diabetes care, and were introduced in GP-practice partly to shift care from hospital to primary care. The aim of this study was to assess whether the referral rate for hospital treatment for diabetes type II (T2DM) patients has changed with the introduction of primary care nurses, and whether these changes were related to the number of diabetes-related contacts in a general practice. Methods: Healthcare utilisation was assessed for a period of 365 days for 301 newly diagnosed and 2124 known T2DM patients in 2004 and 450 and 3226 patients in 2006 from general practices that participated in the Netherlands Information Network of General Practice (LINH). Multilevel logistic and linear regression analyses were used to analyse the effect of the introduction of primary care nurses on referrals to internists, ophthalmologists and cardiologists and diabetes-related contact rate. Separate analyses were conducted for newly diagnosed and known T2DM patients. Results: Referrals to internists for newly diagnosed T2DM patients decreased between 2004 and 2006 (OR:0.44; 95%CI:0.22-0.87) in all practices. For known T2DM patients no overall decrease in referrals to internists was found, but practices with a primary care nurse had a lower trend (OR:0.59). The number of diabetes-related contacts did not differ between practices with and without primary care nurses. Cardiologists’ and ophthalmologists’ referral rate did not change. Conclusions: The introduction of primary care nurses seems to have led to a shift of care from internists to primary care for known diabetes patients, while the diabetes-related contact rate seem to have remained unchanged.

BRCA-ассоциированный рак яичников: обзор современной литературы

Ovarian cancer is a heterogeneous disease and is the leading cause of mortality among all gynecological malignancies. The disease is characterized by a high frequency of germline and somatic mutations in BRCA1/2 suppressor genes, which, according to various sources, occur in 10–27 % of all ovarian cancer cases. Determination of mutations in BRCA1 / 2 genes is a mandatory diagnostic criteria and includes performing next generation sequencing. Knowledge of the disease mutational status is important not only in the case of determining treatment plan, but also in the case of prevention of the other malignant neoplasms. The purpose of this review is to summarize the current data on the disease characteristics, diagnosis and treatment of BRCA-associated ovarian cancer. Also, the article presents data from a non-interventional multicenter OvATAR study to assess the prevalence of germline and somatic mutations in BRCA1 / 2 genes in the Russian patient population.Рак яичников является гетерогенным заболеванием и занимает одно из ведущих мест по показателю смертности среди всех гинекологических злокачественных новообразований. заболевание характеризуется высокой частотой наличия герминальных и соматических мутаций в генах-супрессорах BRCA1 / 2, которые, по разным источникам, встречаются в 10–27 % случаев. Определение мутаций в генах BRCA1 / 2 является обязательным критерием диагностики и включает выполнение полногеномного секвенирования. знание мутационного статуса заболевания важно не только для определения тактики лечения, но и в случае профилактики ряда злокачественных новообразований. Целью данного обзора является обобщение современных данных о течении, диагностике и лечении BRCA-ассоциированного рака яичников. Также в статье представлены данные неинтервенционного многоцентрового исследования OvATAR по оценке распространенности герминальных и соматических мутаций в генах BRCA1 / 2 в российской популяции пациенток

Involvement of Dopamine Receptors in Binge Methamphetamine-Induced Activation of Endoplasmic Reticulum and Mitochondrial Stress Pathways

Single large doses of methamphetamine (METH) cause endoplasmic reticulum (ER) stress and mitochondrial dysfunctions in rodent striata. The dopamine D1 receptor appears to be involved in these METH-mediated stresses. The purpose of this study was to investigate if dopamine D1 and D2 receptors are involved in ER and mitochondrial stresses caused by single-day METH binges in the rat striatum. Male Sprague-Dawley rats received 4 injections of 10 mg/kg of METH alone or in combination with a putative D1 or D2 receptor antagonist, SCH23390 or raclopride, respectively, given 30 min prior to each METH injection. Rats were euthanized at various timepoints afterwards. Striatal tissues were used in quantitative RT-PCR and western blot analyses. We found that binge METH injections caused increased expression of the pro-survival genes, BiP/GRP-78 and P58IPK, in a SCH23390-sensitive manner. METH also caused up-regulation of ER-stress genes, Atf2, Atf3, Atf4, CHOP/Gadd153 and Gadd34. The expression of heat shock proteins (HSPs) was increased after METH injections. SCH23390 completely blocked induction in all analyzed ER stress-related proteins that included ATF3, ATF4, CHOP/Gadd153, HSPs and caspase-12. The dopamine D2-like antagonist, raclopride, exerted small to moderate inhibitory influence on some METH-induced changes in ER stress proteins. Importantly, METH caused decreases in the mitochondrial anti-apoptotic protein, Bcl-2, but increases in the pro-apoptotic proteins, Bax, Bad and cytochrome c, in a SCH23390-sensitive fashion. In contrast, raclopride provided only small inhibition of METH-induced changes in mitochondrial proteins. These findings indicate that METH-induced activation of striatal ER and mitochondrial stress pathways might be more related to activation of SCH23390-sensitive receptors

Chronic Methamphetamine Administration Causes Differential Regulation of Transcription Factors in the Rat Midbrain

Methamphetamine (METH) is an addictive and neurotoxic psychostimulant widely abused in the USA and throughout the world. When administered in large doses, METH can cause depletion of striatal dopamine terminals, with preservation of midbrain dopaminergic neurons. Because alterations in the expression of transcription factors that regulate the development of dopaminergic neurons might be involved in protecting these neurons after toxic insults, we tested the possibility that their expression might be affected by toxic doses of METH in the adult brain. Male Sprague-Dawley rats pretreated with saline or increasing doses of METH were challenged with toxic doses of the drug and euthanized two weeks later. Animals that received toxic METH challenges showed decreases in dopamine levels and reductions in tyrosine hydroxylase protein concentration in the striatum. METH pretreatment protected against loss of striatal dopamine and tyrosine hydroxylase. In contrast, METH challenges caused decreases in dopamine transporters in both saline- and METH-pretreated animals. Interestingly, METH challenges elicited increases in dopamine transporter mRNA levels in the midbrain in the presence but not in the absence of METH pretreatment. Moreover, toxic METH doses caused decreases in the expression of the dopamine developmental factors, Shh, Lmx1b, and Nurr1, but not in the levels of Otx2 and Pitx3, in saline-pretreated rats. METH pretreatment followed by METH challenges also decreased Nurr1 but increased Otx2 and Pitx3 expression in the midbrain. These findings suggest that, in adult animals, toxic doses of METH can differentially influence the expression of transcription factors involved in the developmental regulation of dopamine neurons. The combined increases in Otx2 and Pitx3 expression after METH preconditioning might represent, in part, some of the mechanisms that served to protect against METH-induced striatal dopamine depletion observed after METH preconditioning

Methamphetamine-Induced Dopamine-Independent Alterations in Striatal Gene Expression in the 6-Hydroxydopamine Hemiparkinsonian Rats

Unilateral injections of 6-hydroxydopamine into the medial forebrain bundle are used extensively as a model of Parkinson's disease. The present experiments sought to identify genes that were affected in the dopamine (DA)–denervated striatum after 6-hydroxydopamine-induced destruction of the nigrostriatal dopaminergic pathway in the rat. We also examined whether a single injection of methamphetamine (METH) (2.5 mg/kg) known to cause changes in gene expression in the normally DA-innervated striatum could still influence striatal gene expression in the absence of DA. Unilateral injections of 6-hydroxydopamine into the medial forebrain bundle resulted in METH-induced rotational behaviors ipsilateral to the lesioned side and total striatal DA depletion on the lesioned side. This injection also caused decrease in striatal serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels. DA depletion was associated with increases in 5-HIAA/5-HT ratios that were potentiated by the METH injection. Microarray analyses revealed changes (± 1.7-fold, p<0.025) in the expression of 67 genes on the lesioned side in comparison to the intact side of the saline-treated hemiparkinsonian animals. These include follistatin, neuromedin U, and tachykinin 2 which were up-regulated. METH administration caused increases in the expression of c-fos, Egr1, and Nor-1 on the intact side. On the DA-depleted side, METH administration also increased the expression of 61 genes including Pdgf-d and Cox-2. There were METH-induced changes in 16 genes that were common in the DA-innervated and DA-depleted sides. These include c-fos and Nor-1 which show greater changes on the normal DA side. Thus, the present study documents, for the first time, that METH mediated DA-independent changes in the levels of transcripts of several genes in the DA-denervated striatum. Our results also implicate 5-HT as a potential player in these METH-induced alterations in gene expression because the METH injection also caused significant increases in 5-HIAA/5-HT ratios on the DA-depleted side