A Randomized Trial of Dolutegravir Plus Darunavir/Cobicistat as a Switch Strategy in HIV-1-Infected Patients With Resistance to at Least 2 Antiretroviral Classes.

Background: Suppressed patients with drug-resistant HIV-1 require effective and simple antiretroviral therapy to maintain treatment adherence and viral suppression. Methods: This randomized, open-label, noninferiority, multicenter pilot study involved HIV-infected adults who met the following criteria: confirmed HIV-1 RNA <50 copies/mL for ≥6 months preceding the study randomization, treatment with at least 3 antiretroviral drugs, and a history of drug resistance mutations against at least 2 antiretroviral classes but remaining fully susceptible to darunavir (DRV) and integrase inhibitors. Participants were randomized 1:1 to switch to dolutegravir (DTG; 50 mg once per day) plus DRV boosted with cobicistat (DRV/c; 800/150 mg once per day; 2D group) or continue with their baseline regimen (standard-of-care [SOC] group). The primary endpoint was the proportion of patients with HIV-1 RNA <50 copies/mL at week 48 relative to time to loss of virologic response, with a noninferiority margin set at -12.5%. Virologic failure was defined as confirmed HIV-1 RNA ≥50 copies/mL or a single determination of HIV-1 RNA >50 copies/mL followed by antiretroviral therapy discontinuation. Results: Forty-five participants were assigned to the 2D group and 44 to the SOC group. Time to loss of virologic response showed no difference in the proportion maintaining HIV-1 RNA <50 copies/mL at week 48: 39 of 45 (86.7%; 95% CI, 73.21%-94.95%) in the 2D group vs 42 of 44 (95.4%; 95% CI, 84.53%-99.44%) in the SOC group (log-rank P = .159) with an estimated difference of -8.7 (95% CI, -22.72 to 5.14). Only 2 (4.5%) in the SOC group experienced virologic failure, and 3 participants from the 2D group experienced adverse events leading to treatment discontinuation. Conclusions: In suppressed patients with at least 2 resistant antiretroviral classes, noninferiority could not be demonstrated by fully active DRV/c plus DTG. Nevertheless, there were no unexpected adverse events or virologic failure. DRV/c plus DTG may be considered a once-daily therapy option only for well-selected patients. Clinical Trials Registration. ClinicalTrials.gov (NCT03683524).

Outbreaks of dermatopathy caused by Tephrosia noctiflora intoxication in Brazilian cattle.

This study aims to update the knowledge concerning the intoxication by Tephrosia noctiflora in Brazilian cattle herds by reporting new cases of intoxication in lactating cows, their calves and bulls and highlight the epidemiology, clinical signs, pathogenesis, gross, and microscopic lesions. The morbidity and mortality of this intoxication in the farms studied was low. Gross lesions in all affected cattle consisted of dermatitis with hyperpigmentation, crusts, ulceration, erythema, and lichenification in the skin of limbs, ventral abdomen, perianal and perineal areas of lactating calves and adult cattle. Microscopically, the main lesion observed consisted of severe dermatitis with parakeratotic hyperkeratosis, papillated proliferation, and diffuse, accentuated lymphoplasmacytic inflammatory infiltrate in the epidermis and dermis. The presence of skin lesions mainly in the limbs and ventral abdomen of cattle implies the pathogenesis of intoxication is related to a primary contact dermatitis, and the occurrence of similar lesions on the skin of nursing calves reinforces this hypothesis. The putative toxins of T. noctiflora have been thought to be rotenoids. Additional work is needed to define better if these compounds are the main toxin responsible for the dermatopathy observed in these herds.

Aging accentuates decrease in tyrosine hydroxylase immunoreactivity associated with the increase in the motor impairment in a model of reserpine-induced parkinsonism.

Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by progressive dopaminergic neuron loss. Animal models have been used to develop a better understanding of the pathophysiologic mechanisms of PD. However, these models are usually conducted with young animals diverging of the age of PD patients, suggesting a bias in translational science. Thus, the aim of the study was to evaluate the effect of the age on rats in a progressive parkinsonism model induced by reserpine (RES). Adult (6 - 8 month-old) or elderly (18 - 24 month-old) male rats were assigned to six groups: control-elderly (CTL-ELDERLY), reserpine-elderly (RES-ELDERLY), reserpine-elderly withdrawal (RES-ELDERLY WITHDRAWAL), control-adult (CTL-ADULT), reserpine-adult (RES-ADULT), and reserpine-adult withdrawal (RES-ADULT WITHDRAWAL). Animals received 15 injections every other day of RES (0.1 mg / kg) or vehicle during 30 days. Throughout treatment, animals were evaluated in the catalepsy test (every 48 h) and open field test (24 h after the second injection), and weight assessment (every 4 days) was also made. Upon completion of behavioral tests, rat brains were collected for tyrosine hydroxylase (TH) immunohistochemical analysis. Main results demonstrated that RES-treated animals spent more time in the catalepsy bar compared with control groups, moreover the RES-elderly group showed a longer catalepsy time compared with the RES-ADULT group. A shorter time from RES treatment to the development of symptoms was observed in the RES-ADULT group, compared with the RES-ELDERLY group. In addition, RES-induced weight loss in both RES-ELDERLY and RES-ADULT when compared with their corresponding controls. Cessation of RES treatment was followed by weight gain only in the RES-ADULT group. A significant decrease in TH-immunoreactive cells was observed in the substantia nigra pars compacta (SNpc) and dorsal striatum (STR) in the rats in both the RES-ADULT and RES-ELDERLY groups and in the ventral tegmental area in rats in the RES-ADULT group. Furthermore, TH immunoreactivity decrease was not reversible in SNpc and STR in the RES-ELDERLY. These results show that RES has an age-dependent effect in rats, suggesting a greater sensitivity of the dopaminergic pathway to RES with advancing age. These suggest that the RES rat model of parkinsonism can be useful in improving our knowledge on the effect of aging on neurodegeneration.

Neuroinflammation in early, late and recovery stages in a progressive parkinsonism model in rats.

Parkinson's disease (PD) is characterized by motor and non-motor signs, which are accompanied by progressive degeneration of dopaminergic neurons in the substantia nigra. Although the exact causes are unknown, evidence links this neuronal loss with neuroinflammation and oxidative stress. Repeated treatment with a low dose of reserpine-inhibitor of VMAT2-has been proposed as a progressive pharmacological model of PD. The aim of this study was to investigate whether this model replicates the neuroinflammation characteristic of this disease. Six-month-old Wistar rats received repeated subcutaneous injections of reserpine (0.1 mg/kg) or vehicle on alternate days. Animals were euthanized after 5, 10, or 15 injections, or 20 days after the 15th injection. Catalepsy tests (motor assessment) were conducted across treatment. Brains were collected at the end of each treatment period for immunohistochemical and RT-PCR analyzes. Reserpine induced a significant progressive increase in catalepsy duration. We also found decreased immunostaining for tyrosine hydroxylase (TH) in the substantia nigra pars compacta (SNpc) and increased GFAP + cells in the SNpc and dorsal striatum after 10 and 15 reserpine injections. Phenotyping microglial M1 and M2 markers showed increased number of CD11b + cells and percentage of CD11b + /iNOS + cells in reserpine-treated animals after 15 injections, which is compatible with tissue damage and production of cytotoxic factors. In addition, increased CD11b + /ArgI + cells were found 20 days after the last reserpine injection, together with an increment in IL-10 gene expression in the dorsal striatum, which is indicative of tissue repair or regeneration. Reserpine also induced increases in striatal interleukin TNF-alpha mRNA levels in early stages. In view of these results, we conclude that reserpine-induced progressive parkinsonism model leads to neuroinflammation in regions involved in the pathophysiology of PD, which is reversed 20 days after the last injection. These findings reveal that withdrawal period, together with the shift of microglial phenotypes from the pro-inflammatory to the anti-inflammatory stage, may be important for the study of the mechanisms involved in reversing this condition, with potential clinical applicability.

COVID-19-associated mucormycosis: A review of an emergent epidemic fungal infection in the era of COVID-19 pandemic.

At a time when the COVID-19's second wave is still picking up in countries like India, a number of reports describe the potential association with a rise in the number of cases of mucormycosis, commonly known as the black fungus. This fungal infection has been around for centuries and affects those people whose immunity has been compromised due to severe health conditions. In this article, we provide a detailed overview of mucormycosis and discuss how COVID-19 could have caused a sudden spike in an otherwise rare disease in countries like India. The article discusses the various symptoms of the disease, class of people most vulnerable to this infection, preventive measures to avoid the disease, and various treatments that exist in clinical practice and research to manage the disease.

Testosterone propionate improves motor alterations and dopaminergic damage in the reserpine-induced progressive model of Parkinson's disease.

Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder with a higher susceptibility to occur in men. Studies suggest that this susceptibility is related to the hormonal differences observed between men and women, being a risk factor for PD. In addition, testosterone supplementation has shown controversial results in animal models of PD and parkinsonian patients. This study evaluated the effect of chronic administration of testosterone propionate (TP) on motor behavior and neurochemical parameters in the reserpine-induced rat model of parkinsonism. Male Wistar rats received 15 injections of reserpine (RES - 0.1 mg/kg) every other day and were concomitantly treated with different doses (0.1, 1.0, or 5.0 mg/kg) of daily TP for 30 days. The rats were euthanized 48 h after the 15th injection of RES or vehicle. Brains were removed and subjected to Tyrosine hydroxylase (TH) immunohistochemistry. TP at 1.0 mg/kg reduced the damages caused by reserpine in the vacuous chewing and tong protrusion behaviors and prevented dopaminergic damage in the SNpc, VTA, and Striatum. TP at 5.0 mg/kg reduced the damages caused by reserpine in the catalepsy and tong protrusion behaviors, prevented the weight loss, and prevented dopaminergic damage in the VTA. Our results suggest that chronic administration of TP has a protective effect in a rat model of parkinsonism, improving motor alterations and dopamine depletion induced by RES.

Involvement of nitric oxide in the neurobiology of fear-like behavior.

Fear is an emotional reaction that arises in dangerous situations, inducing the adaptation to an existing condition. This behavior was conserved in all vertebrates throughout evolution and is observed in mammals, birds, fish, amphibians, and reptiles. The neurocircuitry of fear involves areas of the limbic system, cortical regions, midbrain, and brainstem. These areas communicate with each other so that there is an expression of fear and memory formation to deal with the same situation at another time. The effect of nitric oxide (NO) on fear modulation has been explored. NO is a gaseous compound that easily diffuses through the cell membrane and is produced through the oxidation reaction of l-Arginine to l-citrulline catalyzed by nitric oxide synthase (NOS). Activating the intracellular NO receptor (soluble guanylyl cyclase enzyme - sGC) triggers an enzymatic cascade that can culminate in plastic events in the neuron. NOS inhibitors induce anxiolytic-like responses in fear modulation, whereas NO donors promote fear- and anxiety-like behaviors. This review describes the neurobiology of fear in mammals and non-mammals, how NO is produced in the central nervous system, and how NO acts in fear-like behavior.

Motor, memory, and anxiety-like behavioral impairments associated with brain-derived neurotrophic factor and dopaminergic imbalance after inhalational exposure to deltamethrin.

Believed to cause damage to the nervous system and possibly being associated with neurodegenerative diseases, deltamethrin (DM) is a type II pyrethroid used in pest control, public health, home environment, and vector control. The objective of this study was to evaluate the motor, cognitive and emotional changes associated with dopaminergic and BDNF imbalance after DM exposure in rats. Sixty Wistar rats (9-10 months-old) were used, under Ethics Committee on Animal Research license (ID 19/2017). The animals were randomly divided into four groups: control (CTL, 0.9% saline), DM2 (2 mg DM in 1.6 mL 0.9% saline), DM4 (4 mg of DM in 1.6 mL of 0.9% saline), and DM8 (8 mg of DM in 1.6 mL of 0.9% saline). DM groups were submitted to 9 or 15 inhalations, one every 48 h. Half of the animals from each group were randomly selected and perfused 24 h after the 9th or 15th inhalation. Throughout the experiment, the animal's behavior were evaluated using catalepsy test, open field, hole-board test, Modified Elevated Plus Maze, and social interaction. At the end of the experiments, the rats were perfused transcardially and their brains were processed for Tyrosine Hydroxylase (TH) and Brain derived neurotrophic factor (BDNF) immunohistochemistries. The animals submitted to 9 inhalations of DM showed a reduction in immunoreactivity for TH in the Substantia nigra pars compacta (SNpc), ventral tegmental area (VTA), and dorsal striatum (DS) areas, and an increase in BDNF in the DS and CA1, CA3 and dentate gyrus (DG) hippocampal areas. Conversely, the animals submitted to 15 inhalations of DM showed immunoreactivity reduced for TH in the SNpc and VTA, and an increase in BDNF in the hippocampal areas (CA3 and DG). Our results indicate that the DM inhalation at different periods induce motor and cognitive impairments in rats. Such alterations were accompanied by dopaminergic system damage and a possible dysfunction on synaptic plasticity.

Dermatopathy caused by Tephrosia noctiflora intoxication in cattle.

An outbreak of a disease characterized by emaciation, dermatitis with erythema, alopecia, foul-smelling exudation, crusting, hyperpigmentation, lichenification, and edema of fore- and hindlimbs, chest and dewlap is described affecting cattle in the State of Alagoas, Northeastern Brazil. Microscopically, the main lesions were characterized by diffuse dermatitis with infiltration of lymphocytes, histiocytes, parakeratotic hyperkeratosis and acanthosis. The plant Tephrosia noctiflora, which exhibited signs of consumption, infested the grazing areas of cattle. To test its toxicity, T. noctiflora was harvested, dried in the shade, crushed and sourced at a concentration of 50% mixed with commercial food for three guinea pigs. The main clinical signs in guinea pigs included weight loss and multifocal, moderate to severe areas of alopecia, diffuse erythema of the skin, vaginal edema and hematuria. Microscopically, lymphocytic and histiocytic dermatitis, parakeratotic hyperkeratosis and acanthosis were noted in guinea pigs. This experiment confirms that T. noctiflora is the cause of outbreaks of dermatitis observed in cattle grazing in areas infested by this plant.

Female Rats Are Resistant to Cognitive, Motor and Dopaminergic Deficits in the Reserpine-Induced Progressive Model of Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease. The main symptoms are motor signs such as resting tremor and difficulty in initializing movements. Non-motor alterations, such as cognitive deficits, can precede the motor symptoms. PD is more frequent in men than women. The mechanisms related to this difference are not completely understood. There is evidence that females present distinct characteristics in dopaminergic function compared to males. While the severity of motor impairments is often compared between sexes, little is known about sex differences in the prodromal stage. Most animal models of PD present acute severe motor impairment, which precludes the study of non-motor symptoms. Our research group have proposed an adaptation of the classic reserpine protocol, using low doses in a chronic treatment. This method allows the observation of progressive motor impairment as well as premotor deficits. Here we investigate possible behavioral and neuronal sex differences in the effects of the repeated treatment with a low dose of reserpine in rats. Male and female Wistar rats received 10-15 injections of reserpine (0.1 mg/kg) or vehicle, on alternate days. We followed-up the estrous cycle phases and conducted motor and cognitive assessments (catalepsy, open field, oral movements and object recognition tests). The euthanasia occurred 48 h after the 10th or 15th injections, with the collection of blood for the quantification of sex hormones and brains for tyrosine hydroxylase (TH) immunohistochemistry in the substantia nigra pars compact (SNpc). Reserpine induced progressive catalepsy, involuntary oral movements and cognitive deficits in male rats. The behavioral effects of reserpine were attenuated (motor) or absent (cognitive) in females. Reserpine decreased TH immunoreactivity in males, but not in females. Estrogen levels in females negatively correlated with catalepsy duration. Our findings show that females present a delay and/or a prevention in the reserpine-induced motor alterations in the progressive PD model, compatible with the lower prevalence of this disease in women. Further, females were protected from the deficit in object recognition at the prodromal stage. The absence of reserpine-induce decrease in TH immunoreactivity suggests that differences in dopaminergic function/plasticity are related to this protection in female sex.

Nociception alterations precede motor symptoms in a progressive model of parkinsonism induced by reserpine in middle-aged rats.

Nociception alterations are frequent non-motor symptoms of the prodromal phase of Parkinson's disease (PD). The period for the onset of symptoms and the pathophysiological mechanisms underlying these alterations remain unclear. We investigated the course of nociception alterations in a progressive model of parkinsonism induced by reserpine (RES) in rats. Male Wistar rats (6-7 months) received 5 or 10 subcutaneous injections of RES (0.1 mg/kg) or vehicle daily for 20 days. Motor evaluation and nociceptive assessment were performed throughout the treatment. At the end of the treatment rats were euthanized, the brains removed and processed for immunohistochemical analysis (TH and c-Fos). The RES-treated rats exhibited an increased nociceptive response to mechanical and chemical stimulation in the electronic von Frey and formalin tests, respectively. Moreover, these alterations preceded the motor impairment observed in the catalepsy test. In addition, the RES treatment reduced the TH-immunoreactivity in the ventral tegmental area (VTA) and increased the c-Fos expression in the ventral-lateral periaqueductal gray (vlPAG), rostral ventral medulla (RVM) and dorsal raphe nucleus (DRN) after noxious stimuli induced by formalin. Taken together, our results reinforce that nociceptive changes are one of the early signs of PD and monoamine depletion in basal ganglia can be involved in the abnormal processing of nociceptive information in PD.

Telencephalic distributions of doublecortin and glial fibrillary acidic protein suggest novel migratory pathways in adult lizards.

Adult neurogenesis has been reported in all major vertebrate taxa. However, neurogenic rates and the number of neurogenic foci vary greatly, and are higher in ancestral taxa. Our study aimed to evaluate the distribution of doublecortin (DCX) and glial fibrillary acidic protein (GFAP) in telencephalic areas of the adult tropical lizard Tropidurus hispidus. We describe evidence for four main neurogenic foci, which coincide anatomically with the ventricular sulci described by the literature. Based on neuronal morphology, we infer four migratory patterns/pathways. In the cortex, patterns of GFAP and DCX staining support radial migrations from ventricular zones into cortical areas and dorsoventricular ridge. Cells radiating from the sulcus septomedialis (SM) seemed to migrate to the medial cortex and dorsal cortex. From the sulcus lateralis (SL), they seemed to be bound for the lateral cortex, central amygdala and nucleus sphericus. We describe a DCX-positive stream originating in the caudal sulcus ventralis and seemingly bound for the olfactory bulb, resembling a rostral migratory stream. We provide evidence for a previously undescribed tangential dorso-septo-caudal migratory stream, with neuroblasts supported by DCX-positive fibers. Finally, we provide evidence for a commissural migration stream seemingly bound for the contralateral nucleus sphericus. Therefore, in addition to two previously known migratory streams, this study provides anatomical evidence in support for two novel migratory routes in amniotes.

Balance alterations and reduction of pedunculopontine cholinergic neurons in early stages of parkinsonism in middle-aged rats.

The purpose of the present study was to investigate balance alterations and the possible role of the cholinergic neurons in the pedunculopontine nucleus (PPN) in the early stages of a progressive animal model of Parkinson's disease (PD). Twenty-eight middle-aged (8-9 months) male Wistar rats received 4 or 10 subcutaneous vehicle (control, CTL) or reserpine (RES) injections (0.1 mg/kg). The animals were submitted to different behavioral tests. Forty-eight hours after the 4th injection, half of the animals of each group (n = 7) were perfused and submitted to immunohistochemical analysis for tyrosine hydroxylase (TH) and choline acetyltransferase (ChAT). The remaining animals (n = 7 per group) were killed 48 h after the 10th injection. RES group presented motor deficits in the catalepsy and open field tests starting at days 12 and 20 of treatment, respectively (only for the animals that received 10 injections). On the other hand, dynamic and static balance changes were observed at earlier stages of RES treatment, starting at days 6 and 4, respectively. At this point of the treatment, there was no decrease in the number of TH immunoreactivity neurons in the substantia nigra pars compacta (SNpc), ventral tegmental area (VTA) and dorsal striatum (DS). However, a decrease was observed in SNpc and dorsal striatum of animals that received 10 injections. In contrast, there was a decrease in the number of ChAT immunoreactive cells in PPN concomitantly to the balance alterations at the early stages of treatment (after 4 RES injections). Thus, by mimicking the progressiveness of PD, the reserpine model made it possible to identify static and dynamic balance impairments prior to the motor alterations in the catalepsy and open field tests. In addition, changes in balance were accompanied by a reduction in the number of ChAT immunoreactive cells in NPP in the early stages of treatment.

Short-term but not long-term exposure to an enriched environment facilitates the extinction of aversive memory.

Environmental enrichment (EE) has been used to investigate behavioral changes and neuroplasticity in brain in normal and pathological conditions. Besides, the EE has been used to understand the neurobehavioral systems involved in learning experiences, visual inputs, defensive responses, social interactions and memory. However, the required exposure duration to remove aversive memories remains lacking. Therefore, the purpose of the present study was to investigate the time-course effect of EE exposure on the extinction of aversive memory. Young adult male Wistar rats were exposed to two different EE protocols: short-term environmental enrichment (EE2 - animal kept under enriched conditions for two weeks) and long-term environmental enrichment (EE4 - animal kept under enriched conditions for four weeks). The contextual fear conditioning test was used to assess aversive memory. The both EE protocols provide changes in Zif-268 immunoreactivity in mesocorticolimbic areas such as CA1 and central amygdala; however, only short-term EE reduces the ZIF-268 immunoreactivity in VTA. Besides, both EE protocols also provide an increase in TH immunoreactivity in VTA and nucleus accumbens, but only the short-term EE modifies the TH immunoreactivity in CA1 and infralimbic region of the prefrontal cortex. The time-course effect of EE interferes differently on the extinction of aversive memory, being two weeks of exposure with EE sufficient to cause improvement in coping during aversive situations, favoring the extinction of conditioned fear memory.

HIV-1 Gag mutations alone are sufficient to reduce darunavir susceptibility during virological failure to boosted PI therapy.

BACKGROUND: Virological failure (VF) to boosted PIs with a high genetic barrier is not usually linked to the development of resistance-associated mutations in the protease gene. METHODS: From a cohort of 520 HIV-infected subjects treated with lopinavir/ritonavir or darunavir/ritonavir monotherapy, we retrospectively identified nine patients with VF. We sequenced the HIV-1 Gag-protease region and generated clonal virus from plasma samples. We characterized phenotypically clonal variants in terms of replicative capacity and susceptibility to PIs. Also, we used VESPA to identify signature mutations and 3D molecular modelling information to detect conformational changes in the Gag region. RESULTS: All subjects analysed harboured Gag-associated polymorphisms in the absence of resistance mutations in the protease gene. Most Gag changes occurred outside Gag cleavage sites. VESPA analyses identified K95R and R286K (P < 0.01) as signature mutations in Gag present at VF. In one out of four patients with clonal analysis available, we identified clonal variants with high replicative capacity and 8- to 13-fold reduction in darunavir susceptibility. These clonal variants harboured K95R, R286K and additional mutations in Gag. Low susceptibility to darunavir was dependent on the Gag sequence context. All other clonal variants analysed preserved drug susceptibility and virus replicative capacity. CONCLUSIONS: Gag mutations may reduce darunavir susceptibility in the absence of protease mutations while preserving viral fitness. This effect is Gag-sequence context dependent and may occur during boosted PI failure.

IN VITRO AND IN VIVO MODELS OF AMYOTROPHIC LATERAL SCLEROSIS: AN UPDATED OVERVIEW.

Amyotrophic Lateral Sclerosis (ALS) is a progressive, neurodegenerative disease characterized by loss of upper motor neurons (UMN) and lower motor neurons (LMN). Disease affects people all over the world and is more prevalent in men. Patients with ALS develop extensive muscle wasting, paralysis and ultimately death, with a median survival of usually fewer than five years after disease onset. ALS may be sporadic (sALS, 90%) or familial (fALS, 10%). The large majority of fALS cases are associated with genetic alterations, which are mainly related to the genes SOD1, TDP-43, FUS, and C9ORF72. In vitro and in vivo models have helped elucidate ALS etiology and pathogenesis, as well as its molecular, cellular, and physiological mechanisms. Many studies in cell cultures and animal models, such as Caenorhabditis elegans, Drosophila melanogaster, zebrafish, rodents, and non-human primates have been performed to clarify the relationship of these genes to ALS disease. However, there are inherent limitations to consider when using experimental models. In this review, we provide an updated overview of the most used in vitro and in vivo studies that have contributed to a better understanding of the different ALS pathogenic mechanisms.

Intracerebroventricular injection of deltamethrin increases locomotion activity and causes spatial working memory and dopaminergic pathway impairment in rats.

Deltamethrin (DM) is widely used in agriculture, veterinary medicine and control of domestic pests. Epidemiological studies suggest that DM exposure is a risk factor for neurodegenerative disorders such as Parkinson's (PD) and Alzheimer diseases; however the mechanisms are elusive. In the present study we evaluated the effects of intracerebroventricular (i.c.v.) administration of DM on locomotion activity, spatial working memory and dopaminergic pathway in the rat. Middle-aged male Wistar rats received three i.c.v. injections of DM 0.5 µg, DM 5 µg or vehicle, every other day. Across the treatment, the animals were submitted to behavioral evaluation in the catalepsy test, open field test, and spontaneous alternation task. Following completion of behavioral tests, rats were perfused and their brains were processed to tyrosine hydroxylase (TH) immunohistochemistry. We observed that i.c.v. administration of DM 5 µg increased locomotion activity (open field) and caused spatial working memory impairment (spontaneous alternation task). These alterations were accompanied by reduction TH immunoreactivity in the substantia nigra pars compacta (SNpc), ventral tegmental area (VTA) and dorsal striatum. Conversely, no motor change was observed in the catalepsy test. These results indicate that i.c.v. administration of DM can cause hyperactivity and cognitive alteration which may be related to disruption of the dopaminergic pathway.

Simplification of Antiretroviral Treatment from Darunavir/Ritonavir Monotherapy to Darunavir/Cobicistat Monotherapy: Effectiveness and Safety in Routine Clinical Practice.

Our aim was to evaluate the effectiveness and safety of darunavir/cobicistat (DRV/c) monotherapy as an antiretroviral treatment simplification strategy in HIV-infected patients already on suppressive darunavir/ritonavir (DRV/r) monotherapy in routine clinical practice. We conducted a retrospective multicenter study including all adult patients switched from DRV/r monotherapy to DRV/c monotherapy while HIV-1 RNA was <50 copies/mL and who had at least one follow-up visit. The primary endpoint was the percentage of patients remaining free of treatment failure (TF), defined as discontinuation of monotherapy for any reason, including loss of follow-up. Virological failure (VF) was defined as a confirmed HIV-1 RNA ≥50 copies/mL or any change in the regimen after a single determination with HIV-1 RNA ≥50 copies/mL. Changes in renal function parameters and lipid profile were also evaluated. Factors associated with VF were analyzed using Cox regression. In this study, 173 subjects were included. The median (interquartile range) time of follow-up was 58 (50-67) weeks. Overall, 90% of patients remained free of TF during follow-up. Ten (6%) patients discontinued DRV/c monotherapy for nonvirological reasons and eight (5%) developed VF. No DRV-related mutations were identified in patients with VF. A decrease in triglyceride levels (p = .006) and estimated glomerular filtration rate (p = .005) were observed during follow-up. The presence of blips and CD4+ nadir <100 cells/mm3 were predictors of VF. In conclusion, switching to DRV/c monotherapy seems to be safe and effective in routine clinical practice in HIV-infected patients undergoing suppressive DRV/r monotherapy.

Sex differences in the progressive model of parkinsonism induced by reserpine in rats.

Parkinson's disease (PD) exhibits sexual differences in susceptibility and pathogenesis in humans, with a high incidence in men and a high severity of motor symptoms in male rodents. Furthermore, studies showed that the administration of low dose of reserpine (RES) induces a progressive appearance of motor alterations similar with parkinsonism in male rodents. Here, we investigated sex differences in motor deficits and tyrosine hydroxylase (TH) immunoreactivity induced by a progressive model of parkinsonism. Gonadally intact male and female Wistar rats and ovariectomized female rats received 15 subcutaneous injections (s.c.) every other day of 0.1 mg/kg of RES or vehicle. The repeated administration of low doses of RES (0.1 mg/kg) produces sexually dimorphic impairments on motor performance (catalepsy and open field test). Intact and ovariectomized females were more resistant to the deleterious effect of repeated administration of reserpine in the early, but this resistance in intact female disappears over time. However, intact females showed a reduction of the TH immunoreactivity in substantia nigra pars compacta, but not in ventral tegmental area and dorsal striatum. These results suggest a possible application of this model in the study of sexual dimorphism throughout the progression of PD.

Serotonergic dysfunction in a model of parkinsonism induced by reserpine.

Parkinson's disease (PD) is mainly characterized by a dopamine deficiency accompanied by structural and functional changes in striatal neuronal projections. However, studies have considered PD as a multi-systemic disease in which the neurodegenerative process extends beyond the dopaminergic system. Therefore, the purpose of the present study was to investigate the time-course of serotonergic neuron damage in a progressive model of parkinsonism induced by a low dose of reserpine. Thus, male Wistar rats received 4 (ST, short-treatment of reserpine) or 10 (MT, middle-term treatment of reserpine) subcutaneous injections of vehicle or reserpine (0.1 mg/kg) at a volume of 1 mL/kg body weight, on alternate days. Animals were euthanized 48 h after the last injection for immunohistochemical analysis. After ST, 5-HT immunoreactivity decreased in hippocampal subareas (CA1 and CA3) and medial prefrontal cortex (mPFC) compared to vehicle. Furthermore, animals MT-treated also showed progressive decrease of 5-HT immunoreactivity in CA1 and CA3 subareas. Conversely, a significant increase of 5-HT immunoreactivity was found in mPFC and dorsal raphe nucleus (DRN) in animals submitted to MT when compared to ST exposure. The results showed that, in the repeated low-dose reserpine rat model, variations in the immunoreactivity of 5-HT start early in the course of progressive parkinsonism.