Selective modulation of placental and fetal MDR transporters by chronic in utero exposure to NRTIs in Sprague-Dawley rats: Importance for fetoprotection

Multidrug resistance (MDR) transporters present in placenta and fetal tissues reduce intracellular accumulation of their substrates. Consequently, induction of protein expression may further reduce toxic effects of specific xenobiotics. This work aimed to study whether sustained drug treatments in utero could modulate MDR transporters P-gp, BCRP, and MRP2 and thus impact their fetoprotective action. Pregnant Sprague-Dawley rats were daily treated by gavage with zidovudine (AZT, 60 mg/kg) or lamivudine (3TC, 30 mg/kg) from gestation day (GD) 11 to 20. On GD 21, DNA damage and MDR protein abundance were assessed by comet assay and western blotting, respectively. Moreover, a single IV dose of AZT or 3TC was administered on GD 21 and drug concentrations were measured in maternal blood and fetal liver by HPLC-UV. Chronic exposure to 3TC caused significantly higher DNA damage than AZT in fetal liver cells, whereas no differences were observed in maternal blood cells. Increased levels of BCRP protein were found in the placenta and fetal liver after AZT, but not 3TC, chronic in utero exposure. Contrarily, no modifications in the protein abundance of P-gp or MRP2 were found after sustained exposure to these drugs. The area under the curve of AZT in fetal liver was significantly lower in the AZT-pretreated rats than in the VEH or 3TC groups. Moreover, pre-administration of the BCRP inhibitor gefitinib (20 mg/kg, IP) increased AZT levels to the values observed in the VEH-treated group in this tissue. On the other hand, the disposition of 3TC in maternal blood or fetal liver was not modified after chronic treatment in either group. In conclusion, chronic exposure to AZT selectively induces BCRP expression in the placenta and fetal liver decreasing its own accumulation which may account for the lower DNA damage observed for AZT compared to 3TC in fetal liver cells.Fil: Minoia, Juan Mauricio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: Filia, Maria Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: Roma, Martin Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: de Fino, Fernanda Teresa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: Copello, Guillermo Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Metabolismo del Fármaco; ArgentinaFil: Peroni, Roxana Noemi. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentin

Induction of ABCG2/BCRP restricts the distribution of zidovudine to the fetal brain in rats

Safety concerns for fetus development of zidovudine (AZT) administration as prophylaxis of vertical transmission of HIV persist. We evaluated the participation of the ATP-binding cassette efflux transporter ABCG2 in the penetration of AZT into the fetal brain and the relevance for drug safety. Oral daily doses of AZT (60 mg/kg body weight) or its vehicle were administered between post gestational days 11 (E11) and 20 (E20) to Sprague-Dawley pregnant rats. At E21, animals received an intravenous bolus of 60 mg AZT/kg body weight in the presence or absence of the ABCG2 inhibitor gefitinib (20 mg/kg body weight, ip) and AZT in maternal plasma and fetal brain were measured by HPLC-UV. ABCG2 protein expression in placenta and fetal brain, as well as mitochondrial function and ultrastructure in fetal brain were also analyzed. In utero chronic exposure to AZT markedly induced ABCG2 expression in placenta and fetal brain whereas did not significantly alter mitochondrial functionality in the fetal brain. The area-under-the-concentration-time-curve of AZT significantly decreased in fetal brains isolated from AZT-exposed fetuses compared to control group, but this effect was abolished by ABCG2 inhibition. Our results suggest that the absence of mitochondrial toxicity in the fetal brain after chronic in utero administration of AZT could be attributed to its low accumulation in the tissue caused, at least in part, by ABCG2 overexpression. We propose that any interference with ABCG2 activity due to genetic, pathological or iatrogenic factors would increase the amount of AZT reaching the fetal brain, which could increase the risk of toxicity of this drug on the tissue.Fil: Filia, Maria Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: Marchini, Timoteo Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; ArgentinaFil: Minoia, Juan Mauricio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: Roma, Martin Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: de Fino, Fernanda Teresa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: Rubio, Modesto Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: Copello, Guillermo Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Metabolismo del Fármaco; ArgentinaFil: Evelson, Pablo Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; ArgentinaFil: Peroni, Roxana Noemi. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentin

Nascidos vivos com fenda palatina e labial: estudo epidemiológico

Introduction: Cleft lip and palate is a congenital malformation resulting from the inadequate fusion of bony structures during embryonic development. The etiology is multifactorial, involving genetic and environmental factors. Methodology: This study constitutes a descriptive epidemiological analysis focusing on the investigation of cases of live births with cleft lip and palate in Brazil. Data collection will be conducted through the Live Birth Information System (SINASC) during the period from 2017 to 2021. Results: The gender distribution of live births with cleft lip and palate indicates a male predominance in the sample, representing approximately 58.49% (n=4,390) of the total. Meanwhile, the percentage of female individuals is approximately 41.01% (n=3,078). The category "Unknown" has a very small representation, accounting for only 0.51% (n=38) of the sample. Conclusion: It is observed that live births with cleft lip and palate should not be overlooked. There is a significant number of cases each year, necessitating further related studies to provide solutions in society that directly benefit those affected.Introdução: A fenda labial e palatina é uma malformação congênita resultante da não fusão das estruturas ósseas adequadas durante o desenvolvimento embrionário. A etiologia é multifatorial, envolvendo fatores genéticos e ambientais. Metodologia: Este estudo constitui uma análise epidemiológica descritiva com enfoque na investigação dos casos de nascidos vivos com fenda labial e palatina no Brasil. A coleta de dados será realizada por meio do Sistema de Informações sobre Nascidos Vivos (SINASC) durante o período de 2017 a 2021. Resultado: A distribuição de gênero dos nascidos vivos com fenda labial e palatina indica que há uma maioria masculina na amostra, representando cerca de 58,49%  (n= 4.390) do total. Enquanto isso, a porcentagem de pessoas do sexo feminino é de aproximadamente 41,01% (n = 3.078) A categoria "Ignorado" tem uma representação muito pequena, com apenas 0,51% (n = 38) da amostra. Conclusão: Observa-se que os nascidos vivos com fenda labial e palatina não devem ser negligenciados. Há uma quantidade significativa de nascidos por ano, sendo indispensável mais estudos relacionados, a fim de trazer soluções na sociedade que beneficiem diretamente os acometidos

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Delivering patient-centered care: outcomes of comprehensive geriatric assessment across healthcare settings

Comprehensive geriatric assessment (CGA) is a systematic multidimensional and interdisciplinary evaluation that enables clinicians to recognize age-related impairments and develop a coordinated treatment plan and follow-up suited to the patient’s needs. Considering the growing number of older persons requiring care in health systems everywhere and the importance of shifting from a disease-specific care model to a more comprehensive care model, we aimed to present the benefits of CGA for older people in different healthcare settings using a narrative review. This patient-centered model of care has been associated with lower hospital (re)admission, maintenance of function, improved quality of life, less caregiver burden, and higher patient satisfaction with the care provided across different healthcare settings. In some contexts — for example, hospitalized older people —, CGA has already been established as the standard model of care as it was consistently related to reduced mortality. Consistent findings from specific contexts (eg, oncology, orthopaedics) also show the importance of CGA in aiding clinicians make better decisions for older patients. It is noteworthy that further evidence from cost-effectiveness studies is still warranted, particularly in community settings. Another encouraging topic for future research is the role of technology in disseminating CGA-based models of care.</p

Influence of milking management techniques and technologies on milk quality

The objectives of this study were to verify if the use of techniques and technologies involved in milking activity influence milk quality of small dairy farms, before and after technical training. The experiment was carried out in the northeastern region of Sao Paulo state with 36 dairy producers assisted by the CATI Leite program. Visits were carried out at the farms and a semi-structured questionnaire was applied to collect milking management information and mastitis identification techniques. All questionnaires were answered by the farmers (completed by the CATI agents). Milk samples were collected monthly from the bulk milk tank from March to June 2016, before technical training, and from March to June 2017, after technical training. Technical training related to the management of milking and control of mastitis was carried out by the CATI agents, who also provided technical assistance to the farmers participating in this experiment. The data were analyzed by frequencies, through the SAS 9.2 program. According to the somatic cell count (SCC) values specified in Normative Instruction 7 (NI-7) from the Brazilian Ministry of Agriculture, two classes were established: class 1: less than or equal to 400,000 cells/mL, and class 2, greater than 400,000 cells/mL. For total bacterial count (TBC), two classes were established: class 1: less than or equal to 100,000 cfu/mL, and class 2: greater than 100,000 cfu/mL. The frequencies were determined by contrasting the calves’ presence during milking (C1 = no, C2 = yes) versus SCC class versus training class (1 = before, 2 = after training). For TBC, the frequencies were determined by contrasting the type of milking (1 = bucket milking system, 2 = does not use bucket milking system) versus TBC class versus training class (1 = before and 2 = after training). For TBC, 42.55% of the producers using bucket milking system were classified in class 1 (values less than or equal to 100,000 cfu/mL) before technical training, while after the training the figure was 57.45%. The increase in the frequency of class 1 is due to the adoption of good hygiene practices of the milking instruments and shorter cooling time of the milk, an improvement of 14 percentage points. For the SCC results regarding the calves’ presence during milking, 44.04% of the producers were classified as class 1 (values less than or equal to 400,000 cells/mL) before training, while the figure afterward was 55.96%, an increase of almost 12 percentage points, in compliance with NI-7 standards. As conclusion, the use of milking techniques and technologies can improve milk quality for SCC and TBC parameters, as defined in NI-7, but requires intensification and expansion of training programs for technicians and extension agent aimed at improving milk quality and sustainability of milk productio

Action of permethrin on Rhipicephalus sanguineus (Latreille, 1806) (Acari: Ixodidae) semi-engorged females: Morpho-physiological evaluation of salivary glands

Currently the most effective method of tick control is the use of acaricides, among which stands out permethrin (active ingredient of acaricide Advantage (R) Max3, Bayer), a neurotoxic pyrethroid. However, assessments of their effects on other tick systems such as glandular are still scarce. Thus, this study provides information, through histochemical techniques, about the toxic effect of this pyrethroid on the morphophysiology of salivary glands of semi-engorged Rhipicephalus sanguineus females exposed to different concentrations of permethrin (206, 1031, and 2062 ppm). The results showed that permethrin caused significant changes in the salivary gland metabolism accelerating the process of glandular degeneration, an event which would occur naturally and with great intensity only in the final engorgement stage. Furthermore, this study pointed out that permethrin reduces the salivary gland secretion ability through a drastic reduction of proteins, lipids, and polysaccharides in acinar cells. These changes impair the females to finalize the feeding process, what indirectly affects the reproductive process. (c) 2012 Elsevier GmbH. All rights reserved.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Cytotoxic effects of permethrin in salivary glands of Rhipicephalus sanguineus (Latreille, 1806) (Acari: Ixodidae) semi-engorged females

Because of the medical and veterinary importance of ticks and the wide use of synthetic chemical substances such as permethrin (active ingredient of Advantage(R) Max3 - Bayer)for their control, this study evaluated the effects of different concentrations (206, 1031 and 2062 ppm) of the acaricide on the salivary glands of Rhipicephalus sanguineus semi-engorged females. Results showed that permethrin is a potent substance that acts morpho-physiologically in the tick glandular tissue, causing changes in the acini shape intense vacuolation in acinar cells, and disruption of the tissue by cell death process, with subsequent formation of apoptotic bodies, especially at higher concentrations, thus precluding the accurate identification of different types of acini. Importantly, it is demonstrated that permethrin acts on salivary gland tissue, as well as affecting the nervous system, accelerating the process of glandular degeneration, and interfering with the engorgement process of female ticks, preventing them from completing the feeding process. (C) 2011 Elsevier B.V. All rights reserved.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq