Role of Oestrogen Receptors on the Modulation of NADPH‐Diaphorase‐Positive Cell Number in Supraoptic and Paraventricular Nuclei of Ovariectomised Female Rats

Modulation of the nitric oxide producing system (demonstrated via the NADPH‐diaphorase histochemical reaction) by oestradiol has been established in several structures of the rat brain. The present study aimed to explore the possible regulation of NADPH‐diaphorase activity by oestradiol in neurones of the supraoptic (SON) and paraventricular (PVN) nuclei and the role of oestrogen receptors (ERα and ERβ) in this regulation. Adult ovariectomised rats were divided into six groups and injected either with vehicle or a single dose of oestradiol, a selective ERα agonist‐PPT [4,4′,4″‐(4‐propyl‐[1H]‐pyrazole‐1,3,5‐triyl)trisphenol], a selective ERβ agonist‐DPN [2,3‐bis(4‐hydroxyphenyl)‐propionitrile], a selective ERα antagonist‐MPP [1,3‐bis(4‐hydroxyphenyl)‐4‐methyl‐5‐[4‐(2‐piperidinylethoxy)phenol]‐1H‐pyrazole dihydrochloride] or a selective ERβ antagonist‐PHTPP (4‐[2‐phenyl‐5,7‐bis(trifluoromethyl)pyrazolo[1,5‐a]pyrimidin‐3‐yl]phenol). The number of NADPH‐diaphorase positive elements in the SON and the PVN was modulated by both ERs but, depending on the nucleus, ERα and ERβ ligands induced different effects. These results suggest that the regulation of nitrergic system by ERs may play a role in the control of oestrogen‐dependent physiological mechanisms regulated by the SON and the PVN.     

COMPARISON OF METHODS OF CARBAMAZEPINE DOSAGE, INDIVIDUALIZATION IN EPILEPTIC PATIENTS

The aim of the present work was to analyse the predictive capacity of different optimization methods for carbamazepine dosage regimens according to population pharmacokinetic parameters and/or serum levels data. Calculations were performed using a multiple non-linear regression program (MULTI 2 BAYES) with two different options: (a) using the ordinary least squares methods and (b) the least squares method based on the Bayesian algorithm. The predictive capacity of the three methods was analysed comparing the serum levels values in patients predicted by each method and those observed later. The performance obtained was poor and even unacceptable when dosage prediction was based on the mean parameters of the population studied (Method A) and when only one data point relating to the serum carbamazepine levels was available (Method B). When two serum levels data were used the standard deviation of the mean prediction error was only clinically acceptable when Bayesian non-linear regression was applied (Method C). When the number of serum levels data points was 3 or 4 the errors were acceptable from a clinical point of view and no significant differences could be found between the use of the simple and Bayesian version at the same level of information.     

Psychosis in a cocaine-dependent patient with ADHD during treatment with methylphenidate

Objective

The objective was to report a case of experienced psychosis during the treatment with methylphenidate (MPH) in a cocaine-dependent adult treated for attention-deficit/hyperactivity disorder (ADHD) with comorbid cocaine dependence.

Conclusion

ADHD is a frequent comorbidity in substance use disorder (SUD) patients. MPH may be effective in treating ADHD symptoms in SUD patients, thus preventing possible adverse outcomes. Cocaine-induced psychosis may be a risk factor for development of psychosis in the presence of a concurrent treatment with MPH.     

Basic cardiopulmonary resuscitation

Since the introduction of the modern techniques for cardiopulmonary resuscitation in the 1960s, professionals have discussed the need to standardize its application and teaching both among health care professionals and the general public. The "ILCOR", Committee to Coordinate Resuscitation Techniques, in an effort to simplify resuscitation techniques, set out some recommendations in August 2000 which were adopted by the leading organizations such as AHA and ERC, in charge of diffusing Vital Suport techniques. In these, different levels of attention have been incorporated depending on the qualifications which the person has who is provide this treatment. The most important changes are the necessity to put Emergency Medical Services into action rapidly; the techniques to follow if there are one or two persons apply resuscitation techniques; for artificial resuscition emergency care, new volumes depending on the use or non-use of oxygen; the acceptance of devices to open up alternate air passageways; recommendations whether or not it is pertinent to check on a patient's pulse depending on the qualifications of the person attending that patient; heart message techniques exterpulmonary resuscition woth only thorax compression and automatic external defibrillation.     

Golexanolone,a GABAA receptor modulating steroid antagonist,restores motor coordination and cognitive function in hyperammonemic rats by dual effects on peripheral inflammation and neuroinflammation

AimsHyperammonemic rats show peripheral inflammation, increased GABAergic neurotransmission and neuroinflammation in cerebellum and hippocampus which induce motor incoordination and cognitive impairment. Neuroinflammation enhances GABAergic neurotransmission in cerebellum by enhancing the TNFR1‐glutaminase‐GAT3 and TNFR1‐CCL2‐TrkB‐KCC2 pathways. Golexanolone reduces GABA_A receptors potentiation by allopregnanolone. This work aimed to assess if treatment of hyperammonemic rats with golexanolone reduces peripheral inflammation and neuroinflammation and restores cognitive and motor function and to analyze underlying mechanisms.MethodsRats were treated with golexanolone and effects on peripheral inflammation, neuroinflammation, TNFR1‐glutaminase‐GAT3 and TNFR1‐CCL2‐TrkB‐KCC2 pathways, and cognitive and motor function were analyzed.ResultsHyperammonemic rats show increased TNFα and reduced IL‐10 in plasma, microglia and astrocytes activation in cerebellum and hippocampus, and impaired motor coordination and spatial and short‐term memories. Treating hyperammonemic rats with golexanolone reversed changes in peripheral inflammation, microglia and astrocytes activation and restored motor coordination and spatial and short‐term memory. This was associated with reversal of the hyperammonemia‐enhanced activation in cerebellum of the TNFR1‐glutaminase‐GAT3 and TNFR1‐CCL2‐TrkB‐KCC2 pathways.ConclusionReducing GABA_A receptors activation with golexanolone reduces peripheral inflammation and neuroinflammation and improves cognitive and motor function in hyperammonemic rats. The effects identified would also occur in patients with hepatic encephalopathy and, likely, in other pathologies associated with neuroinflammation.     

The Relationship between Serum Adipokines,miR-222-3p,miR-103a-3p and Glucose Regulation in Pregnancy and Two to Three Years Post-Delivery in Women with Gestational Diabetes Mellitus Adhering to Mediterranean Diet Recommendations

The San Carlos Gestational Diabetes Mellitus (GDM) prevention study, a nutritional intervention RCT based on a Mediterranean Diet (MedDiet), has been shown to reduce the incidence of GDM. The objective of this study is to investigate the relationship of leptin, adiponectin, interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-α), insulin and HOMA-IRand circulating miRNAs (miR-29a-3p, miR-103a-3p, miR-132-3p, miR-222-3p) with the appearance of GDM and with MedDiet-based nutritional intervention, at 24–28 gestational weeks (GW), and in glucose regulation 2–3 years post-delivery (PD). A total of 313 pregnant women, 77 with GDM vs. 236 with normal glucose tolerance (NGT), 141 from the control group (CG, MedDiet restricting the consumption of dietary fat including EVOO and nuts during pregnancy) vs. 172 from the intervention group (IG, MedDiet supplemented with extra virgin olive oil (EVOO) and pistachios during pregnancy) were compared at Visit 1 (8–12 GW), Visit 2 (24–28 GW) and Visit 3 (2–3 years PD). Expression of miRNAs was determined by the Exiqon miRCURY LNA RT-PCR system. Leptin, adiponectin, IL-6 and TNF-α, were measured by Milliplex^® immunoassays on Luminex 200 and insulin by RIA. Women with GDM vs. NTG had significantly higher leptin median (Q1–Q3) levels (14.6 (9.2–19.4) vs. 9.6 (6.0–15.1) ng/mL; p < 0.05) and insulin levels (11.4 (8.6–16.5) vs. 9.4 (7.0–12.8) µUI/mL; p < 0.001) and lower adiponectin (12.9 (9.8–17.2) vs. 17.0 (13.3–22.4) µg/mL; p < 0.001) at Visit 2. These findings persisted in Visit 3, with overexpression of miR-222-3p (1.45 (0.76–2.21) vs. 0.99 (0.21–1.70); p < 0.05)) and higher levels of Il-6 and TNF-α. When the IG is compared with the CG lower levels of insulin, HOMA-IR-IR, IL-6 levels at Visit 2 and 3 and leptin levels only at Visit 2 were observed. An overexpression of miR-222-3p and miR-103a-3p were also observed in IG at Visit 2 and 3. The miR-222-3p and miR103a-3p expression correlated with insulin levels, HOMA-IR, IL-6 and TNF-α at Visit 2 (all p < 0.05). These data support the association of leptin, adiponectin and insulin/HOMA-IR with GDM, as well as the association of insulin/HOMA-IR and IL-6 and miR-222-3p and miR-103a-3p expression with a MedDiet-based nutritional intervention.     

Diagnosis of immune thrombocytopenia,including secondary forms,and selection of second-line treatment

This article summarizes our approach to the diagnosis of immune thrombocytopenia (ITP), its secondary forms, and choice of second-line treatment options. We very briefly summarize first-line treatment and then utilize a case-based approach. We first explore persistent, chronic ITP in a younger female. We consider many possibilities beyond primary ITP e.g., hypogammaglobulinemia, chronic infection, and anemia, and how to approach their diagnosis and management. The journey continues throughout pregnancy and the post-partum period and eventually includes fourth-line treatment after a late relapse. We then consider an older male, emphasizing differences in diagnostic considerations and management. The focus is on initiation and continuation of second-line treatment, the pros and cons of each option, and briefly the impact of treatment choices related to the endemic presence of severe acute respiratory syndrome coronavirus 2. During the review of potential second-line treatment options, we also briefly touch upon novel treatments. Finally, there is a short section on refractory disease drawn from our previous extensive review published in February 2020.¹ The clinical nature of the discussions, replete with figures and tables and with the interspersion of pearls regarding efficacy and toxicity at different ages and genders, will serve the reader in the management of “typical” adult patients who develop persistent and chronic ITP.     

Raciocínio Clínico em Cardiologia: Passado,Presente e Futuro

Clinical reasoning was born 2,500 years ago with Hippocrates, having evolved over the centuries, becoming a mixture of art and science. Several personalities throughout history have contributed to improving diagnostic accuracy. Nonetheless, diagnostic error is still common and causes a severe impact on healthcare systems. To face this challenge, several clinical reasoning models have emerged to systematize the clinical thinking process. This paper describes the history of clinical reasoning and current diagnostic reasoning methods, proposes a new clinical reasoning model, called Integrative Reasoning, and brings perspectives about the future of clinical reasoning.