Hyperaldosteronism and hyperparathyroidism. A disturbing friendship.

Classically, aldosterone actions are associated with the stability of the effective circulating volume and with blood pressure control, while parathormone actions are linked to bone mineral metabolism, calcium, and phosphate homeostasis. Nevertheless, the relationship between these two hormonal axes surpasses these areas. A bidirectional interrelation between calcium-phosphorus metabolism and blood pressure control can lead to alterations in both. This can have significant implications for the evolution and treatment of patients. To illustrate this relationship, we present two clinical cases that demonstrate the pathophysiology involved.).

Pharmacokinetics and Endocrine Effects of an Oral Dose of D-Pinitol in Human Fasting Healthy Volunteers.

The present study characterizes the oral pharmacokinetics of D-Pinitol, a natural insulin mimetic inositol, in human healthy volunteers (14 males and 11 females). D-Pinitol absorption was studied in (a) subjects receiving a single oral dose of 15 mg/kg (n = 10), or (b) 5 mg/kg pure D-Pinitol (n = 6), and (c) subjects receiving D-Pinitol as part of carbohydrate-containing carob pods-derived syrup with a 3.2% D-Pinitol (Dose of 1600 mg/subject, n = 9). The volunteers received a randomly assigned single dose of either D-Pinitol or carob pod-derived syrup. Blood samples were collected at 0, 15, 30, 45, 60, 90, 120, 180, 240, 360 and 1440 min after intake. Plasma concentration of D-Pinitol was measured and pharmacokinetic parameters obtained. The data indicate that when given alone, the oral absorption of D-Pinitol is dose-dependent and of extended duration, with a Tmax reached after almost 4 h, and a half-life greater than 5 h. When the source of D-Pinitol was a carob pods-derived syrup, Cmax was reduced to 40% of the expected based on the data of D-Pinitol alone, suggesting a reduced absorption probably because of competition with monosaccharide transport. In this group, Tmax was reached before that of D-Pinitol alone, but the estimated half-life remained the same. In the D-Pinitol groups, plasma concentrations of glucose, insulin, glucagon, ghrelin, free fatty acids, and pituitary hormones were additionally measured. A dose of 15 mg/kg of D-Pinitol did not affect glucose levels in healthy volunteers, but reduced insulin and increased glucagon and ghrelin concentrations. D-Pinitol did not increase other hormones known to enhance plasma glucose, such as cortisol or GH, which were surprisingly reduced after the ingestion of this inositol. Other pituitary hormones (gonadotropins, prolactin, and thyroid-stimulating hormone) were not affected after D-Pinitol ingestion. In a conclusion, D-Pinitol is absorbed through the oral route, having an extended half-life and displaying the pharmacological profile of an endocrine pancreas protector, a pharmacological activity of potential interest for the treatment or prevention of insulin resistance-associated conditions.

Endocrine and Metabolic Impact of Oral Ingestion of a Carob-Pod-Derived Natural-Syrup-Containing D-Pinitol: Potential Use as a Novel Sweetener in Diabetes.

The widespread use of added sugars or non-nutritive sweeteners in processed foods is a challenge for addressing the therapeutics of obesity and diabetes. Both types of sweeteners generate health problems, and both are being blamed for multiple complications associated with these prevalent diseases. As an example, fructose is proven to contribute to obesity and liver steatosis, while non-nutritive sweeteners generate gut dysbiosis that complicates the metabolic control exerted by the liver. The present work explores an alternative approach for sweetening through the use of a simple carob-pod-derived syrup. This sweetener consists of a balanced mixture of fructose (47%) and glucose (45%), as sweetening sugars, and a functional natural ingredient (D-Pinitol) at a concentration (3%) capable of producing active metabolic effects. The administration of this syrup to healthy volunteers (50 g of total carbohydrates) resulted in less persistent glucose excursions, a lower insulin response to the hyperglycemia produced by its ingestion, and an enhanced glucagon/insulin ratio, compared to that observed after the ingestion of 50 g of glucose. Daily administration of the syrup to Wistar rats for 10 days lowered fat depots in the liver, reduced liver glycogen, promoted fat oxidation, and was devoid of toxic effects. In addition, this repeated administration of the syrup improved glucose handling after a glucose (2 g/kg) load. Overall, this alternative functional sweetener retains the natural palatability of a glucose/fructose syrup while displaying beneficial metabolic effects that might serve to protect against the progression towards complicated obesity, especially the development of liver steatosis.

More difficult still: Treating severe rapidly progressive glomerulonephritis in the context of COVID-19 pneumonia. / Más difícil todavía: tratar una glomerulonefritis rápidamente progresiva grave en el seno de una neumonía por COVID-19.

We present the case of a male patient with severe SARS-CoV-2 pneumonia, with simultaneous onset of p-ANCA positive rapidly progressive glomerulonephritis. We discuss the different therapeutic possibilities, emphasising the appropriateness of their administration according to the time in the course of the infection.

Systemic thrombosis in a large cohort of COVID-19 patients despite thromboprophylaxis: A retrospective study.

BACKGROUND: Incidence of thrombotic events associated to Coronavirus disease-2019 (COVID-19) is difficult to assess and reported rates differ significantly. Optimal thromboprophylaxis is unclear. OBJECTIVES: We aimed to analyze the characteristics of patients with a confirmed thrombotic complication including inflammatory and hemostatic parameters, compare patients affected by arterial vs venous events and examine differences between survivors and non-survivors. We reviewed compliance with thromboprophylaxis and explored how the implementation of a severity-adjusted protocol could have influenced outcome. METHODS: Single-cohort retrospective study of COVID-19 patients admitted, from March 3 to May 3 2020, to the Infanta Leonor University Hospital in Madrid, epicenter of the Spanish outbreak. RESULTS: Among 1127 patients, 80 thrombotic events were diagnosed in 69 patients (6.1% of the entire cohort). Forty-three patients (62%) suffered venous thromboembolism, 18 (26%) arterial episodes and 6 (9%) concurrent venous and arterial thrombosis. Most patients (90%) with a confirmed thrombotic complication where under low-molecular-weight heparin treatment. Overt disseminated intravascular coagulation (DIC) was rare. Initial ISTH DIC score and pre-event CRP were significantly higher among non-survivors. In multivariate analysis, arterial localization was an independent predictor of mortality (OR = 18, 95% CI: 2.4-142, p < .05). CONCLUSIONS: Despite quasi-universal thromboprophylaxis, COVID-19 lead to a myriad of arterial and venous thrombotic events. Considering the subgroup of patients with thrombotic episodes, arterial events appeared earlier in the course of disease and conferred very poor prognosis, and an ISTH DIC score ≥ 3 at presentation was identified as a potential predictor of mortality. Severity-adjusted thromboprophylaxis seemed to decrease the number of events and could have influenced mortality. Randomized controlled trials are eagerly awaited.

Imbalance of Endocannabinoid/Lysophosphatidylinositol Receptors Marks the Severity of Alzheimer's Disease in a Preclinical Model: A Therapeutic Opportunity.

Alzheimer's disease (AD) is the most common form of neurodegeneration and dementia. The endocannabinoid (ECB) system has been proposed as a novel therapeutic target to treat AD. The present study explores the expression of the ECB system, the ECB-related receptor GPR55, and cognitive functions (novel object recognition; NOR) in the 5xFAD (FAD: family Alzheimer's disease) transgenic mouse model of AD. Experiments were performed on heterozygous (HTZ) and homozygous (HZ) 11 month old mice. Protein expression of ECB system components, neuroinflammation markers, and ß-amyloid (Aß) plaques were analyzed in the hippocampus. According to the NOR test, anxiety-like behavior and memory were altered in both HTZ and HZ 5xFAD mice. Furthermore, both animal groups displayed a reduction of cannabinoid (CB1) receptor expression in the hippocampus, which is related to memory dysfunction. This finding was associated with indirect markers of enhanced ECB production, resulting from the combination of impaired monoacylglycerol lipase (MAGL) degradation and increased diacylglycerol lipase (DAGL) levels, an effect observed in the HZ group. Regarding neuroinflammation, we observed increased levels of CB2 receptors in the HZ group that positively correlate with Aß's accumulation. Moreover, HZ 5xFAD mice also exhibited increased expression of the GPR55 receptor. These results highlight the importance of the ECB signaling for the AD pathogenesis development beyond Aß deposition.

Oxidative stress modulates rearrangement of endoplasmic reticulum-mitochondria contacts and calcium dysregulation in a Friedreich's ataxia model.

Friedreich ataxia (FRDA) is a neurodegenerative disorder characterized by neuromuscular and neurological manifestations. It is caused by mutations in the FXN gene, which results in loss of the mitochondrial protein frataxin. Endoplasmic Reticulum-mitochondria associated membranes (MAMs) are inter-organelle structures involved in the regulation of essential cellular processes, including lipid metabolism and calcium signaling. In the present study, we have analyzed in both, unicellular and multicellular models of FRDA, calcium management and integrity of MAMs. We observed that function of MAMs is compromised in our cellular model of FRDA, which was improved upon treatment with antioxidants. In agreement, promoting mitochondrial calcium uptake was sufficient to restore several defects caused by frataxin deficiency in Drosophila Melanogaster. Remarkably, our findings describe for the first time frataxin as a member of the protein network of MAMs, where interacts with two of the main proteins implicated in endoplasmic reticulum-mitochondria communication. These results suggest a new role of frataxin, indicate that FRDA goes beyond mitochondrial defects and highlight MAMs as novel therapeutic candidates to improve patient's conditions.

Millennial climate oscillations controlled the structure and evolution of Termination II.

The controls that affect the structure and timing of terminations are still poorly understood. We studied a tufa deposit from the Iberian Peninsula that covers Termination II (T-II) and whose chronology was synchronized to speleothem records. We used the same chronology to synchronize ocean sediments from the North Atlantic to correlate major climate events in a common timescale. We identify two stages within T-II. The first stage started with the increase of boreal summer integrated solar insolation, and during this stage three millennial climate oscillations were recorded. These oscillations resulted from complex ocean-atmosphere interactions in the Nordic seas, caused by the progressive decay of Northern Hemisphere ice-sheets. The second stage commenced after a glacial outburst that caused the collapse of the Thermohaline Circulation, a massive Heinrich event, and the onset of the Bipolar Seesaw Mechanism (BSM) that eventually permitted the completion of T-II. The pace of the millennial oscillations during the first stage of T-II controlled the onset of the second stage, when the termination became a non-reversible and global phenomenon that accelerated the deglaciation. During the last the two terminations, the BSM was triggered by different detailed climate interactions, which suggests the occurrence of different modes of terminations.

D-Chiro-Inositol Treatment Affects Oocyte and Embryo Quality and Improves Glucose Intolerance in Both Aged Mice and Mouse Models of Polycystic Ovarian Syndrome.

Polycystic ovarian syndrome (PCOS) is the main cause of female infertility. It is a multifactorial disorder with varying clinical manifestations including metabolic/endocrine abnormalities, hyperandrogenism, and ovarian cysts, among other conditions. D-Chiro-inositol (DCI) is the main treatment available for PCOS in humans. To address some of the mechanisms of this complex disorder and its treatment, this study examines the effect of DCI on reproduction during the development of different PCOS-associated phenotypes in aged females and two mouse models of PCOS. Aged females (8 months old) were treated or not (control) with DCI for 2 months. PCOS models were generated by treatment with dihydrotestosterone (DHT) on Days 16, 17, and 18 of gestation, or by testosterone propionate (TP) treatment on the first day of life. At two months of age, PCOS mice were treated with DCI for 2 months and their reproductive parameters analyzed. No effects of DCI treatment were produced on body weight or ovary/body weight ratio. However, treatment reduced the number of follicles with an atretic cyst-like appearance and improved embryo development in the PCOS models, and also increased implantation rates in both aged and PCOS mice. DCI modified the expression of genes related to oocyte quality, oxidative stress, and luteal sufficiency in cumulus-oocyte complexes (COCs) obtained from the aged and PCOS models. Further, the phosphorylation of AKT, a main metabolic sensor activated by insulin in the liver, was enhanced only in the DHT group, which was the only PCOS model showing glucose intolerance and AKT dephosphorylation. The effect of DCI in the TP model seemed mediated by its influence on oxidative stress and follicle insufficiency. Our results indicate that DCI works in preclinical models of PCOS and offer insight into its mechanism of action when used to treat this infertility-associated syndrome.

D-Pinitol from Ceratonia siliqua Is an Orally Active Natural Inositol That Reduces Pancreas Insulin Secretion and Increases Circulating Ghrelin Levels in Wistar Rats.

To characterize the metabolic actions of D-Pinitol, a dietary inositol, in male Wistar rats, we analyzed its oral pharmacokinetics and its effects on (a) the secretion of hormones regulating metabolism (insulin, glucagon, IGF-1, ghrelin, leptin and adiponectin), (b) insulin signaling in the liver and (c) the expression of glycolytic and neoglucogenesis enzymes. Oral D-Pinitol administration (100 or 500 mg/Kg) resulted in its rapid absorption and distribution to plasma and liver compartments. Its administration reduced insulinemia and HOMA-IR, while maintaining glycaemia thanks to increased glucagon activity. In the liver, D-Pinitol reduced the key glycolytic enzyme pyruvate kinase and decreased the phosphorylation of the enzymes AKT and GSK-3. These observations were associated with an increase in ghrelin concentrations, a known inhibitor of insulin secretion. The profile of D-Pinitol suggests its potential use as a pancreatic protector decreasing insulin secretion through ghrelin upregulation, while sustaining glycaemia through the liver-based mechanisms of glycolysis control.

Hedgehog Signaling Modulates Glial Proteostasis and Lifespan.

The conserved Hedgehog signaling pathway has well-established roles in development. However, its function during adulthood remains largely unknown. Here, we investigated whether the Hedgehog signaling pathway is active during adult life in Drosophila melanogaster, and we uncovered a protective function for Hedgehog signaling in coordinating correct proteostasis in glial cells. Adult-specific depletion of Hedgehog reduces lifespan, locomotor activity, and dopaminergic neuron integrity. Conversely, increased expression of Hedgehog extends lifespan and improves fitness. Moreover, Hedgehog pathway activation in glia rescues the lifespan and age-associated defects of hedgehog mutants. The Hedgehog pathway regulates downstream chaperones, whose overexpression in glial cells was sufficient to rescue the shortened lifespan and proteostasis defects of hedgehog mutants. Finally, we demonstrate the protective ability of Hedgehog signaling in a Drosophila Alzheimer's disease model expressing human amyloid beta in the glia. Overall, we propose that Hedgehog signaling is requisite for lifespan determination and correct proteostasis in glial cells.

Immunosuppression as a trigger for hyperinflammatory syndrome due to Strongyloides stercolaris in membranous nephropathy. / Inmunosupresión como desencadenante de un síndrome de hiperinfestación por Strongyloides stercolaris en la nefropatía membranosa.

The relationship between parasites and glomerulonephritis (GN) is well documented in certain parasitoses, but not in cases of Strongyloides stercolaris (S. stercolaris) where there are few cases described being the majority GN of minimal changes. We report a case of hyperinfestation by S. stercolaris in a patient affected by a membranous GN treated with oral corticosteroids with fatal outcome for the patient. This case provides a double teaching: first about a rare association of strongyloid and membranous GN and second about the importance of establishing a diagnosis of suspected and appropriate treatment for certain infections or diseases with little clinical expression before starting any immunosuppressive treatment.