Combining renin-angiotensin system blockade and sodium-glucose cotransporter-2 inhibition in experimental diabetes results in synergistic beneficial effects.

BACKGROUND: Sodium-glucose cotransporter-2 (SGLT2) inhibition exerts cardioprotective and renoprotective effects, often on top of renin-angiotensin system (RAS) blockade. We investigated this in diabetic hypertensive (mREN2)27 rats. METHODS: Rats were made diabetic with streptozotocin and treated with vehicle, the angiotensin receptor blocker valsartan, the SGLT2 inhibitor empagliflozin, or their combination. Blood pressure (BP) was measured by telemetry. RESULTS: Diabetes resulted in albuminuria, accompanied by glomerulosclerosis, without a change in glomerular filtration rate. Empagliflozin did not lower BP, while valsartan did, and when combined the BP drop was largest. Only dual blockade reduced cardiac hypertrophy and prevented left ventricular dilatation. Valsartan, but not empagliflozin, increased renin, and the largest renin rise occurred during dual blockade, resulting in plasma angiotensin II [but not angiotensin-(1-7)] upregulation. In contrast, in the kidney, valsartan lowered angiotensin II and angiotensin-(1-7), and empagliflozin did not alter this. Although both valsartan and empagliflozin alone tended to diminish albuminuria, the reduction was significant only when both drugs were combined. This was accompanied by reduced glomerulosclerosis, no change in glomerular filtration rate, and a favorable expression pattern of fibrosis and inflammatory markers (including SGLT2) in the kidney. CONCLUSION: RAS blockade and SGLT2 inhibition display synergistic beneficial effects on BP, kidney injury and cardiac hypertrophy in a rat with hypertension and diabetes. The synergy does not involve upregulation of angiotensin-(1-7), but may relate to direct RAS-independent effects of empagliflozin in the heart and kidney.

The right ventricle in tetralogy of Fallot: adaptation to sequential loading.

Right ventricular dysfunction is a major determinant of outcome in patients with complex congenital heart disease, as in tetralogy of Fallot. In these patients, right ventricular dysfunction emerges after initial pressure overload and hypoxemia, which is followed by chronic volume overload due to pulmonary regurgitation after corrective surgery. Myocardial adaptation and the transition to right ventricular failure remain poorly understood. Combining insights from clinical and experimental physiology and myocardial (tissue) data has identified a disease phenotype with important distinctions from other types of heart failure. This phenotype of the right ventricle in tetralogy of Fallot can be described as a syndrome of dysfunctional characteristics affecting both contraction and filling. These characteristics are the end result of several adaptation pathways of the cardiomyocytes, myocardial vasculature and extracellular matrix. As long as the long-term outcome of surgical correction of tetralogy of Fallot remains suboptimal, other treatment strategies need to be explored. Novel insights in failure of adaptation and the role of cardiomyocyte proliferation might provide targets for treatment of the (dysfunctional) right ventricle under stress.

Guiding Interventions for Secondary Tricuspid Regurgitation: Follow the Intricate Interplay Between Form and Function.

Secondary tricuspid regurgitation (TR) has long been considered a benign and well-tolerated valvular lesion that resolves after treatment of the underlying disease. This view has been challenged by data indicating that long-standing TR can be a progressive disorder, contributing to right ventricular failure and end-organ damage, despite adequate treatment of the underlying disease. Surgical correction is curative, but infrequently performed and historically associated with poor outcomes. This may be due to delayed diagnosis, lack of well-defined surgical indications, and, consequently, late intervention in patients in poor clinical condition with failing right ventricles. Because of limited evidence about timing and corresponding outcome of tricuspid valve surgery, current guideline recommendations are rather conservative and show several inconsistencies. Nevertheless, there has been a trend toward a more aggressive approach in the surgical treatment of TR with improved outcomes. Moreover, emerging transcatheter options claim to provide a lower-risk alternative for selected patients. This may facilitate earlier treatment and improve the attitude toward an early treatment strategy of secondary TR, yet is not reflected in the guidelines. Future research is needed for risk stratification to determine inclusion criteria and optimal timing for intervention.

Smo-Shh signaling activator purmorphamine ameliorates neurobehavioral, molecular, and morphological alterations in an intracerebroventricular propionic acid-induced experimental model of autism.

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disease characterized by cognitive and sensorimotor impairment. Numerous research findings have consistently shown that alteration of Smo-Shh (smoothened-sonic hedgehog) signaling during the developmental process plays a significant role in ASD and triggers neuronal changes by promoting neuroinflammation and apoptotic markers. Purmorphamine (PUR), a small purine-derived agonist of the Smo-Shh pathway, shows resistance to hippocampal neuronal cell oxidation and decreases neuronal cell death. The goal of this study was to investigate the neuroprotective potential of PUR in brain intoxication induced by intracerebroventricular-propionic acid (ICV-PPA) in rats, with a focus on its effect on Smo-Shh regulation in the brain of rats. In addition, we analyze the impact of PUR on myelin basic protein (MBP) and apoptotic markers such as Caspase-3, Bax (pro-apoptotic), and Bcl-2 (anti-apoptotic) in rat brain homogenates. Chronic ICV-PPA infusion was administered consecutively for 11 days to induce autism in rats. In order to investigate behavioral alterations, rats were tested for spatial learning in the Morris Water Maze (MWM), locomotive alterations using actophotometer, and beam crossing task, while Forced Swimming Test (FST) for depressive behavior. PUR treatment with 5 mg/kg and 10 mg/kg (i.p.) was administered from day 12 to 44. Besides cellular, molecular and neuroinflammatory analyses, neurotransmitter levels and oxidative markers have also been studied in brain homogenates. The results of this study have shown that PUR increases the level of Smo-Shh and restores the neurochemical levels, and potentially prevents morphological changes, including demyelination.

Therapeutic potential of bioactive compounds from Punica granatum extracts against aging and complicity of FOXO orthologue DAF-16 in Caenorhabditis elegans.

Some natural fruits have significant importance in improving health which provides many nutritional supplements essential to maintain proper metabolism with the age. In this study, phytochemical screening of extract (methanolic) of Punica granatum arils, outer and inner peels was confirmed by the respective spot tests. Quantification of phytochemical constituents revealed the plentiful of total phenols in the outer peels in comparison to inner peels and juice whereas total flavonoids and vitamin C are abundant in inner peel and juice, respectively. High-performance liquid chromatography, Gas chromatography along with mass spectrometry and Fourier-transform infrared spectroscopy analysis revealed the presence of compound 9, 17-octadecadienal, (Z) in the outer/inner peels. A compound N-hexadecanoic acid was also observed in the outer peels. Extracts from every section of the fruits were comprehensively evaluated for their antioxidant activity. Contrary to fruit aril juice, the extracts of outer and inner peels exhibited significant and dose-dependent in vitro antioxidant and radical-scavenging potentials. The supplementation of P. granatum extracts (PGEs) significantly enhanced the lifespan of C. elegans. The protective effect of PGEs was also observed against oxidative stress in C. elegans. Additionally, the involvement of FOXO orthologue DAF-16 dependent longevity was obtained with PGEs (outer peel and inner peel) fed TJ356 worms. Overall, the results indicate the vital role of PGEs especially the extracts of outer peels in life-saving mechanisms of C. elegans by virtue of their antioxidant asset and life-prolonging effects via daf-16 dependent Insulin signaling pathway. See also Figure 1(Fig. 1).

Identification of the inverted chromosome 16 using chromosome painting.

The inverted chromosome 16 is commonly associated with acute myelomonocytic leukaemia (AML) M4 with bone marrow eosinophilia. Cytogenetic identification of the inverted chromosome 16 can be difficult. To help identify the inversion in bone marrow samples from patients referred for the diagnosis of AML-M4, we applied the molecular cytogenetic technique of chromosome painting using chromosome 16 p-arm paint. The results were concordant with standard chromosome analyses and clearly allowed for the identification of a pericentric inversion within chromosome 16 even in poor-quality metaphase spreads.

[Value of sonography in prolonged neonatal jaundice. Findings in 13 cases]. / Place de l'échographie dans l'ictère néonatal prolongé. A propos de 13 cas.

BACKGROUND: Different conditions are associated with a prolonged cholestatic jaundice in the neonatal period: viral hepatitis, biliary atresia and choledocal cyst are the most frequent causes. Laboratory findings are necessary, although they do not permit an etiologic diagnosis in all cases. Serial ultrasonographic study could be proposed for the evaluation of biliary excretion before and after feeding, in order to differentiate between these three conditions. PATIENTS AND METHODS: Between February 1993 and January 1997, 13 newborns (seven girls and six boys) aged from 30 to 186 days, presented with jaundice and conjugated hyperbilirubinemia. They were evaluated by laboratory tests; serial ultrasonographic examinations were performed after 4 hours fasting then 1 and 2 hours after meal. RESULTS: The gallbladder (GB) was visualized in nine patients. In five of these patients, it contracted after feeding suggesting the diagnosis of neonatal hepatitis, that was confirmed by the clinical evolution. In three patients, the GB did not change in size and the diagnosis of biliary atresia was surgically proven. In one patient, a choledocal cyst was visualized and confirmed by surgery. The GB was not identified after 4 hours of fasting in four patients; biliary atresia was suspected and confirmed by surgery. CONCLUSION: Serial ultrasound of the GB is an easy and non-invasive method. It was useful in identifying those conditions requiring surgery in eight patients. We recommend its use as the initial method in the evaluation of neonatal jaundice before the other invasive methods.

Ictal cerebral blood flow in seizures originating in the posterolateral cortex.

UNLABELLED: In selecting patients for epilepsy surgery, it is important to distinguish mesial temporal seizures from seizures originating in the posterolateral cortex. We studied ictal cerebral perfusion in five patients with complex partial seizures with clear posterior EEG ictal onsets and clinical seizures semiology suggesting seizure origin in the posterolateral cortex. METHODS: Ictal SPECT was performed during video EEG monitoring using 99mTc-HMPAO as a cerebral perfusion tracer and a rotating gamma camera to acquire images. RESULTS: Three patterns of ictal hyperperfusion were seen: pattern A = temporoparieto-occipital junction extending into the lateral temporal cortex, involving the mesial temporal cortex and basal ganglia to a lesser degree and a small area of hyperperfusion in the contralateral parietal cortex (two patients); pattern B = pattern A but with no hyperperfusion of the mesial temporal cortex (one patient); and pattern C = localized hyperperfusion in the area of the temporoparieto-occipital junction (two patients). CONCLUSION: Our results suggest distinct patterns of ictal perfusion in seizures with posterolateral ictal EEG onsets. Ictal SPECT may be useful in distinguishing such seizures.

Immunodiagnosis of ocular chlamydial infection.

The diagnostic roles of enzyme immunoassay and indirect immunofluorescence tests were studied in 99 patients with various grades of active trachoma and in 72 patients with inactive trachoma. Normal individuals and patients with non-specific chronic conjunctivitis were used as a control group. Chlamydial antigens were detected in the conjunctival swabs from a large proportion of patients with severe or moderate trachoma. Cases with 'antigen-negative' but clinically severe trachoma showed presence of specific IgG in the blood, thus indicating that serological tests may complement the ELISA test for the detection of chlamydia in infected tissues. The nature of cellular reaction in the conjunctiva seems to be related to the severity of trachoma and presence of the infective organism. 'Antigen-negative' trachoma thus represents either an error of diagnosis or limited sensitivity of currently available immunologic techniques, or a predominantly hypersensitivity state triggered by transient tissue parasitism. Recombinant DNA technology and chronobiologic study of infiltrating lymphocytes are likely to provide some insight in such cases.