Function of Presynaptic Inhibitory Cannabinoid CB1 Receptors in Spontaneously Hypertensive Rats and Its Modification by Enhanced Endocannabinoid Tone.

We studied whether the function of presynaptic inhibitory cannabinoid CB1 receptors on the sympathetic nerve fibres innervating resistance vessels is increased in spontaneously hypertensive rats (SHR) like in deoxycorticosterone (DOCA)-salt hypertension. An increase in diastolic blood pressure (DBP) was induced by electrical stimulation of the preganglionic sympathetic neurons or by phenylephrine injection in pithed SHR and normotensive Wistar-Kyoto rats (WKY). The electrically (but not the phenylephrine) induced increase in DBP was inhibited by the cannabinoid receptor agonist CP55940, similarly in both groups, and by the endocannabinoid reuptake inhibitor AM404 in SHR only. The effect of CP55940 was abolished/reduced by the CB1 receptor antagonist AM251 (in both groups) and in WKY by endocannabinoid degradation blockade, i.e., the monoacylglycerol lipase (MAGL) inhibitor MJN110 and the dual fatty acid amide hydrolase (FAAH)/MAGL inhibitor JZL195 but not the FAAH inhibitor URB597. MJN110 and JZL195 tended to enhance the effect of CP55940 in SHR. In conclusion, the function of presynaptic inhibitory CB1 receptors depends on the hypertension model. Although no differences occurred between SHR and WKY under basal experimental conditions, the CB1 receptor function was better preserved in SHR when the endocannabinoid tone was increased by the inhibition of MAGL or the endocannabinoid transporter.

Sympathetic System in Wound Healing: Multistage Control in Normal and Diabetic Skin.

In this review, we discuss sympathetic regulation in normal and diabetic wound healing. Experimental denervation studies have confirmed that sympathetic nerve endings in skin have an important and complex role in wound healing. Vasoconstrictor neurons secrete norepinephrine (NE) and neuropeptide Y (NPY). Both mediators decrease blood flow and interact with inflammatory cells and keratinocytes. NE acts in an ambiguous way depending on receptor type. Beta2-adrenoceptors could be activated near sympathetic endings; they suppress inflammation and re-epithelialization. Alpha1- and alpha2-adrenoceptors induce inflammation and activate keratinocytes. Sudomotor neurons secrete acetylcholine (ACh) and vasoactive intestinal peptide (VIP). Both induce vasodilatation, angiogenesis, inflammation, keratinocytes proliferation and migration. In healthy skin, all effects are important for successful healing. In treatment of diabetic ulcers, mediator balance could be shifted in different ways. Beta2-adrenoceptors blockade and nicotinic ACh receptors activation are the most promising directions in treatment of diabetic ulcers with neuropathy, but they require further research.

Effector mechanisms in the baroreceptor control of blood pressure.

While the effects of changing heart rate and systemic vascular resistance have been generally understood and appreciated, the effects of changes in left ventricular contractility on end-systolic volume may have been less understood and appreciated and the effects of changes in venous capacitance on end-diastolic volume may have been unknown to many readers. Herein, we have provided a brief review for the medical student and beginning graduate student highlighting these sometimes-complex relationships.

The Interplay between Autonomic Nervous System and Inflammation across Systemic Autoimmune Diseases.

The autonomic nervous system (ANS) and the immune system are deeply interrelated. The ANS regulates both innate and adaptive immunity through the sympathetic and parasympathetic branches, and an imbalance in this system can determine an altered inflammatory response as typically observed in chronic conditions such as systemic autoimmune diseases. Rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis all show a dysfunction of the ANS that is mutually related to the increase in inflammation and cardiovascular risk. Moreover, an interaction between ANS and the gut microbiota has direct effects on inflammation homeostasis. Recently vagal stimulation techniques have emerged as an unprecedented possibility to reduce ANS dysfunction, especially in chronic diseases characterized by pain and a decreased quality of life as well as in chronic inflammation.

Changes in vascular function and autonomic balance during the first trimester of pregnancy and its relationship with the new-born weight.

This study aimed to evaluate vascular function changes and autonomic balance during the first trimester of pregnancy and its relationship with the new-born weight. This prospective study performed in pregnant (PG) women and after delivery (not pregnant: NPG) evaluated the endothelial function (EF) and arterial stiffness (AS) by a non-invasive method. We evaluated the heart rate variability (HRV), parasympathetic nervous system (PNS), sympathetic nervous system (SNS) indexes by electrocardiogram (5 min) and the urinary nitrite excretion (NOx). PG increased EF and NOx and decreased AS and HRV. PG decreased the PNS index and augmented the SNS index. The new-born weight positively correlated with the PNS index (Pearson's r: 0.4291; p<.05), NOx, HRV and negatively correlated with AS. In summary, in pregnancy, although haemodynamically, the SNS activation plays a compensatory role, the low rates of PNS inhibition are essential to ensure normal foetal growth.Impact StatementWhat is already known on this subject? In pregnancy, there are adaptive physiological changes in the cardiovascular system that include increases of EF and decreases AS with an SNS activation. The study of HRV lets to predict the SNS and PNS balance and how they affect blood pressure and vascular function.What the results of this study add? Although it is known that SNS activation plays a compensatory role in healthy pregnancy, this study adds the critical role of PNS. Early in pregnancy, the low rates of PNS inhibition are essential to ensure normal foetal growth.What the implications are of these findings for clinical practice and/or further research? The present results show a potential predictive value of SNS and PNS activity early in pregnancy. It will provide valuable information not only on the pregnant woman's vascular function but also on the new-born weight.

Increased angiotensin II formation in the brain modulates cardiovascular homeostasis and erythropoiesis.

In spite of the fact that the modulatory effects of angiotensin II (Ang II) on the sympathetic nerve activity to targeted organs involved in blood pressure (BP) regulation is well acknowledged, the local production of this peptide in the brain and the consequences of enhanced central Ang II beyond the cardiovascular system are not yet well comprehended. In the present study, we generated and validated a new transgenic mouse line overexpressing the rat full-length angiotensinogen (Agt) protein specifically in the brain (Agt-Tg). Adult Agt-Tg mice presented overall increased gene expression of total Agt in the brain including brainstem and hypothalamus. In addition, the excess of Agt led to abundantly detectable brain Ang II levels as well as increased circulating copeptin levels. Agt-Tg displayed raised BP in acute recordings, while long-term telemetrically measured basal BP was indistinguishable from wild-types. Agt-Tg has altered peripheral renin-angiotensin system and vasomotor sympathetic tone homeostasis because renal gene expression analysis, plasma Ang II measurements and ganglionic blockade experiments revealed suppressed renin expression and reduced Ang II and higher neurogenic pressure response, respectively. Plasma and urine screens revealed apparently normal fluid and electrolyte handling in Agt-Tg. Interestingly, hematological analyses showed increased hematocrit in Agt-Tg caused by enhanced erythropoiesis, which was reverted by submitting the transgenic mice to a long-term peripheral sympathectomy protocol. Collectively, our findings suggest that Agt-Tg is a valuable tool to study not only brain Ang II formation and its modulatory effects on cardiovascular homeostasis but also its role in erythropoiesis control via autonomic modulation.

Improving the prognosis of renal patients: The effects of blood flow-restricted resistance training on redox balance and cardiac autonomic function.

NEW FINDINGS: What is the central question of this study? Can resistance training with and without blood flow restriction improve redox balance and positively impact the autonomic cardiac modulation in chronic kidney disease patients? What is the main finding and its importance? Resistance training with and without blood flow restriction improved antioxidant defence (paraoxonase 1), decreased the pro-oxidative myeloperoxidase, improved cardiac autonomic function and slowed the decrease in renal function. We draw attention to the important clinical implications for the management of redox balance and autonomic cardiac function in chronic kidney disease patients. ABSTRACT: Patients with chronic kidney disease (CKD) are prone to cardiovascular diseases secondary to abnormalities in both autonomic cardiac function and redox balance [myeloperoxidase (MPO) to paraoxonase 1 (PON1) ratio]. Although aerobic training improves both autonomic balance and redox balance in patients with CKD, the cardioprotective effects of resistance training (RT), with and without blood flow restriction (BFR), remain unknown. We aimed to compare the effects of RT and RT+BFR on antioxidant defence (PON1), pro-oxidative status (MPO), cardiac autonomic function (quantified by heart rate variability analysis) and renal function. Conservative CKD (stages 1 to 5 who do not need hemodialysis) patients (n = 105, 33 female) of both sexes were randomized into three groups: control (CTL; 57.6 ± 5.2 years; body mass index, 33.23 ± 1.62 kg/m2 ), RT (58.09 ± 6.26 years; body mass index 33.63 ± 2.05 kg/m2 ) and RT+BFR (58.06 ± 6.47 years; body mass index, 33.32 ± 1.87 kg/m2 ). Patients completed 6 months of RT or RT+BFR on three non-consecutive days per week under the supervision of strength and conditioning professionals. Training loads were adjusted every 2 months. Heart rate variability was recorded with a Polar-RS800 and data were analysed for time and frequency domains using Kubios software. The redox balance markers were PON1 and MPO, which were analysed in plasma samples. Renal function was estimated as estimated glomerular filtration rate. The RT and RT+BFR decreased pro-oxidative MPO (RT, ∼34 ng/ml and RT+BFR, ∼27 ng/ml), improved both antioxidant defence (PON1: RT, ∼23 U/L and RT+BFR, ∼31 U/L) and cardiac autonomic function (R-R interval: RT, ∼120.4 ms and RT+BFR, ∼117.7 ms), and slowed the deterioration of renal function (P < 0.0001). Redox balance markers were inversely correlated with heart rate variability time-domain indices. Our data indicated that both training models were effective as non-pharmacological tools to increase the antioxidant defences, decrease oxidative stress and improve the cardiac autonomic function of CKD patients.

Renal arteries denervation: from the treatment of resistant hypertension to the treatment of atrial fibrillation.

Renal denervation (RDN) is a therapeutic strategy for patients with uncontrolled arterial hypertension characterized by considerable fluctuations during its progression. After initial strong enthusiasm, the procedure came to an abrupt halt following the publication of the Symplicity HTN-3 study results. The results of recently published studies highlight the reduction in blood pressure values after RDN and justify the inclusion in the Guidelines of new recommendations for the use of RDN in clinical practice, in selected patients. Additionally, RDN findings are summarized in view of other potential indications such as atrial fibrillation. Six prospective, randomized studies are presented that evaluated RDN as an adjunct therapy to pulmonary vein isolation for the treatment of atrial fibrillation. In five studies, patients had uncontrolled hypertension despite therapy with three antihypertensive drugs. The analysis of these studies showed that RDN reduced the recurrence of atrial fibrillation (AF) by 57% compared to patients with pulmonary vein isolation (PVI) only. Modulation of the autonomic nervous system by RDN has been shown not only to reduce blood pressure but also to have an antiarrhythmic effect in symptomatic AF patients when the strategy is combined with PVI, thus opening up new therapeutic scenarios.

Masked hypertension is related to alteration of myocardial arrhythmia Parameters.

BACKGROUND: Imbalance in autonomic nervous system and impaired myocardial repolarization have been shown to increase the risk for arrhythmias in patients with arterial hypertension. This study evaluated the effects of masked hypertension on QT interval dynamicity. METHODS: The study group consisted of 108 consecutive patients with masked hypertension and 102 control subjects. Twenty-four-hour Holter monitoring was performed before anti-hypertensive treatment. CONTEC holter software was used to calculate HRV and QT dynamicity parameters. All subjects had a complete history, laboratory examination, and transthoracic echocardiography. RESULTS: There was no significant difference in age-gender distribution between patients and controls. Non-sustained VT was present in four patients (2.9%). SDNN, RMSSD, PNN50, LFnu, HFnu were significantly decreased in masked hypertension, whereas LF/HF ratio was significantly increased. QT/RR slopes over 24 hours were significantly increased in masked hypertension for QT end and QT apex (QTapex/RR: 0,15 ± 0,12 vs 0,27 ± 0,18 p < .001; QTend/RR: 0.19 ± 0.12 vs 0.35 ± 0.22, p < .001). CONCLUSIONS: This study showed for the first time that masked hypertension was associated with a significant worsening of HRV and QT dynamicity parameters.

CardioMEMS, the real progress in heart failure home monitoring.

The burden of hospitalizations driven by exacerbation of acute heart failure remains unacceptably high. The associated use of hospital resources drives increasing patient, caregiver, and economic costs. Noninvasive telemedical systems investigated in randomized controlled trials have failed to demonstrate to reduce hospitalization rates probably because of the indirect (non-linear) relationship of the measured biological signals with the patient congestion status. Instead, there is increasing evidence that direct measure of intracardiac and pulmonary artery pressure can effectively guide heart failure management and reduce hospitalizations. Early studies adopting implantable hemodynamic monitors in the right heart unveiled the potential of pressure-based heart failure management, whereas subsequent investigations showed the powerful preemptive approach for heart failure exacerbations. One large randomized trial (CHAMPION) proved that a direct pulmonary pressure monitor system (CardioMEMS) substantially reduced heart failure hospitalizations in subjects randomized to active pulmonary pressure-guided management. The system monitoring safety and efficacy were also excellent. The study proved that early management in response to increased pulmonary pressure is able to provide the most effective therapeutic intervention to prevent heart failure exacerbations.

Diabetes and subclinical hypothyroidism on heart rate variability.

BACKGROUND: We aimed to analyse if the effects of coexistent diabetes and subclinical hypothyroidism extend to the cardio autonomic nervous system, using heart rate variability baseline data from the Brazilian Longitudinal Study of Adult Health. MATERIALS AND METHODS: Heart rate variability analyses were performed by linear time and frequency domains in 5-minute time series collected in the supine position. The associations of diabetes and subclinical hypothyroidism with the lowest quartile group for heart rate and the highest quartile group for each heart rate variability parameter were analysed using additive and multiplicative terms in logistic models. For the first approach, the subsample was categorized into four groups: subjects without diabetes and normal thyroid function (controls); subjects without diabetes and subclinical hypothyroidism; patients with diabetes and normal thyroid function; and patients with diabetes and subclinical hypothyroidism. For the interaction alnalysis, diabetes and subclinical hypothyroidism diagnoses were included in separate, along with a multiplicative interaction term between them. RESULTS: Point odds ratio estimates for the 4th quartiles of heart rate, and 1st quartiles of all heart rate variability measurements were higher for subjects with combined diabetes and subclinical hypothyroidism than for diabetes only, independently of main sociodemographic and clinical variables (HR: 8.33 vs 2.63; SDNN: 2.59 vs 1.61; RMSSD: 2.37 vs 1.42; LF: 2.83 vs 1.71; HF: 3.06 vs 1.39), but not independently of HbA1c and TSH. Only the interaction term for the association with heart rate, adjusted for sociodemographic and clinical variables, had borderline statistical significance. CONCLUSION: Diabetes and subclinical hypothyroidism exert a potential joint impact on cardiac autonomic control, showed by additive effects between diabetes and subclinical hypothyroidism, as well as a significant interaction term for the association with heart rate.

Orthostatic change in systolic blood pressure associated with cold pressor reflection and heart rate variability in the elderly.

Background: Impaired orthostatic blood pressure (BP) response is a frequent finding in the elderly. The goal of the study was to investigate the association of variability of supine-to-orthostatic BP with cold pressor reflection and heart rate variability in the elderly.Methods: From June 2010 to September 2013, 287 elderly aged ≥ 60 years were enrolled in Jinan area, China. The elderly were classified into lower (n = 96), intermediate (n = 95), and higher (n = 96) tertile groups according to the tertile of the percentage change of supine-to-orthostatic systolic BP.Results: There were significant increasing trends in systolic BP response to the CPT at 0 and 60 sec; the plasma levels of epinephrine, norepinephrine, and angiotensin II; and decreasing trends in DNN, SDNN index, and SDANN from the lower to the higher tertile group, and differences between any two groups were significant (P < .05). The percentage change of supine-to-orthostatic systolic BP was positively correlated with systolic BP response to CPT at 0 and 60 sec, VLF, epinephrine, norepinephrine, and angiotensin II (P < .001) and negatively correlated with SDNN, SDNN index, SDANN, rMSSD, pNN50, LF, and ratio of LF/HF (P < .001). The BP response to CPT, parameters of HRV, and the plasma levels of norepinephrine and angiotensin II were independently associated with the percentage change of supine-to-orthostatic systolic BP after adjustment for confounders.Conclusion: Aggressive variability of supine-to-orthostatic systolic BP might be significantly associated with the imbalance of sympathetic and parasympathetic activity, especially high sensitivity sympathetic response in the elderly.Abbreviations: BP: blood pressure; BMI: body mass index; CPT: cold pressor test; HRV: heart rate variability; SDNN: standard deviation of all normal-to-normal R-R intervals; SDNN index: mean of the standard deviations of all 5-min normal-to-normal R-R intervals of the entire recording; SDANN: standard deviation of the averages of normal-to-normal R-R intervals during all 5-min periods of the entire recording; rMSSD: square root of the mean squared differences between successive normal R-R intervals; pNN50: number of adjacent normal R-R intervals differing by more than 50 ms; VLF: very low frequency; LF: low frequency; HF: high frequency; TCHO: total cholesterol; HDL-c: high-density lipoprotein cholesterol; LDL-c: low-density lipoprotein cholesterol; FPG: fasting plasma glucose; SD: standard deviation.

The Etiology of Primary Hyperhidrosis: A Systematic Review.

PURPOSE: Primary hyperhidrosis is a pathological disorder of unknown etiology, affecting 0.6-5% of the population, and causing severe functional and social handicaps. As the etiology is unknown, it is not possible to treat the root cause. Recently some differences between affected and non-affected people have been reported. The aim of this review is to summarize these new etiological data. METHODS: Search of the literature was performed in the PubMed/Medline Database and pertinent articles were retrieved and reviewed. Additional publications were obtained from the references of these articles. RESULTS: Some anatomical and pathophysiological characteristics (as well as enzymatic, metabolic, and neurological dysfunctions) have been observed in hyperhidrotic subjects; three main possible etiological factors predominate. A familial trait seems to exist, and genetic loci associated with hyperhidrosis have been identified. Histological differences were observed in sympathetic ganglia of hyperhidrotic subjects: the ganglia were larger and contained a higher number of ganglion cells. A higher expression of acetylcholine and alpha-7 neuronal nicotinic receptor subunit in the sympathetic ganglia of patients with hyperhidrosis has been reported. CONCLUSIONS: Despite these accumulated data, the etiology of primary hyperhidrosis remains obscure. Nevertheless, three main lines for future research seem to be delineated: genetics, histological observations, and enzymatic studies.

Renalase in Children with Glomerular Kidney Diseases.

Studies suggest that renalase, a renal catecholamine-inactivating enzyme, plays a major role in the pathogenesis of kidney and cardiovascular diseases in adults. This study seeks to determine the role of renalase in children with glomerular kidney diseases. We evaluated the serum renalase, arterial stiffness, intima-media thickness, blood pressure, and clinical and biochemical parameters in 78 children (11.9 ± 4.6 years of age) with glomerulopathies such as idiopathic nephrotic syndrome (40 cases), IgA nephropathy (12 cases), Henoch-Schönlein nephropathy (12 cases), and other glomerulopathies (14 cases). The control group consisted of 38 healthy children aged 11.8 ± 3.3 years. The mean renalase was 25.74 ± 8.94 µg/mL in the glomerulopathy group, which was not significantly different from the 27.22 ± 5.15 in the control group. The renalase level did not differ among various glomerulopathies either. However, proteinuric patients had a higher renalase level than those without proteinuria (28.43 ± 11.71 vs. 24.05 ± 6.23, respectively; p = 0.03). In proteinuric patients, renalase correlated with daily proteinuria. In the entire glomerulopathy group, renalase correlated with age, systolic central blood pressure (BP), diastolic peripheral and central BP, mean peripheral and central BP; peripheral diastolic BP Z-score, glomerular filtration rate, cholesterol, triglycerides, and pulse wave velocity. We conclude that in children with glomerulopathies renalase, although basically not enhanced, may underlie blood pressure elevation and arterial damage.

Comparison of pupillary dynamics to light in the mild traumatic brain injury (mTBI) and normal populations.

PURPOSE: To determine if mTBI adversely affects the pupillary light reflex (PLR). METHODS: The PLR was evaluated in mTBI and compared to normal individuals under a range of test conditions. Nine pupil parameters (maximum, minimum and final pupil diameter, latency, amplitude and peak and average constriction and dilation velocities) and six stimulus conditions (dim pulse, dim step, bright pulse, bright step, bright red step and bright blue step) were assessed in 32 adults with mTBI (21-60 years of age) and compared to 40 normal (22-56 years of age). The Neuroptics, infrared, DP-2000 binocular pupillometer was used (30 Hz sampling rate; 0.05 mm resolution) with binocular stimulation and recording. RESULTS: Different test conditions allowed for discrimination of different parameters. For any of the given six test conditions, five-to-eight of the nine pupillary parameters were statistically different (p < 0.05) between the two diagnostic groups. The most promising parameters for diagnostic differentiation were constriction latency, all pupillary diameters, average constriction velocity and peak dilation velocity. CONCLUSIONS: MTBI adversely affects the PLR. This suggests an impairment of the autonomic nervous system. The findings suggest the potential for quantitative pupillary dynamics to serve as an objective mTBI biomarker.

Can the adrenergic system be implicated in the pathophysiology of bladder pain syndrome/interstitial cystitis? A clinical and experimental study.

AIMS: To evaluate sympathetic system activity in bladder pain syndrome/interstitial cystitis (BPS/IC) patients and to investigate if chronic adrenergic stimulation in intact rats induces BPS/IC-like bladder modifications. METHODS: Clinical study--In BPS/IC patients and aged and body mass index matched volunteers TILT test was undertaken and catecholamines were measured in plasma and 24 hr urine samples. Experimental study--Phenylephrine was injected subcutaneously (14 days) to female Wistar rats. Pain behavior, spinal Fos expression, urinary spotting, number of fecal pellets expelled, frequency of reflex bladder contractions, and urothelial height were analyzed. Urothelium permeability was investigated by trypan blue staining. Immunoreactivity against caspase 3 and bax were studied in the urothelium and against alpha-1-adrenoreceptor and TRPV1 in suburothelial nerves. Mast cell number was determined in the sub-urothelium. In rats with lipopolysaccharide-induced cystitis, urinary catecholamines, and Vesicular Monoamine Transporter 2 (VMAT2) expression in bladder nerves were analyzed. RESULTS: The TILT test showed an increase of sympathetic activity. Noradrenaline levels in blood at resting conditions and in 24-hr urine samples were higher in BPS/IC patients. Phenylephrine administration increased visceral pain, spinal Fos expression, bladder reflex activity, urinary spotting and the number of expelled fecal pellets. The mucosa showed urothelial thinning and increased immunoreactivity for caspase 3 and bax. Trypan blue staining was only observed in phenylephrine treated animals. Suburothelial nerves co-expressed alpha1 and TRPV1. Mastocytosis was present in the suburothelium. Cystitis increased sympathetic nerve density and urinary noradrenaline levels. CONCLUSIONS: Excessive adrenergic stimulation of the bladder may contribute to the pathophysiological mechanisms of BPS/IC.

Systolic and diastolic short-term blood pressure variability and its determinants in patients with controlled and uncontrolled hypertension: a retrospective cohort study.

Absolute blood pressure (BP) values are not the only causes of adverse cardiovascular consequences. BP variability (BPV) has also been demonstrated to be a predictor of mortality for cardiovascular events; however, its determinants are still unknown. This study considers 426 subjects with ambulatory BP monitoring (ABPM) measuring 24-h, diurnal and nocturnal absolute BP values and their standard deviations of the mean, along with nocturnal fall, age, sex and current treatment. Patients were divided in two subgroups, controlled and uncontrolled BP, and BPV of patients with "true" and "false" resistant hypertension was also analyzed. Nocturnal and 24-h BPV were higher in the group with uncontrolled hypertension. Multiple regression analysis showed that absolute BP, age, nocturnal fall, but not sex predicted BPV. Patients with "true" resistant hypertension had greater BPV than "false" resistant hypertension patients. Absolute BP resulted as the main determinant of 24-h and nocturnal BPV but not daytime BPV. Also nocturnal BP fall and age resulted as predictors of BPV in treated and untreated patients. Patients with "true" resistant hypertension have a higher BPV, suggesting a higher sympathetic activation. Evidence is still limited regarding the importance of short-term BPV as a prognostic factor and assessment of BPV cannot yet represent a parameter for routine use in clinical practice. Future prospective trials are necessary to define which targets of BPV can be achieved with antihypertensive drugs and whether treatment-induced reduction in BPV is accompanied by a corresponding reduction in cardiovascular events.

Pupillary responses to light in chronic non-blast-induced mTBI.

PURPOSE: To evaluate objectively and quantitatively human pupillary responses to a light stimulus under photopic conditions in individuals with non-blast-induced, chronic, mild traumatic brain injury (mTBI). METHODS: Seventeen individuals with chronic, non-blast-induced mTBI and 15 visually-normal (VN) controls were tested (aged 21-45 years). Pupillary responsivity to a brief step-input light stimulus was assessed objectively in each eye for 5 seconds using the Neuroptics PLR-200 monocular, hand-held pupillometer with its pre-set and automated eight parameter analysis. RESULTS: Five of the eight parameters assessed were significantly reduced (p ≤ 0.05) in the mTBI group as compared to the VN control group: maximum (or peak) constriction velocity, average constriction velocity, average dilation velocity, maximum diameter and amplitude of constriction. The remaining three parameters were similar in each group (p > 0.05): constriction latency, 75% dilation recovery time and minimum diameter. CONCLUSIONS: The slowed dilation dynamics and reduced maximum pupillary diameter in mTBI suggest deficiency primarily of the sympathetic control system. The reduced peak velocities and related amplitudes suggest subtle parasympathetic involvement.

Reprogramming of the developing heart by Hif1a-deficient sympathetic system and maternal diabetes exposure.

Introduction: Maternal diabetes is a recognized risk factor for both short-term and long-term complications in offspring. Beyond the direct teratogenicity of maternal diabetes, the intrauterine environment can influence the offspring's cardiovascular health. Abnormalities in the cardiac sympathetic system are implicated in conditions such as sudden infant death syndrome, cardiac arrhythmic death, heart failure, and certain congenital heart defects in children from diabetic pregnancies. However, the mechanisms by which maternal diabetes affects the development of the cardiac sympathetic system and, consequently, heightens health risks and predisposes to cardiovascular disease remain poorly understood. Methods and results: In the mouse model, we performed a comprehensive analysis of the combined impact of a Hif1a-deficient sympathetic system and the maternal diabetes environment on both heart development and the formation of the cardiac sympathetic system. The synergic negative effect of exposure to maternal diabetes and Hif1a deficiency resulted in the most pronounced deficit in cardiac sympathetic innervation and the development of the adrenal medulla. Abnormalities in the cardiac sympathetic system were accompanied by a smaller heart, reduced ventricular wall thickness, and dilated subepicardial veins and coronary arteries in the myocardium, along with anomalies in the branching and connections of the main coronary arteries. Transcriptional profiling by RNA sequencing (RNA-seq) revealed significant transcriptome changes in Hif1a-deficient sympathetic neurons, primarily associated with cell cycle regulation, proliferation, and mitosis, explaining the shrinkage of the sympathetic neuron population. Discussion: Our data demonstrate that a failure to adequately activate the HIF-1α regulatory pathway, particularly in the context of maternal diabetes, may contribute to abnormalities in the cardiac sympathetic system. In conclusion, our findings indicate that the interplay between deficiencies in the cardiac sympathetic system and subtle structural alternations in the vasculature, microvasculature, and myocardium during heart development not only increases the risk of cardiovascular disease but also diminishes the adaptability to the stress associated with the transition to extrauterine life, thus increasing the risk of neonatal death.

Alzheimer's Disease: An Attempt of Total Recall.

This review is an attempt to compile existing hypotheses on the mechanisms underlying the initiation and progression of Alzheimer's disease (AD), starting from sensory impairments observed in AD and concluding with molecular events that are typically associated with the disease. These events include spreading of amyloid plaques and tangles of hyperphosphorylated tau and formation of Hirano and Biondi bodies as well as the development of oxidative stress. We have detailed the degenerative changes that occur in several neuronal populations, including the cholinergic neurons in the nucleus basalis of Meynert, the histaminergic neurons in the tuberomammillary nucleus, the serotonergic neurons in the raphe nuclei, and the noradrenergic neurons in the locus coeruleus. Furthermore, we discuss the potential role of iron accumulation in the brains of subjects with AD in the disease progression which served as a basis for the idea that iron chelation in the brain may mitigate oxidative stress and decelerate disease development. We also draw attention to possible role of sympathetic system and, more specifically, noradrenergic neurons of the superior cervical ganglion in triggering of the disease. We also explore the alternative possibility of compensatory protective changes that may occur in these neurons to support cholinergic function in the forebrain of subjects with AD.