Effect of Low-Frequency Renal Nerve Stimulation on Renal Glucose Release during Normoglycemia and a Hypoglycemic Clamp in Pigs.

Previously, we demonstrated that renal denervation in pigs reduces renal glucose release during a hypoglycemic episode. In this study we set out to examine changes in side-dependent renal net glucose release (SGN) through unilateral low-frequency stimulation (LFS) of the renal plexus with a pulse generator (2-5 Hz) during normoglycemia (60 min) and insulin-induced hypoglycemia ≤3.5 mmol/L (75 min) in seven pigs. The jugular vein, carotid artery, renal artery and vein, and both ureters were catheterized for measurement purposes, blood pressure management, and drug and fluid infusions. Para-aminohippurate (PAH) and inulin infusions were used to determine side-dependent renal plasma flow (SRP) and glomerular filtration rate (GFR). In a linear mixed model, LFS caused no change in SRP but decreased sodium excretion (p < 0.0001), as well as decreasing GFR during hypoglycemia (p = 0.0176). In a linear mixed model, only hypoglycemic conditions exerted significant effects on SGN (p = 0.001), whereas LFS did not. In a Wilcoxon signed rank exact test, LFS significantly increased SGN (p = 0.03125) and decreased sodium excretion (p = 0.0017) and urinary flow rate (p = 0.0129) when only considering the first instance LFS followed a preceding period of non-stimulation during normoglycemia. To conclude, this study represents, to our knowledge, the first description of an induction of renal gluconeogenesis by LFS.

Renal Glucose Release after Unilateral Renal Denervation during a Hypoglycemic Clamp in Pigs with an Altered Hypothalamic Pituitary Adrenal Axis after Late-Gestational Dexamethasone Injection.

Previously, we demonstrated in pigs that renal denervation halves glucose release during hypoglycaemia and that a prenatal dexamethasone injection caused increased ACTH and cortisol concentrations as markers of a heightened hypothalamic pituitary adrenal axis (HPAA) during hypoglycaemia. In this study, we investigated the influence of an altered HPAA on renal glucose release during hypoglycaemia. Pigs whose mothers had received two late-gestational dexamethasone injections were subjected to a 75 min hyperinsulinaemic-hypoglycaemic clamp (<3 mmol/L) after unilateral surgical denervation. Para-aminohippurate (PAH) clearance, inulin, sodium excretion and arterio-venous blood glucose difference were measured every fifteen minutes. The statistical analysis was performed with a Wilcoxon signed-rank test. PAH, inulin, the calculated glomerular filtration rate and plasma flow did not change through renal denervation. Urinary sodium excretion increased significantly (p = 0.019). Side-dependent renal net glucose release (SGN) decreased by 25 ± 23% (p = 0.004). At 25 percent, the SGN decrease was only half of that observed in non-HPAA-altered animals in our prior investigation. The current findings may suggest that specimens with an elevated HPAA undergo long-term adaptations to maintain glucose homeostasis. Nonetheless, the decrease in SGN warrants further investigations and potentially caution in performing renal denervation in certain patient groups, such as diabetics at risk of hypoglycaemia.

Altered Cerebral Blood Flow and Potential Neuroprotective Effect of Human Relaxin-2 (Serelaxin) During Hypoxia or Severe Hypovolemia in a Sheep Model.

Specific neuroprotective strategies to minimize cerebral damage caused by severe hypoxia or hypovolemia are lacking. Based on previous studies showing that relaxin-2/serelaxin increases cortical cerebral blood flow, we postulated that serelaxin might provide a neuroprotective effect. Therefore, we tested serelaxin in two emergency models: hypoxia was induced via inhalation of 5% oxygen and 95% nitrogen for 12 min; thereafter, the animals were reoxygenated. Hypovolemia was induced and maintained for 20 min by removal of 50% of the total blood volume; thereafter, the animals were retransfused. In each damage model, the serelaxin group received an intravenous injection of 30 µg/kg of serelaxin in saline, while control animals received saline only. Blood gases, shock index values, heart frequency, blood pressure, and renal blood flow showed almost no significant differences between control and treatment groups in both settings. However, serelaxin significantly blunted the increase of lactate during hypovolemia. Serelaxin treatment resulted in significantly elevated cortical cerebral blood flow (CBF) in both damage models, compared with the respective control groups. Measurements of the neuroproteins S100B and neuron-specific enolase in cerebrospinal fluid revealed a neuroprotective effect of serelaxin treatment in both hypoxic and hypovolemic animals, whereas in control animals, neuroproteins increased during the experiment. Western blotting showed the expression of relaxin receptors and indicated region-specific differences in relaxin receptor-mediated signaling in cortical and subcortical brain arterioles, respectively. Our findings support the hypothesis that serelaxin is a potential neuroprotectant during hypoxia and hypovolemia. Due to its preferential improvement of cortical CBF, serelaxin might reduce cognitive impairments associated with these emergencies.

A Systematic Review of Neuroprotective Strategies in the Management of Hypoglycemia.

Severe hypogylcemia has been found to induce cerebral damage. While a number of illnesses can lead to hypoglycemic episodes, antidiabetic medications prescribed for glycemic control are a common cause. Considering the rising prevalence of diabetes mellitus in the population, we investigated neuroprotective strategies during hypoglycemia in the form of a systematic review in adherence to the PRISMA statement. A review protocol was registered in the PROSPERO database. A systematic literature search of PubMed, Web of Science, and CENTRAL was performed in September 2018. Based on a predefined inclusion protocol, results were screened and evaluated by two researchers. Both animal experiments and human studies were included, and their risk of bias was assessed with SYRCLE's and the Cochrane risk of bias tools, respectively. Of a total of 16,230 results, 145 were assessed in full-text form: 27 articles adhered to the inclusion criteria and were qualitatively analyzed. The retrieved neuroprotective strategies could be categorized into three subsets: (1) Energy substitution, (2) hypoglycemia unawareness, and (3) other neuroprotective strategies. While on a study level, the individual results appeared promising, more research is required to investigate not only specific neuroprotective strategies against hypoglycemic cerebral damage, but also its underlying pathophysiological mechanisms.

Effects of human relaxin-2 (serelaxin) on hypoxic pulmonary vasoconstriction during acute hypoxia in a sheep model.

PURPOSE: Hypoxia induces pulmonary vasoconstriction with a subsequent increase of pulmonary artery pressure (PAP), which can result in pulmonary hypertension. Serelaxin has shown an increase of pulmonary hemodynamic parameters after serelaxin injection. We therefore investigated the response of pulmonary hemodynamic parameters after serelaxin administration in a clinically relevant model. METHODS: Six controls and six sheep that received 30 µg/kg serelaxin underwent right heart catheterization during a 12-minute hypoxia period (inhalation of 5% oxygen and 95% nitrogen) and subsequent reoxygenation. Systolic, diastolic, and mean values of both PAP (respectively, PAPs, PAPd, and PAPm) and pulmonary capillary wedge pressure (respectively, PCWPs, PCWPd, and PCWPm), blood gases, heart rate (HR), and both peripheral and pulmonary arterial oxygen saturation were obtained. Cardiac output (CO), stroke volume (SV), pulmonary vascular resistance (PVR), pulmonary arterial compliance (PAcompl), and systemic vascular resistance (SVR) were calculated. RESULTS: The key findings of the current study are that serelaxin prevents the rise of PAPs (p≤0.001), PAPm, PCWPm, PCWPs (p≤0.03), and PAPd (p≤0.05) during hypoxia, while it simultaneously increases CO and SV (p≤0.001). Similar courses of decreases of PAPm, PAPd, PAPs, CO, SVR (p≤0.001), and PCWPd (p≤0.03) as compared to hypoxic values were observed during reoxygenation. In direct comparison, the experimental groups differed during hypoxia in regard to HR, PAPm, PVR, and SVR (p≤0.03), and during reoxygenation in regard to HR (p≤0.001), PAPm, PAPs, PAPd, PVR, SVR (p≤0.03), and PCWPd (p≤0.05). CONCLUSION: The findings of this study suggest that serelaxin treatment improves pulmonary hemodynamic parameters during acute hypoxia.

Pulmonary hemodynamic effects and pulmonary arterial compliance during hypovolemic shock and reinfusion with human relaxin-2 (serelaxin) treatment in a sheep model.

BACKGROUND: Previous studies on the recombinant form of human relaxin-2 (serelaxin) have shown a decrease of pulmonary hemodynamics after serelaxin injection. Currently, the effect of serelaxin treatment during hypovolemia in a large animal model remains mostly unknown. METHODS: 12 sheep were randomly assigned to a sham or serelaxin (30µg/kg serelaxin) group and underwent right heart catheterization. 50% of the estimated total blood volume were removed to induce hypovolemia, and subsequently retransfused 20 min later (reinfusion). Blood gases, heart rate, peripheral and pulmonary arterial oxygen saturation, systolic, diastolic and mean values of both pulmonary artery pressure (PAP) and pulmonary capillary wedge pressure (PCW) were measured. Cardiac output (CO), pulmonary vascular resistance (PVR), pulmonary arterial compliance (PAcompl) and systemic vascular resistance (SVR) were calculated. RESULTS: Hypovolemia and shock led to a similar decrease of PAP and PCW in both groups (p≤0.001). CO, SV and PAcompl decreased only in the control group (p≤0.05) and remained higher in the serelaxin-treated group. The results of this study suggest that serelaxin treatment did not negatively influence hemodynamic parameters during hypovolemic shock. CONCLUSION: The main conclusion of this study is that cardiopulmonary adaption mechanisms are not critically altered by serelaxin administration during severe hypovolemia and retransfusion.

The relaxin peptide family - potential future hope for neuroprotective therapy? A short review.

Since its discovery in the 1920's the relaxin peptide hormone family has not only grown in number to now seven members (relaxin-1, relaxin-2, relaxin-3, insulin-like peptide (INSL) 3, INSL4, INSL5 and INSL6), but ever more effects, suchs as vasodilatory, angiogenic, anti-apoptopic, anti-fibriotic and anti-inflammatory, have been linked to them. While relaxin-2 has mainly been investigated in the context of cardiac protection, most comprehensively in the RELAX-AHF and RELAX AHF2 studies, a small number of studies have furthermore assessed the potential neuroprotective effects of especially relaxin-2 and other members of the relaxin family. In this short review we summarise and discuss recent efforts to utilize relaxin hormones for neuroprotection and point out potential future fields of research and translational applications. While many questions still need to be answered, the promising results of the available studies definitely warrant future well-designed studies on neuroprotection by relaxin peptides.

Effects of Late Gestational Fetal Exposure to Dexamethasone Administration on the Postnatal Hypothalamus-Pituitary-Adrenal Axis Response to Hypoglycemia in Pigs.

BACKGROUND: Prenatal glucocorticoid administration alters the activity of the fetal hypothalamic-pituitary-adrenocortical axis (HPAA), and correspondingly the adenocorticotropic hormone (ACTH) and cortisol levels after birth. The dosages required for these effects are critically discussed. Activation of the HPAA is related to metabolic syndrome and diabetes mellitus. Hypoglycemia is the classic side effect of antidiabetic treatment. We hypothesized that a low dosage of dexamethasone in late pregnancy alters the HPAA response to hypoglycemia in pigs. METHODS: 12 pregnant sows were randomly assigned to two groups which received either a low-dose intramuscular injection (99th and 100th day of gestation) of dexamethasone (0.06 µg/kg body weight) or vehicle. Three months after birth, 18 dexamethasone-treated anaesthetized offspring and 12 control offspring underwent a 75 min hypoglycemic clamp (blood glucose below 4 mmol/L) procedure. Heart rate (HR), blood pressure, ACTH and cortisol levels and body weight (at birth and after three months) were recorded. RESULTS: Dexamethasone-treated animals exhibited significantly elevated ACTH (139.9 ± 12.7 pg/mL) and cortisol (483.1 ± 30.3 nmol/L) levels during hypoglycemia as compared to the control group (41.7 ± 6.5 pg/mL and 257.9 ± 26.7 nmol/L, respectively), as well as an elevated HR (205.5 ± 5.7 bpm) and blood pressure (systolic: 128.6 ± 1.5, diastolic: 85.7 ± 0.7 mmHg) response as compared to the control group (153.2 ± 4.5 bpm; systolic: 118.6 ± 1.6, diastolic: 79.5 ± 1.4 mmHg, respectively; p < 0.001). CONCLUSIONS: Low-dose prenatal administration of dexamethasone not only exerts effects on the HPAA (ACTH and cortisol concentration) and vital parameters (HR and diastolic blood pressure) under baseline conditions, but also on ACTH, HR and systolic blood pressure during hypoglycemia.

A Systematic Review of Neuroprotective Strategies during Hypovolemia and Hemorrhagic Shock.

Severe trauma constitutes a major cause of death and disability, especially in younger patients. The cerebral autoregulatory capacity only protects the brain to a certain extent in states of hypovolemia; thereafter, neurological deficits and apoptosis occurs. We therefore set out to investigate neuroprotective strategies during haemorrhagic shock. This review was performed in accordance to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Before the start of the search, a review protocol was entered into the PROSPERO database. A systematic literature search of Pubmed, Web of Science and CENTRAL was performed in August 2017. Results were screened and evaluated by two researchers based on a previously prepared inclusion protocol. Risk of bias was determined by use of SYRCLE's risk of bias tool. The retrieved results were qualitatively analysed. Of 9093 results, 119 were assessed in full-text form, 16 of them ultimately adhered to the inclusion criteria and were qualitatively analyzed. We identified three subsets of results: (1) hypothermia; (2) fluid therapy and/or vasopressors; and (3) other neuroprotective strategies (piracetam, NHE1-inhibition, aprotinin, human mesenchymal stem cells, remote ischemic preconditioning and sevoflurane). Overall, risk of bias according to SYRCLE's tool was medium; generally, animal experimental models require more rigorous adherence to the reporting of bias-free study design (randomization, etc.). While the individual study results are promising, the retrieved neuroprotective strategies have to be evaluated within the current scientific context-by doing so, it becomes clear that specific promising neuroprotective strategies during states of haemorrhagic shock remain sparse. This important topic therefore requires more in-depth research.

[Clinical correlations between dry eye and cataract surgery]. / Corelatii clinice între ochiul uscat si chirurgia cataractei.

Cataract procedure is sometimes followed by dry eye symptoms. The dimensions of the incisions, topical medication and other manoeuvres are responsible for these phenomena. I tried to objective them by break-up-time (BUT) and Schirmer test. The favourable outcomes of artificial tears confirm this theory.

[Autologous serum utilization in patients with lacrimal hyposecretion and persistent epithelial defects of cornea--clinical study]. / Utilizarea serului autolog la pacientii cu hiposecretie lacrimala si defecte epiteliale corneene persistente--studiu clinic--.

Autologous serum was supposed to be efficient in the treatment of keratoconjunctivitis sicca and persistent epithelial defects. 14 of 24 eyes of patients with keratoconjunctivitis sicca improved fluorescein and rose Bengal scores. 3 of 6 eyes with persistent epithelial defects healed completely after this treatment and 2 improved fluorescein and rose bengal scores. All patients had been unsuccessfully treated with conventional treatment. Allergic or immune adverse reactions were not present and economical benefit was appreciated by some patients with poor socioeconomic condition.