Effect of Dopamine as a Vascular Endothelial Growth Factor Antagonist on the Development of Acute Lung Injury in Sepsis Patients.

BACKGROUND: Sepsis is a dysregulated host immune response stemming from a systemic inflammatory response to microbial invasion, encompassing bacteria, viruses, and other pathogens. The vascular endothelial growth factor (VEGF) was initially identified for its potent induction of endothelial permeability. Studies have proposed a therapeutic role of dopamine in mitigating VEGF-induced permeability, shedding light on its potential in acute respiratory distress syndrome (ARDS) management. MAIN OBJECTIVE: To determine the effect of dopamine as an inhibitor of VEGF and to prevent the progression of sepsis to acute lung injury (ALI) and ARDS. METHODS: A total of 154 critical care unit patients with a diagnosis of sepsis were randomized into two groups: Group I (control group) and Group II (Study group). Both received standard treatment, as per ICU protocol. In addition, the study group (Group II) received a dopamine infusion of 2 micrograms/kg/min. Baseline routine investigation, procalcitonin, and chest X-ray were done. Day one and day seven blood samples were stored for analysis of VEGF levels. Murray's score and sequential organ failure assessment (SOFA) score (organ dysfunction) were calculated from day one to day seven. RESULTS: VEGF levels on day seven were significantly lower in the study group compared to the control group (p<0.05). The PaO2/FiO2 ratio at day seven was significantly increased in the study group than in the control group, indicating an improvement in oxygenation status in the study group. There was a mean ICU stay of 9.3 days in the study group versus 11.6 days in the control group (p<0.05). The SOFA score showed a significant improvement in the study group from day five onwards, indicating a therapeutic effect of dopamine on organ dysfunction in sepsis. CONCLUSION: Dopamine reduces VEGF and lung injury mediated by increased endothelial permeability.

Determinants of Readmission in the Intensive Care Unit: A Prospective Observational Study.

Background The antecedents of readmission among survivors of intensive care units (ICUs) are complex and comprise an array of elements that impact the rehabilitation process after leaving the ICU. The aforementioned determinants may comprise socioeconomic factors, access to follow-up healthcare, the nature and severity of the initial illness or injury, the presence of comorbidities, the sufficiency of transitional care and rehabilitation services, and patient and family support systems. Added to this, the risk of readmission may be increased by complications that develop during the ICU stay, including but not limited to infections, organ dysfunction, and psychological distress. Comprehending these determinants is of the utmost importance for healthcare providers in order to execute focused interventions that seek to diminish readmission rates, enhance patient outcomes, and elevate the standard of care for survivors of ICUs. Objective The objective of the study is to determine the factors associated with readmission among ICU survivors and the cause of readmission. Methodology This prospective observational study was conducted in a tertiary-level ICU. The duration of the study was one year and we enrolled 108 ICU survivors in our study. We have recorded patient demographic data, comorbidity, primary diagnosis, previous treatment history (vasopressor, sedation), causes of readmission, duration of previous ICU stay, and outcome of readmitted patient (discharge, death, and transfer to lower facility). Result The incidence of readmission in our ICU is 10.4%; 50-70 age groups are more prone to readmission of which the male sex is predominant (64.81%). In our study, hypertension (cardiac, 18.52%) and diabetes mellitus (11.11%) were the most common comorbidities reported in readmitted patients. The majority of patients who get readmission suffered from blunt trauma abdomen. In the majority of readmitted patients, sedation was used in the previous admission for ventilation and patient comfort (66.67%). Most of the readmitted patients (68.51%) have a previous ICU stay of more than five days. Patients were readmitted mainly because of respiratory (30.56%) and neurological (25%) complications. In this study, readmitted patients have high mortality (59.26%). Conclusion In a tertiary care ICU, the incidence rate of readmitted patients was 10.4%. Respiratory and neurological problems were the main cause of readmission. In readmitted patients, mortality was high up to 59.26%. Old age, male sex, prolonged ICU stay, comorbidities like hypertension, blunt trauma abdomen, use of sedation, and prolonged mechanical ventilation in previous ICU admission are major risk factors for ICU readmission.

Effect of Deferasirox on Shunt Fraction During Thoracic Surgery With One-Lung Ventilation: A Randomized Controlled Study.

Context Deferasirox, an iron chelator, can potentially reduce intraoperative right-to-left shunt and improve oxygenation in patients undergoing thoracic surgery requiring one-lung ventilation (OLV) by potentiating hypoxic pulmonary vasoconstriction (HPV). Aim The aim was to determine the effect of deferasirox on the intraoperative shunt fraction (SF) of patients undergoing thoracic surgery using OLV. Study design and settings This was a prospective, single-blind, randomized, controlled study. The study was conducted at a tertiary-care hospital. Methods Before surgery, 64 patients were allocated to two groups comprising 32 patients each. Group D patients were administered deferasirox, while those in group C were given a placebo. We included patients with the American Society of Anesthesiologists physical status III or IV, aged 18-60 years, undergoing elective thoracic surgery needing OLV. SF was the primary outcome variable. Secondary outcome variables were arterial oxygen tension (PaO2), peripheral oxygen saturation (SpO2), the ratio of PaO2 and inspired oxygen concentration (P/F), and complications such as desaturation episodes, hypotension, and tachycardia. Results Baseline and postoperative values of outcome variables were statistically similar in both groups. Intraoperative values of SF were lower and PaO2, SpO2, and P/F were higher in group D. The incidence of intraoperative desaturation was lower in group D. Conclusion We conclude that pre-treatment with deferasirox reduces intraoperative SF and improves oxygenation during thoracic surgery using OLV.

A Randomized, Double-Blind, Prospective Study to Evaluate the Effect of Oral Pregabalin in Upper Limb Surgeries Under Brachial Plexus Block.

Context The oral pregabalin administration preoperatively has been reported to reduce acute postoperative pain and prolong the duration of anesthesia produced by single-injection peripheral nerve blockade. Aim To study the effect of single dose pregabalin on duration of brachial plexus block Settings and design Prospective, randomised, double blind, comparative study Material and methods Patients were divided into two groups (groups A and B), with each group having 50 patients. In group A, the patient received a pregabalin capsule of 300 mg orally two hours before surgery with a sip of water. Group B received a placebo (vitamin B complex capsule) orally two hours before surgery. Brachial plexus block was performed, and data was collected. Statistical analysis Data analysis was done using SPSS version 21.0 statistical analysis software. Demographic data and clinical variables were compared using the student's t-test, chi-square test, and Mann-Whitney U test. Results The requirement of the first dose of analgesia was significantly earlier in group B as compared to group A (4:56±0:20 vs. 8:01±0:30 hours). Group B patients, as compared to group A patients, had significantly higher levels of pain after two hours of surgery (0.32±0.47 vs. 0.00±0.00) and at four hours of surgery (2.42±0.50 vs. 0.34±0.59). Conclusions Oral pregabalin prolongs analgesia from brachial plexus block without significant effect on the motor block. In addition, premedication with oral pregabalin increases the sensory block of brachial plexus block.

Efficacy of Oral Care Protocols in the Prevention of Ventilator-Associated Pneumonia in Mechanically Ventilated Patients.

BACKGROUND: Ventilator-associated pneumonia (VAP) is one of the most common infections in intubated intensive care unit (ICU) patients. Oral care with chlorhexidine is a conventional method for maintaining hygiene. Recently, adjuvant methods have been introduced into routine oral care, including teeth brushing and the application of moisturizing lotion. The objective of this study was to compare the incidence of VAP in critical care patients receiving oral care with and without manual teeth brushing and the application of moisturizers to the mouth. METHODS: We conducted a prospective randomized control study comprised of 220 ICU patients between 18 and 65 years of age, and of either sex. The patients were divided into two groups of 110 each. Care for the study group (group S) consisted of chlorhexidine wash, tooth brushing, and moisturizing gel over gums, buccal mucosa, and lips. The control group (group C) was treated with chlorhexidine wash only. The oral assessment was done at 4, 6, 8, and 12 hours using the Beck Oral Assessment Scale (BOAS). Pneumonia was assessed based on abnormal chest x-rays, fever, chest auscultation, endotracheal culture report, and the incidence of VAP, and mortality was observed Results: Abnormal chest x-rays, positive auscultatory findings, fevers, and positive culture reports were significantly reduced in group S compared to these measurements in group C. The incidences of VAP and mortality were also significantly lower in group S compared with the incidences in group C. CONCLUSIONS: Oral care with chlorhexidine mouth wash and the adjuvant measures reduced VAP and, consequently mortality and hospital stays. Tooth brushing along with standard oral care provides an additional advantage in the prevention of VAP in mechanically ventilated patients. Compulsory tooth brushing, if included in regular oral care yields better results in terms of decreased incidence of VAP, length of ICU stay, and mortality.

A Comparative Study of the ProSeal Laryngeal Mask Airway Versus Endotracheal Tube in Neonates With Anorectal Malformations.

BACKGROUND: Laryngeal mask airways (LMAs) are widely used in paediatric anaesthesia. However, LMA use in neonatal age groups (younger than seven days) is limited because many anaesthesiologists prefer to use endotracheal tube in neonates. In this study, we compared the ProSeal LMA and endotracheal tube by measuring their performance, including ease of insertion via number of attempts for placement of device, total effective time for intubation and extubation, hemodynamic responses and perioperative complications. METHODS: In this prospective randomized study, 70 patients (neonates) weighing >2.5 kg, with American Society of Anaesthesiologists (ASA) classification grade 4 requiring emergency surgery for anorectal malformation were enrolled and divided into two groups. After induction, patients' airways were secured with either ProSeal LMA size 1 (Group I) or endotracheal tube (Group II). Anaesthesia was maintained on oxygen and sevoflurane with muscle relaxant atracurium. RESULTS: Demographic and surgical data were similar between the two groups. The ProSeal LMA insertion time was shorter than endotracheal intubation. Hemodynamic variations were less in the ProSeal LMA group as compared to the endotracheal tube group. The total time for removal of airway devices from the end of surgery for the ProSeal group was lower than that for the endotracheal intubation group. Postoperative complications were less in the ProSeal group as compared to the endotracheal group. CONCLUSIONS: The ProSeal LMA can be a better alternative to the endotracheal tube in neonates due to the ease of insertion, lesser changes in hemodynamic parameters and minimal postoperative complications.

How alcohol affects insulin-like growth factor-1's influences on the onset of puberty: A critical review.

Alcohol (ALC) is capable of delaying signs associated with pubertal development in laboratory animals, as well as in humans. The normal onset of puberty results from a timely increase in gonadotropin-releasing hormone (GnRH) secretion, which is associated with a gradual decline in prepubertal inhibitory influences, and the establishment of excitatory inputs that increase GnRH release, which together drive pubertal development. In recent years, insulin-like growth factor-1 (IGF-1) has emerged as a pivotal contributor to prepubertal GnRH secretion and pubertal development, whose critical actions are interfered with by ALC abuse. Here we review the neuroendocrine research demonstrating the important role that IGF-1 plays in pubertal development, and describe the detrimental effects and mechanisms of action of ALC on the onset and progression of pubertal maturation.

IGF-1 Influences Gonadotropin-Releasing Hormone Regulation of Puberty.

The pubertal process is initiated as a result of complex neuroendocrine interactions within the preoptic and hypothalamic regions of the brain. These interactions ultimately result in a timely increase in the secretion of gonadotropin-releasing hormone (GnRH). Researchers for years have believed that this increase is due to a diminished inhibitory tone which has applied a prepubertal brake on GnRH secretion, as well as to the gradual development of excitatory inputs driving the increased release of the peptide. Over the years, insulin-like growth factor-1 (IGF-1) has emerged as a prime candidate for playing an important role in the onset of puberty. This review will first present initial research demonstrating that IGF-1 increases in circulation as puberty approaches, is able to induce the release of prepubertal GnRH, and can advance the timing of puberty. More recent findings depict an early action of IGF-1 to activate a pathway that releases the inhibitory brake on prepubertal GnRH secretion provided by dynorphin, as well as demonstrating that IGF-1 can also act later in the process to regulate the synthesis and release of kisspeptin, a potent stimulator of GnRH at puberty.

Cigarette smoking dose-response and suicidal ideation among young people in Nepal: a cross-sectional study.

BACKGROUND: Worldwide, tobacco smoking is a major risk factor for morbidity and early mortality among adult population. The present study aimed to find out the association between current smoking and suicidal ideation among young people in Nepal. MATERIALS AND METHODS: A cross-sectional questionnaire-based survey was carried out among 452 youths from Pokhara, Nepal. The present study included both genders (age 18-24 years) who were smokers as well as non-smokers. RESULTS: Across the study period, 452 participants were identified after matching for age, and sex (226 in the smoking group and 226 in the non-smoking group). The mean age of participants was 21.6±1.2 years and 58.8% were males. The overall rate of suicidal ideation in our cohort was 8.9%. Smokers were slightly more likely to report suicidal ideation than non-smokers (aOR 1.12). The risk of developing suicidal ideation was 3.56 (95% CI 1.26-10.09) times more in individuals who smoked greater than 3.5 cigarettes per week (p=0.01). CONCLUSION: The rate of suicidal ideation was slightly higher among smokers and a dose-response relationship was identified with the number of cigarettes smoked per week. Being aware of the link between smoking and suicidal ideation may help health care professionals working with young people to address more effectively the issues of mental well-being and thoughts about suicide.

Colombo Declaration on Epidemiology in Southeast Asia.

The Colombo Declaration on Epidemiology in Southeast Asia is based on the deliberations by the delegates of the conference and representatives of the Regional Public Health/Epidemiology Associations held during the Southeast Asia Regional Group Meeting of International Epidemiological Association/College of Community Physicians of Sri Lanka at Colombo, Sri Lanka, on September 19-21, 2019.

Regulation of prepubertal dynorphin secretion in the medial basal hypothalamus of the female rat.

The onset of puberty is the result of an increase in secretion of hypothalamic gonadotrophin-releasing hormone (GnRH). This action is a result of not only the development of stimulatory inputs to its release, but also the gradual decrease in inhibitory inputs that restrain release of the peptide prior to pubertal onset. Dynorphin (DYN) is one of the inhibitory inputs produced in the medial basal hypothalamus (MBH); however, little is known about what substance(s) control its prepubertal synthesis and release. Because neurokinin B (NKB) increases in the hypothalamus as puberty approaches, we considered it a candidate for such a role. An initial study investigated the acute effects of an NKB agonist, senktide, on the secretion of DYN from MBH tissues incubated in vitro. In other experiments, central injections of senktide were administered to animals for 4 days then MBHs were collected for assessment of DYN synthesis or for the in vitro secretion of both DYN and GnRH. Because insulin-like growth factor (IGF)-1 has been shown to play an important role at puberty, additional animals received central injections of this peptide for 4 days to assess NKB and DYN synthesis or the in vitro secretion of NKB. The results obtained show that senktide administration up-regulates the NKB receptor protein, at the same time as suppressing the DYN and its receptor. Senktide consistently suppressed DYN and elevated GnRH secretion in the same tissue incubates from both the acute and chronic studies. IGF-1 administration caused an increase in NKB protein, at the same time as decreasing DYN protein. Furthermore, the central administration of IGF-1 caused an increase in NKB release, an action blocked by the IGF-1 receptor blocker, JB-1. These results indicate that the IGF-1/NKB pathway contributes to suppressing the DYN inhibitory tone on prepubertal GnRH secretion and thus facilitates the puberty-related increase in the release of GnRH to accelerate the onset of puberty.

Alcohol Delays the Onset of Puberty in the Female Rat by Altering Key Hypothalamic Events.

BACKGROUND: Because alcohol (ALC) delays signs of pubertal development, we assessed the time course of events associated with the synthesis of critical hypothalamic peptides that regulate secretion of luteinizing hormone-releasing hormone (LHRH), the peptide that drives the pubertal process. METHODS: Immature female rats were administered either laboratory chow or BioServe isocaloric control or ALC-liquid diets from 27 through 33 days of age. On days 28, 29, 31, and 33, animals were killed by decapitation and tissue blocks containing the medial basal hypothalamus (MBH) and the rostral hypothalamic area (RHA) were isolated and stored frozen until assessed by Western blot analysis. RESULTS: Synthesis of dynorphin (DYN), a prepubertal inhibitor of LHRH secretion, was increased (p < 0.05) in the MBH of ALC-treated animals by day 29. DYN was further elevated (p < 0.01) on day 33 and was associated with an increase (p < 0.01) in DYN receptor expression. ALC did not affect synthesis of neurokinin B (NKB), a prepubertal stimulator of LHRH; however, it did suppress (p < 0.05) NKB receptor expression in the MBH by day 31. The most potent stimulator of prepubertal LHRH secretion, kisspeptin (Kp), was also decreased (p < 0.05) in the MBH as early as day 29, with continued suppression (p < 0.01) through day 33. Similar timely suppressions of mammalian target of rapamycin (mTOR), an immediate upstream regulator of Kp, were also noted. These decreases in mTOR and Kp were consistent with ALC stimulating (p < 0.05) the p-AMP-activated protein kinase/Raptor inhibitory pathway to mTOR on day 29, then later suppressing (p < 0.001) an Akt-mediated induction pathway to mTOR by day 31. In the RHA, ALC affected the pathways regulating Kp in a manner similar to that described in the MBH; however, these effects were not noted until day 33. CONCLUSIONS: ALC acts within the MBH as early as 29 days to induce inhibitor and repressor inputs to LHRH, while depressing stimulatory inputs to the peptide. Collectively, these events lead to delayed signs of pubertal development.

Regulation of Kisspeptin Synthesis and Release in the Preoptic/Anterior Hypothalamic Region of Prepubertal Female Rats: Actions of IGF-1 and Alcohol.

BACKGROUND: Alcohol (ALC) causes suppressed secretion of prepubertal luteinizing hormone-releasing hormone (LHRH). Insulin-like growth factor-1 (IGF-1) and kisspeptin (Kp) are major regulators of LHRH and are critical for puberty. IGF-1 may be an upstream mediator of Kp in the preoptic area and rostral hypothalamic area (POA/RHA) of the rat brain, a region containing both Kp and LHRH neurons. We investigated the ability of IGF-1 to stimulate prepubertal Kp synthesis and release in POA/RHA, and the potential inhibitory effects of ALC. METHODS: Immature female rats were administered either ALC (3 g/kg) or water via gastric gavage at 0730 hours. At 0900 hours, both groups were subdivided where half received either saline or IGF-1 into the brain third ventricle. A second dose of ALC (2 g/kg) or water was administered at 1130 hours. Rats were killed 6 hours after injection and POA/RHA region collected. RESULTS: IGF-1 stimulated Kp, an action blocked by ALC. Upstream to Kp, IGF-1 receptor (IGF-1R) activation, as demonstrated by the increase in insulin receptor substrate 1, resulted in activation of Akt, tuberous sclerosis 2, ras homologue enriched in brain, and mammalian target of rapamycin (mTOR). ALC blocked the central action of IGF-1 to induce their respective phosphorylation. IGF-1 specificity and ALC specificity for the Akt-activated mTOR pathway were demonstrated by the absence of effects on PRAS40. Furthermore, IGF-1 stimulated Kp release from POA/RHA incubated in vitro. CONCLUSIONS: IGF-1 stimulates prepubertal Kp synthesis and release following activation of a mTOR signaling pathway, and ALC blocks this pathway at the level of IGF-1R.

Alcohol and Puberty: Mechanisms of Delayed Development

Adolescence represents a vulnerable period for developing youth. Alcohol use and misuse are especially problematic behaviors during this time. Adolescents are more sensitive to alcohol and less tolerant of its detrimental effects than are adults. Research in humans and animals has revealed that early alcohol consumption can result in delayed pubertal development. Animal studies have shown that alcohol detrimentally affects neuroendocrine systems within the hypothalamic region of the brain that are associated with the normal, timely onset of the pubertal process. To effectively restore development and shorten recovery time associated with the adverse effects of alcohol on puberty, researchers must first understand the molecular and physiological mechanisms by which alcohol interferes with critical hypothalamic functions.

An integrated nutrition and health program package on IYCN improves breastfeeding but not complementary feeding and nutritional status in rural northern India: A quasi-experimental randomized longitudinal study.

BACKGROUND: Undernutrition below two years of age remains a major public health problem in India. We conducted an evaluation of an integrated nutrition and health program that aimed to improve nutritional status of young children by improving breast and complementary feeding practices over that offered by the Government of India's standard nutrition and health care program. METHODS: In Uttar Pradesh state, through multi-stage cluster random sampling, 81 villages in an intervention district and 84 villages in a comparison district were selected. A cohort of 957 third trimester pregnant women identified during house-to-house surveys was enrolled and, following childbirth, mother-child dyads were followed every three months from birth to 18 months of age. The primary outcomes were improvements in weight-for-age and length-for-age z scores, with improved breastfeeding and complementary feeding practices as intermediate outcomes. FINDINGS: Optimal breastfeeding practices were higher among women in intervention than comparison areas, including initiating breastfeeding within one hour of delivery (17.4% vs. 2.7%, p<0.001), feeding colostrum (34.7% vs. 8.4%, p<0.001), avoiding pre-lacteals (19.6% vs. 2.1%, p<0.001) and exclusively breastfeeding up to 6 months (24.1% vs. 15.3%, p = 0.001). However, differences were few and mixed between study arms with respect to complementary feeding practices. The mean weight-for-age z-score was higher at 9 months (-2.1 vs. -2.4, p = 0.0026) and the prevalence of underweight status was lower at 12 months (58.5% vs. 69.3%, p = 0.047) among intervention children. The prevalence of stunting was similar between study arms at all ages. Coefficients to show the differences between the intervention and comparison districts (0.13 cm/mo) suggested significant faster linear growth among intervention district infants at earlier ages (0-5 months). INTERPRETATION: Mothers participating in the intervention district were more likely to follow optimal breast, although not complementary feeding practices. The program modestly improved linear growth in earlier age and weight gain in late infancy. Comprehensive nutrition and health interventions are complex; the implementation strategies need careful examination to improve feeding practices and thus impact growth. TRIAL REGISTRATION: The trial was registered with ClinicalTrials.gov, NCT00198835.

Non-governmental organization facilitation of a community-based nutrition and health program: Effect on program exposure and associated infant feeding practices in rural India.

BACKGROUND: Integrated nutrition and health programs seek to reduce undernutrition by educating child caregivers about infant feeding and care. Data on the quality of program implementation and consequent effects on infant feeding practices are limited. This study evaluated the effectiveness of enhancing a nutrition and health program on breastfeeding and complementary-feeding practices in rural India. METHODS: Utilizing a quasi-experimental design, one of the implementing districts of a Cooperative for Assistance and Relief Everywhere (CARE) nutrition and health program was randomly selected for enhanced services and compared with a district receiving the Government of India's standard nutrition and health package alone. A cohort of 942 mother-child dyads was longitudinally followed from birth to 18 months. In both districts, the evaluation focused on responses to services delivered by community-based nutrition and health care providers [anganwadi workers (AWWs) and auxiliary nurse midwives (ANMs)]. FINDINGS: The CARE enhanced program district showed an improvement in program coverage indicators (e.g., contacts, advice) through outreach visits by both AWWs (28.8-59.8% vs. 0.7-12.4%; all p<0.05) and ANMs (8.6-46.2% vs. 6.1-44.2%; <0.05 for ages ≥6 months). A significantly higher percentage of child caregivers reported being contacted by the AWWs in the CARE program district (20.5-45.6% vs. 0.3-21.6%; p<0.05 for all ages except at 6months). No differences in ANM household contacts were reported. Overall, coverage remained low in both areas. Less than a quarter of women received any infant feeding advice in the intervention district. Earlier and exclusive breastfeeding improved with increasing number or quality of visits by either level of health care provider (OR: 2.04-3.08, p = <0.001), after adjusting for potentially confounding factors. Socio-demographic indicators were the major determinants of exclusive breastfeeding up to 6 month and age-appropriate complementary-feeding practices thereafter in the program-enhanced but not comparison district. INTERPRETATION: An enhanced nutrition and health intervention package improved program exposure and associated breastfeeding but not complementary-feeding practices, compared to standard government package. TRIAL REGISTRATION: ClinicalTrials.gov NCT00198835.

Influences of manganese on pubertal development.

The onset of puberty is the result of complex neuroendocrine interactions within hypothalamic region of the brain, as well as from genetic and environmental influences. These interactions ultimately result in the increased synthesis and release of luteinizing hormone-releasing hormone (LHRH). Manganese (Mn) is an essential environmental element known for years to be involved in numerous mammalian physiological processes, including growth and reproductive function. Studies in recent years have shown the ability of Mn to cross the blood-brain barrier and act within the hypothalamus to influence the timing of puberty. This review will depict research showing the molecular and physiological actions of Mn in the control of prepubertal LHRH and discuss the potential for the element to cause either helpful or harmful outcomes on the developmental process depending upon the age and accumulation of Mn within the hypothalamus.

Manganese-Stimulated Kisspeptin Is Mediated by the IGF-1/Akt/Mammalian Target of Rapamycin Pathway in the Prepubertal Female Rat.

Low-dose administration of manganese chloride (MnCl2) causes release of hypothalamic LH-releasing hormone (LHRH) and advances puberty in rat. Recently, this element was shown to up-regulate mammalian target of rapamycin (mTOR), kisspeptin gene (KiSS-1), and LHRH gene expressions in the brain preoptic area (POA)/anteroventral periventricular (AVPV) nucleus. Because these genes are critical for puberty, this study was conducted to identify the upstream mechanism by which Mn activates the mTOR/KiSS-1 pathway. On day 12, immature female rats began receiving a daily supplemental dose of 10 mg/kg of MnCl2 or saline by gavage, and POA/AVPV tissues were collected on day 29 for specific protein assessments. Another experiment assessed in vitro IGF-1 release in response to Mn and assessed signal transduction pathways in the POA/AVPV region after Mn delivery into the third ventricle. Chronic Mn exposure increased (P < .05) basal expressions of mTOR and kisspeptin proteins. Mn increased protein kinase B (Akt) and Ras homolog enriched in brain, both capable of activating mTOR. Central Mn delivery increased expressions of phosphorylated IGF-1 receptor (IGF-1R) (P < .05) and Akt (P < .01) in the POA/AVPV region. The previous central delivery of JB1, an IGF-1R antagonist, blocked Mn-induced expressions of both phosphorylated IGF-1R and Akt. Downstream to Akt, centrally administered Mn increased tuberous sclerosis complex 2 (P < .05), Ras homolog enriched in brain (P < .01), mTOR (P < .05), and kisspeptin (P < .05). Finally, we observed that the early puberty induced by Mn was blocked by the administration of an mTOR inhibitor. These results suggest that Mn acts, at least in part, through the IGF-1/Akt/mTOR pathway to influence prepubertal kisspeptin and LHRH.

Manganese protects against the effects of alcohol on hypothalamic puberty-related hormones.

AIMS: Since manganese (Mn) is capable of stimulating the hypothalamic-pituitary unit and advancing female puberty, we assessed the possibility that this element might overcome some of the detrimental effects of prepubertal alcohol (ALC) exposure on the hypothalamic control of pituitary function. MAIN METHODS: Rats received either saline or Mn (10mg/kg) daily by gastric gavage from day 12 to day 31. After weaning, all rats were provided Lab Chow diet ad libitum until day 27 when they began receiving either the Bio Serv control or ALC diet regime. On day 31, the medial basal hypothalamus (MBH) was collected to assess luteinizing hormone-releasing hormone (LHRH) and cyclooxygenase 2 (COX2) protein levels. Release of prostaglandin-E2 (PGE2), LHRH and serum luteinizing hormone (LH) were also assessed. Other animals were not terminated on day 31, but remained in study to assess timing of puberty. KEY FINDINGS: Short-term ALC exposure caused elevated hypothalamic LHRH content, suggesting an inhibition in peptide release, resulting in a decrease in LH. Both actions of ALC were reversed by Mn supplementation. COX2 synthesis, as well as PGE2 and LHRH release were suppressed by ALC exposure, but Mn supplementation caused an increase in COX2 synthesis and subsequent PGE2 and LHRH release in the presence of ALC. Mn supplementation also ameliorated the action of ALC to delay puberty. SIGNIFICANCE: These results suggest that low level Mn supplementation acts to protect the hypothalamus from some of the detrimental effects of ALC on puberty-related hormones.

Differential Effects of Alcohol on Excitatory and Inhibitory Puberty-Related Peptides in the Basal Hypothalamus of the Female Rat.

BACKGROUND: An increase in development of excitatory inputs along with a decline in inhibitory inputs ultimately govern the timely increased secretion of hypothalamic luteinizing hormone-releasing hormone (LHRH) at the time of puberty. As chronic alcohol (ALC) exposure acts at the hypothalamic level to suppress LHRH secretion and delay puberty, we assessed its ability to differentially affect the expression of key puberty-related proteins. METHODS: ALC was administered to female rats from days 27 to 33, at which time animals were killed and tissues collected for protein expression. In the medial basal hypothalamus (MBH), we assessed kisspeptin (Kp) 10, an excitatory peptide critical for prepubertal LHRH secretion, and Lin28b, a peptide with an inhibitory influence on puberty. As a direct mechanism of action of Lin28b was not known, we determined whether its central administration could induce dynorphin (DYN), a peptide that is inhibitory on LHRH secretion. Also, ALC's effect on DYN protein expression was assessed, as well as its effect on DYN release in vitro. RESULTS: ALC markedly suppressed (p < 0.01) the expression of the excitatory Kp protein, while at the same time increased (p < 0.001) the expression of inhibitory Lin28b protein. Subsequently, we showed for the first time that the central administration of Lin28b stimulated (p < 0.01) the synthesis of DYN. Finally, ALC also induced (p < 0.01) the protein expression and stimulated (p < 0.01) the in vitro release of DYN from the MBH. CONCLUSIONS: These results indicate that ALC can simultaneously and differentially alter both excitatory and inhibitory influences governing pubertal development, show for the first time a mechanism of action by which Lin28b exerts its prepubertal inhibitory tone, and further demonstrate the negative influences of ALC on the pubertal process.