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.

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.

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.

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.

Actions and interactions of alcohol and transforming growth factor ß1 on prepubertal hypothalamic gonadotropin-releasing hormone.

BACKGROUND: Alcohol (ALC) diminishes gonadotropin-releasing hormone (GnRH) secretion and delays puberty. Glial transforming growth factor ß1 (TGFß1) plays a role in glial-neuronal communications facilitating prepubertal GnRH secretion. We assessed the effects of acute ALC administration on TGFß1-induced GnRH gene expression in the brain preoptic area (POA) and release of the peptide from the medial basal hypothalamus (MBH). Furthermore, we assessed actions and interactions of TGFß1 and ALC on an adhesion/signaling gene family involved in glial-neuronal communications. METHODS: Prepubertal female rats were administered ALC or water via gastric gavage at 7:30 am. At 9:00 am, saline or TGFß1 (100 ng/3 µl) was administered into the third ventricle. At 3:00 pm, the POA was removed and frozen for gene expression analysis and repeated for protein assessments. In another experiment, the MBH was removed from ALC-free rats. After equilibration, tissues were incubated in Locke's medium only or medium containing TGFß1 with or without 50 mM ALC for measurement of GnRH peptide released in vitro. RESULTS: TGFß1 induced GnRH gene expression in the POA, and this effect was blocked by ALC. We also described the presence and responsiveness of the TGFß1 receptor in the POA and showed that acute ALC exposure not only altered the TGFß1-induced increase in TGFß-R1 protein expression but also the activation of receptor-associated proteins, Smad2 and Smad3, key downstream components of the TGFß1 signaling pathway. Assessment of an adhesion/signaling family consisting of glial receptor protein tyrosine phosphatase beta and neuronal contactin-associated protein-1 (Caspr1) and contactin showed that the neuronal components were induced by TGFß1 and that ALC blocked these effects. Finally, TGFß1 was shown to induce release of the GnRH peptide in vitro, an action that was blocked by ALC. CONCLUSIONS: We have demonstrated glial-derived TGFß1 induces GnRH gene expression in the POA and stimulates release of the peptide from the MBH, actions necessary for driving the pubertal process. Importantly, ALC acted at both brain regions to block stimulatory effects of TGFß1. Furthermore, ALC altered neuronal components of an adhesion/signaling family previously shown to be expressed on GnRH neurons and implicated in glial-GnRH neuronal communications. These results further demonstrate detrimental effects of ALC at puberty.

Alcohol alters insulin-like growth factor-1-induced transforming growth factor ß1 synthesis in the medial basal hypothalamus of the prepubertal female rat.

BACKGROUND: Insulin-like growth factor-1 (IGF-1) and transforming growth factor ß1 (TGFß1) are produced in hypothalamic astrocytes and facilitate luteinizing hormone-releasing hormone (LHRH) secretion. IGF-1 stimulates release by acting directly on the LHRH nerve terminals and both peptides act indirectly through specific plastic changes on glial/tanycyte processes that further support LHRH secretion. Because the relationship between these growth factors in the hypothalamus is not known, we assessed the ability of IGF-1 to induce TGFß1 synthesis and release and the actions of alcohol (ALC) on this mechanism prior to the onset of puberty. METHODS: Hypothalamic astrocytes were exposed to medium only, medium plus IGF-1 (200 ng/ml), or medium plus IGF-1 with 50 mM ALC. After 18 hours, media were collected and assayed for TGFß1. For the in vivo experiment, prepubertal female rats were administered either ALC (3 g/kg) or water via gastric gavage at 07:30 hours and at 11:30 hours. At 09:00 hours, saline or IGF-1 was administered into the third ventricle. Rats were killed at 15:00 hours and the medial basal hypothalamus (MBH) was collected for assessment of TGFß1, IGF-1 receptor (IGF-1R), and Akt. RESULTS: IGF-1 induced TGFß1 release (p < 0.01) from hypothalamic astrocytes in culture, an action blocked by ALC. In vivo, IGF-1 administration caused an increase in TGFß1 protein compared with controls (p < 0.05), an action blocked by ALC as well as a phosphatidylinositol 3 kinase/Akt inhibitor. IGF-1 stimulation also increased both total (p< 0.01) and phosphorylated (p)-IGF-1R (p < 0.05) protein levels, and phosphorylated (p)-Akt levels (p < 0.01), which were also blocked by ALC. CONCLUSIONS: This study shows that ALC blocks IGF-1 actions to stimulate synthesis and release of hypothalamic TGFß1, total and p-IGF-1R, and p-Akt levels further demonstrating the inhibitory actions of ALC on puberty-related events associated with hypothalamic LHRH release.

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.

Hypothalamic actions and interactions of alcohol and IGF-1 on the expression of glial receptor protein tyrosine phosphatase-ß during female pubertal development.

BACKGROUND: Hypothalamic glial-neuronal communications are important for the activation of luteinizing hormone releasing hormone (LHRH) secretion at the time of puberty. As we have shown that alcohol (ALC) diminishes prepubertal LHRH secretion and delays puberty, we first assessed the effects of short-term ALC administration on the basal expression of a specific gene family involved in glial-neuronal communications. Second, as insulin-like growth factor-1 (IGF-1) is a critical regulator of LHRH secretion and the pubertal process, we then assessed whether IGF-1 could induce the expression of these signaling genes and determine whether ALC can block this affect. METHODS: Immature female rats were fed a liquid diet containing ALC for 6 days beginning when 27 days old. Control animals received either the companion isocaloric liquid diet or rat chow and water. Animals were decapitated on day 33, in the late juvenile stage of development. Medial basal hypothalamic (MBH) tissues were obtained for gene and protein analyses of glial receptor protein tyrosine phosphatase-ß (RPTPß) and the 2 neuronal components, contactin and contactin-associated protein 1 (Caspr1). In the second experiment, IGF-1 was administered into the third ventricle (3V) and the MBH removed 6 hours after peptide delivery, and the above-mentioned 3 genes were analyzed by real-time PCR. To determine whether this action was affected by ALC, immature female rats were administered either ALC (3 g/kg) or water via gastric gavage at 0900 hours. At 1030 hours, the ALC and control groups were subdivided such that half of the animals were injected into the 3V with IGF-1 and the other half with an equal volume of saline. Rats were killed 6 hours after the IGF-1 injection and MBHs collected. RESULTS: Real-time PCR showed that when compared with control animals, ALC caused a marked decrease (p < 0.001) in the basal expression of the RPTPß gene, but did not affect the expression of either contactin or Caspr1. Likewise, analysis by Western blotting demonstrated that ALC caused suppressed (p < 0.001) levels of the RPTPß protein, with the expressions of both contactin and Caspr1 proteins being unaltered. In the second experiment, results showed that only the RPTPß gene was stimulated (p < 0.05) by IGF-1 in the MBH 6 hours after peptide delivery. Assessments revealed that the IGF-1 induced increase (p < 0.01) in the expression of the RPTPß gene was blocked by the presence of ALC. CONCLUSIONS: Prepubertal ALC exposure is capable of interfering with hypothalamic glial-neuronal communications by suppressing the synthesis of the glial product, RPTPß, which is required for binding to the contactin-Caspr1 complex on LHRH neuronal terminals, thus suggesting that this action of ALC contributes to its detrimental effects on the pubertal process.

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.

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.

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.

Insulin-like growth factor-I activates KiSS-1 gene expression in the brain of the prepubertal female rat.

KiSS-1 gene expression has been shown to increase as puberty approaches, and its peptide products, kisspeptins, are involved in LHRH secretion at puberty. Factors contributing to increased KiSS-1 expression, however, have not been identified; thus, the purpose of this study was to assess whether IGF-I could induce transcription of this gene in prepubertal female rats. IGF-I or saline was centrally administered to immature rats that were killed 2, 4, and 6 h later. Real-time PCR revealed that IGF-I induced (P < 0.01) KiSS-1 gene expression at 6 h in a tissue fragment that contained both the anteroventral periventricular (AVPV) and arcuate (ARC) nuclei. Subsequently, the AVPV and ARC nuclei were separated to assess whether region-specific effects could be identified. IGF-I stimulated (P < 0.01) KiSS-1 gene expression in the AVPV nucleus at 6 h after injection, with no change observed in the ARC nucleus. Serum estradiol (E2) levels were not altered at any time point after IGF-I, demonstrating that the increased KiSS-1 expression observed was not caused by an elevation in E2. Additionally, the IGF-I action to induce KiSS-1 gene expression in the AVPV nucleus was further demonstrated when the IGF-I was administered systemically. E2 appears to play an important permissive role because 1-d ovariectomized rats responded to IGF-I with increased (P < 0.01) KiSS-1 expression, whereas, 20 d after ovariectomy, when the E2 levels had fallen below assay sensitivity, the IGF-I was unable to induce KiSS-1 expression. The IGF-I effect was further demonstrated by showing that the IGF-I receptor antagonist, JB-1, blocked the IGF-I-induced increase in KiSS-1 expression. Collectively, these data indicate that IGF-I is an activator of the KiSS-1 gene in the prepubertal female rat.

Short-term alcohol administration alters KiSS-1 gene expression in the reproductive hypothalamus of prepubertal female rats.

BACKGROUND: Kisspeptins bind to the G-protein-coupled receptor (GPR54) to activate hypothalamic luteinizing hormone releasing hormone (LHRH) secretion at the time of puberty. Alcohol (ALC) causes depressed prepubertal LHRH release, resulting in depressed luteinizing hormone (LH) secretion and delayed puberty. Because KiSS-1 and GPR54 are important to the onset of puberty, we assessed the effects of chronic ALC administration on basal expression of these puberty-related genes within the reproductive hypothalamus, as well as hormones and transduction signaling pathways contributing to their activity. METHODS: Immature female rats were fed a liquid diet containing ALC for 6 days beginning when 27 days old. Controls received either companion isocaloric liquid diet or rat chow and water. Animals were decapitated on day 33, in the late juvenile stage of development. Blood was collected for the assessment of serum hormone levels. Brain tissues containing the anteroventral periventricular (AVPV) and arcuate (ARC) nuclei were obtained for assessing expression of specific puberty-related genes and proteins. RESULTS: KiSS-1 mRNA levels in the AVPV and ARC nuclei were suppressed (p < 0.001) in the ALC-treated rats. GPR54 gene and protein expressions were both modestly increased (p < 0.05) in AVPV nucleus, but not in ARC nucleus. Alcohol exposure also resulted in suppressed serum levels of insulin-like growth factor-1 (IGF-1), LH, and estradiol (E(2)). As IGF-1, in the presence of E(2), can induce expression of the KiSS-1 gene, we assessed the potential for ALC to alter IGF-1 signaling in the reproductive hypothalamus. IGF-1 receptor gene and protein expressions were not altered. However, protein expression of phosphorylated Akt, a transduction signal used by IGF-1, was suppressed in the AVPV (p < 0.05) and ARC (p < 0.01) nuclei. CONCLUSIONS: Alcohol causes suppressed KiSS-1 gene expression in the reproductive hypothalamus; hence, contributing to this drug's ability to cause suppressed LHRH secretion and disruption of the pubertal process. We suggest that this action, at least in part, is through altered IGF-1 signaling.

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.

Impact of an integrated nutrition and health programme on neonatal mortality in rural northern India.

OBJECTIVE: To assess the impact of the newborn health component of a large-scale community-based integrated nutrition and health programme. METHODS: Using a quasi-experimental design, we evaluated a programme facilitated by a nongovernmental organization that was implemented by the Indian government within existing infrastructure in two rural districts of Uttar Pradesh, northern India. Mothers who had given birth in the 2 years preceding the surveys were interviewed during the baseline (n = 14 952) and endline (n = 13 826) surveys. The primary outcome measure was reduction of neonatal mortality. FINDINGS: In the intervention district, the frequency of home visits by community-based workers increased during both antenatal (from 16% to 56%) and postnatal (from 3% to 39%) periods, as did frequency of maternal and newborn care practices. In the comparison district, no improvement in home visits was observed and the only notable behaviour change was that women had saved money for emergency medical treatment. Neonatal mortality rates remained unchanged in both districts when only an antenatal visit was received. However, neonates who received a postnatal home visit within 28 days of birth had 34% lower neonatal mortality (35.7 deaths per 1000 live births, 95% confidence interval, CI: 29.2-42.1) than those who received no postnatal visit (53.8 deaths per 1000 live births, 95% CI: 48.9-58.8), after adjusting for sociodemographic variables. Three-quarters of the mortality reduction was seen in those who were visited within the first 3 days after birth. The effect on mortality remained statistically significant when excluding babies who died on the day of birth. CONCLUSION: The limited programme coverage did not enable an effect on neonatal mortality to be observed at the population level. A reduction in neonatal mortality rates in those receiving postnatal home visits shows potential for the programme to have an effect on neonatal deaths.