A role for the cystathionine-ß-synthase /H2S axis in astrocyte dysfunction in the aging brain.

Astrocytic dysfunction is central to age-related neurodegenerative diseases. However, the mechanisms leading to astrocytic dysfunction are not well understood. We identify that among the diverse cellular constituents of the brain, murine and human astrocytes are enriched in the expression of CBS. Depleting CBS in astrocytes causes mitochondrial dysfunction, increases the production of reactive oxygen species (ROS) and decreases cellular bioenergetics that can be partially rescued by exogenous H2S supplementation or by re-expressing CBS. Conversely, the CBS/H2S axis, associated protein persulfidation and proliferation are decreased in astrocytes upon oxidative stress which can be rescued by exogenous H2S supplementation. Here we reveal that in the aging brain, the CBS/H2S axis is downregulated leading to decreased protein persulfidation, together augmenting oxidative stress. Our findings uncover an important protective role of the CBS/H2S axis in astrocytes that may be disrupted in the aged brain.

CPAP-induced airway hyper-reactivity in mice is modulated by hyaluronan synthase-3.

BACKGROUND: Continuous positive airway pressure (CPAP) is a primary mode of respiratory support for preterm infants. Animal studies have shown long-term detrimental effects on lung/airway development, particularly airway (AW) hyper-reactivity, as an unfortunate consequence of neonatal CPAP. Since the hyaluronan (HA) synthesizing enzyme hyaluronan synthase-3 (HAS3) is involved in various adult pulmonary disorders, the present study used a neonatal mouse model to investigate the role of HAS3 in CPAP-induced AW hyper-reactivity. METHODS: Male and female neonatal mice were fitted with a custom-made mask for delivery of daily CPAP 3 h/day for 7 days. At postnatal day 21 (2 weeks after CPAP ended), airway (AW) hyper-reactivity and HAS3 expression were assessed with and without in vitro HAS3 siRNA treatment. RESULTS: MRIs of 3-day-old mice confirmed that CPAP increased lung volume with incrementing inflation pressures. CPAP increased AW reactivity in both male and female mice, which was associated with increased airway smooth muscle and epithelial HAS3 immunoreactivity. CPAP did not affect HA accumulation, but HAS3 siRNA reversed CPAP-induced AW hyper-reactivity and reduced HAS3 expression. CONCLUSIONS: These data in mice implicate a role for HAS3 in long-term effects of CPAP in the developing airway in the context of preterm birth and CPAP therapy. IMPACT: Neonatal CPAP increases airway smooth muscle and epithelial HAS3 expression in mice. CPAP-induced airway hyper-reactivity is modulated by HAS3. These data enhance our understanding of the role mechanical forces play on lung development. These data are a significance step toward understanding CPAP effects on developing airway. These data may impact clinical recognition of the ways that CPAP may contribute to wheezing disorders of former preterm infants.

Hydrogen Sulfide-Clues from Evolution and Implication for Neonatal Respiratory Diseases.

Reactive oxygen species (ROS) have been the focus of redox research in the realm of oxidative neonatal respiratory diseases such as bronchopulmonary dysplasia (BPD). Over the years, nitric oxide (NO) and carbon monoxide (CO) have been identified as important gaseous signaling molecules involved in modulating the redox homeostasis in the developing lung. While animal data targeting aspects of these redox pathways have been promising in treating and/or preventing experimental models of neonatal lung disease, none are particularly effective in human neonatal clinical trials. In recent years, hydrogen sulfide (H2S) has emerged as a novel gasotransmitter involved in a magnitude of cellular signaling pathways and functions. The importance of H2S signaling may lie in the fact that early life-forms evolved in a nearly anoxic, sulfur-rich environment and were dependent on H2S for energy. Recent studies have demonstrated an important role of H2S and its synthesizing enzymes in lung development, which normally takes place in a relatively hypoxic intrauterine environment. In this review, we look at clues from evolution and explore the important role that the H2S signaling pathway may play in oxidative neonatal respiratory diseases and discuss future opportunities to explore this phenomenon in the context of neonatal chronic lung disease.

Tele-Echocardiography for Congenital Heart Disease Screening in a Level II Neonatal Intensive Care Unit with Hybrid Telemedicine System.

Introduction: The nationwide shortage of pediatric cardiologists in medically underserved areas poses a challenge to congenital heart disease (CHD) screening requiring echocardiography, resulting in transfer of neonates to regional Level III/IV Neonatal Intensive Care Units (NICUs). This study aimed to evaluate the accuracy, safety, and cost-effectiveness of tele-echocardiography for advanced CHD screening at a Level II NICU managed by a hybrid telemedicine system. Methods: Retrospective chart review of infants requiring tele-echocardiography at a Level II NICU. Patient demographics, echocardiography indications, and findings were analyzed. Agreement between tele-echocardiography and conventional echocardiography findings was assessed. Transport cost savings were calculated based on preventable transfers to Level IV NICU. Descriptive statistics were computed for demographic and clinical variables. Results: Over 5 years, 52 infants were screened for CHD. Thirty-two infants (62%) had findings consistent with minor CHD or normal neonatal transitional physiology. Twenty infants (38%) had abnormal findings requiring follow-up with either a conventional echocardiography as inpatient at the regional Level IV NICU or as outpatient after discharge. Only 5 infants (10%) required transfer to a Level IV NICU for CHD management, whereas 15 infants (29%) were scheduled for outpatient follow-up. Strong agreement was noted between tele-echocardiography and conventional echocardiography findings. No case of critical congenital heart disease (CCHD) was missed. Tele-echocardiography saved $260,000 in transport costs. Conclusions: Tele-echocardiography can be accurate, safe, and effective in CHD screening, preventing unnecessary transfer of most infants to regional Level III/IV NICUs, saving transfer costs.

Scope of telemedicine in neonatology.

There is a widespread shortage of physicians worldwide, especially in rural areas. This shortage is more prevalent when it comes to subspecialty care, even in developed countries. One way to provide access to specialty care is using technology via telemedicine. Telemedicine has evolved over the last two decades, and its use is becoming widespread in developed countries. However, its use in the neonatal population is still limited and practiced only in some centers. It is now apparent that telemedicine can be successfully used in the neonatal population for screening premature infants for retinopathy of prematurity, congenital heart disease, bedside clinical rounds, neonatal resuscitation with the support of a tertiary care hospital, and family support. This avoids unnecessary transfer and appears to provide the same quality of care that the baby would have received at the tertiary care facility. This approach also improves family satisfaction, as the baby and the mother are kept together, and reduces the cost of care. This review focuses on the use of telemedicine in neonatal care, concentrating on the main areas where telemedicine has been shown to be successful and effective, including the status of telemedicine in China.

Volume Targeted Ventilation and High Frequency Ventilation as the Primary Modes of Respiratory Support for ELBW Babies: What Does the Evidence Say?

Respiratory management of the extremely low birth weight (ELBW) newborn has evolved over time. Although non-invasive ventilation is being increasingly used for respiratory support in these ELBW infants, invasive ventilation still remains the primary mode in this population. Current ventilators are microprocessor driven and have revolutionized the respiratory support for these neonates synchronizing the baby's breath to ventilator breaths. High frequency ventilators with the delivery of tidal volumes less than the dead space have been introduced to minimize barotrauma and chronic lung disease. Despite these advances, the incidence of chronic lung disease has not decreased. There is still controversy regarding which mode is ideal as the primary mode of ventilation in ELBW infants. The most common modes seem to be pressure targeted conventional ventilation, volume targeted conventional ventilation and high frequency ventilation which includes high frequency oscillatory ventilation, high frequency jet ventilation and high frequency flow interrupter. In recent years, several randomized controlled trials and meta-analyses have compared volume vs. pressure targeted ventilation and high frequency ventilation. While volume targeted ventilation and high frequency ventilation does show promise, substantial practice variability among different centers persists. In this review, we weighed the evidence for each mode and evaluated which modes show promise as the primary support of ventilation in ELBW babies.

Vulnerability of the developing airway.

Longer term respiratory morbidity is a frequent concern for former preterm infants. Increased airway reactivity and wheezing disorders are extremely common in this population, both in infants who meet diagnostic criteria for bronchopulmonary dysplasia [BPD], and in the absence of this diagnosis. It is, therefore, imperative to gain a better understanding of normal and abnormal postnatal development of the immature airway. Airway hyperreactivity may be secondary to abnormal bronchoalveolar attachments in the face of parenchymal lung injury, or secondary to an imbalance between constrictor and dilator neural pathways. Finally, the airway itself may undergo functional and/or structural changes, including increased airway smooth muscle mass, and changes in airway extracellular matrix which may, in turn, modulate downstream signaling pathways to hyperoxia or pressure exposed vulnerable airways.

A new logical insight and putative mechanism behind fluoxetine-induced amenorrhea, hyperprolactinemia and galactorrhea in a case series.

With the exception of fluoxetine, all selective serotonin reuptake inhibitors (SSRIs) commonly cause hyperprolactinemia through presynaptic mechanisms indirectly via 5-hydroxytryptamine (5-HT)-mediated inhibition of tuberoinfundibular dopaminergic neurons. However, there is little insight regarding the mechanisms by which fluoxetine causes hyperprolactinemia via the postsynaptic pathway. In this text, analysis of five spontaneously reported clinical cases of hyperprolactinemia resulting in overt symptoms of amenorrhea with or without galactorrhea, were scrupulously analyzed after meticulously correlating relevant literature and an attempt was made to explore the putative postsynaptic pathway of fluoxetine inducing hyperprolactinemia. Hypothetically, serotonin regulates prolactin release either by increasing oxytocin (OT) level via direct stimulation of vasoactitive intestinal protein (VIP) or indirectly through stimulation of GABAergic neurons. The pharmacodynamic exception and pharmacokinetic aspect of fluoxetine are highlighted to address the regulation of prolactin release via serotonergic pathway, either directly through stimulation of prolactin releasing factors (PRFs) VIP and OT via 5-HT2A receptors predominantly on PVN (neurosecretory magnocellular cell) or through induction of 5-HT1A-mediated direct and indirect GABAergic actions. Prospective molecular and pharmacogenetic studies are warranted to visualize how fluoxetine regulate neuroendocrine system and cause adverse consequences, which in turn may explore new ways of approach of drug development by targeting the respective metabolic pathways to mitigate these adverse impacts.

Oral aripiprazole-induced severe hypoglycemia.

This case report highlights a very rare adverse drug reaction caused by oral aripiprazole resulting in severe hypoglycemia. A 72-year-old-male patient suffering from Parkinson disease on prolonged carbidopa plus levodopa combination therapy (carbidopa 25 mg plus levodopa 100 mg, thrice daily) for 1.3 years was recently diagnosed with psychosis and was initiated 10 mg/day oral aripiprazole. After 10 days of aripiprazole therapy, the patient experienced symptoms of hypoglycemia and on the 21st day, he was hospitalized for severe hypoglycemia. Other long-term concomitant medications taken by this patient were oral losartan (25 mg/day) and rosuvastatin (40 mg/day). Dechallenge and rechallenge with aripiprazole revealed that there is a "definite" (according to Naranjo adverse drug reaction probability scale) relationship between administration of aripiprazole and onset of hypoglycemic events.

Oral pantoprazole-induced acute pancreatitis in an 11-year-old child.

This case report highlights a very rare adverse drug reaction caused by oral pantoprazole resulting in acute pancreatitis. An 11-year-old boy was diagnosed with gastroesophageal reflux disease. Apart from general advice for lifestyle and dietary changes, he was symptomatically prescribed oral pantoprazole 40 mg once daily 30 minutes before meals for 4 weeks. The symptoms of gastroesophageal reflux disease were improving gradually, but the patient developed progressive symptoms of acute pancreatitis and was admitted in the emergency department with acute abdominal pain. Relevant investigations were done, and it was diagnosed as a case of acute pancreatitis. There was no evidence of any other possible hereditary, traumatic, surgical, metabolic, infective, organic, or pathologic causes giving rise to this condition, and this acute pancreatitis was probably drug (pantoprazole) induced. Dechallenge was done, and the patient was treated conservatively resulting in reversal of the diseased state. Naranjo adverse drug reaction probability scale suggested that the likelihood that oral administration of pantoprazole was responsible for the acute pancreatitis was 'probable.'