Hepatoprotective Effects of Aureobasidium pullulans Derived ß 1,3-1,6 Glucans in a Murine Model of Non-alcoholic Steatohepatitis.

Background: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are highly prevalent conditions characterized by inflammation and fibrosis of the liver, which can progress to cirrhosis and hepatocellular carcinoma if left untreated. Conventional modalities are mainly symptomatic, with no definite solution. Beta-glucan-based biological response modifiers are a potential strategy in lieu of their beneficial metabolic effects. Aureobasidium pullulans strains AFO-202 and N-163 beta-glucans were evaluated for anti-fibrotic and anti-inflammatory hepatoprotective potentials in a NASH animal model in this study. Methods: In the STAM™ murine model of NASH, five groups were studied for 8 weeks: (1) vehicle (RO water), (2) AFO-202 beta-glucan; (3) N-163 beta-glucan, (4) AFO-202+N-163 beta-glucan, and (5) telmisartan (standard pharmacological intervention). Evaluation of biochemical parameters in plasma and hepatic histology including Sirius red staining and F4/80 immunostaining were performed. Results: AFO-202 beta-glucan significantly decreased inflammation-associated hepatic cell ballooning and steatosis. N-163 beta-glucan decreased fibrosis and inflammation significantly (P value < 0.05). The combination of AFO-202 with N-163 significantly decreased the NAFLD Activity Score (NAS) compared with other groups. Conclusion: This preclinical study supports the potential of N-163 and AFO-202 beta-glucans alone or in combination as potential preventive and therapeutic agent(s), for NASH.

Potential of Combination of Bone Marrow Nucleated and Mesenchymal Stem Cells in Complete Spinal Cord Injury.

BACKGROUND: Cell-based therapies represent one of the definitive treatment approaches to SCI which, to become a routine clinical application, is marred by several known unknowns. The Bone Marrow Mononuclear Cells (BMMNCs) and Mesenchymal Stem Cells (MSCs) represent the most clinically applied cell types for SCI in humans, with safety established, and to an extent, efficacy reported. METHODS: In this review, we have analysed the clinical studies performed using BMMNC and MSC for complete SCI separately, and the potential for applying those cells in combination. We have also analysed those factors whose outcome in animal studies of SCI could be evaluated in depth but the clinical outcome cannot be evaluated intrinsically owing to practical difficulties. CONCLUSION: A combination of these two cell types, BMMNC and MSC, has been proven to be advantageous than applying them separately. Therefore, a thorough evaluation including the rationale and potential implications of applying these two therapies has been presented here, and we hypothesize that such a combination is likely to improvise the outcome of a wholesome approach to spinal cord regeneration after SCI.

Global notes: mysteries of 'the first' and the 'last breath' and the gift of Neonatal Resuscitation Program.

First and last breaths define the life span of a living animal including humans. Humans have been fascinated more with the last breath-the death. Neonatologists are focused on initiating the first breath. Millions of babies around the world do not have a chance of survival beyond a few moments after birth for lack of successful initiation of their first breath. Both neonatologists and other health care providers work hard to separate the last breath from the first breath using resuscitative measures thanks to the NRP developed and propagated two decades ago. This paper is dedicated to the initiators of the program, and all those dedicated health care teams working around the globe to save newborn lives.

Global minute: water and health--walking for water and water wars.

Water is a precious commodity and needs to be conserved. Water plays an important role in daily life: in sustenance of life, sanitation and food production. Scarcity of water may lead to water wars among water-stressed nations. Therefore, there is a need for development of democratic principles among nations to assure free access to water to one and all. In view of the fact that lack of access to clean water affects health and infant mortality gap. Great importance is given to improve water resources in the communities (Millennium Development Goal number 7). As professionals entrusted with the health of mother and child, we must strive to improve access to potable clean water to communities in underdeveloped countries.

Global notes: instinctive resuscitation of a newborn by mother: a lesson to be learned.

The fact is that mother is the best combined pediatrician and neonatologist in the world. She is the most passionate and vested caregiver for the newborn, whether living and delivering in a modern hospital in a developed country or in a village in the remotest part of the globe; whether she is literate or illiterate. Let us focus our efforts on providing mothers the additional skills in caring for the baby in difficult situations immediately after birth.

Global notes: the tale of two giants--China and India.

The two giant nations India and China are the emerging powers of the 21st century. There is a debate as to which of the two will edge ahead. This article compares the gains made by the two nations in economics, technology and human development.

Global notes: counting the world's poor--how do we define poverty?

Health professionals are in constant interaction with parents and infants who are victims of poverty and poor socioeconomic status. But an important question remains: do we know how to define poverty? Defining poverty accurately is important as the definition is the basis of policy development. The definition of poverty has changed during the last quarter century. In addition to economic considerations, it is broadened to include other dimensions of life such as literacy, health and longevity. This article attempts to provide national and international definitions of poverty, the magnitude and effects of poverty.

Insulin and growth-hormone responses in neonatal hyperglycemia.

Glucose, insulin, and growth hormone values were studied prospectively in 75 premature infants during the first five days after birth. Intravenous glucose was given at a mean rate of 4.7-4.9 mg./kg./min. (range 3-7). Mean birth weight was 1,394+/-47 gm. (mean+/-S.E.M.). Blood glucose values were significantly higher on days 1 and 2 than on days 3 to 5. Hypoglycemia (blood glucose less than 20 mg./100 ml.) occurred in two SGA and one AGA infants. On the other hand, hyperglycemia (greater than 125 mg./100 ml.) was found in 32 of the 75 (42.7 per cent) infants. A significantly greater number of deaths occurred in infants with hyperglycemia (19/32) than in those with normoglycemia (19/32) than in those with normoglycemia (5/43). Mean plasma insulin values were significantly higher on days 1 and 2 (15+/-3 and 18+/-4 muU./ml.) than on days 3 and 4-5 (6+/-1 and 7+/-2 muU./ml.). In addition, mean insulin levels were significantly higher during hyperglycemic than during normoglycemic glucose levels at similar postnatal age. Growth hormone values were higher during the first three days than subsequently, but the values were similar in normoglycemic and hyperglycemic groups. Significant negative correlations were seen between glucose values on the first two days of postnatal life and birth weight, gestational age, and Apgar scores, whereas positive correlations were found with FiO2 and respiratory distress score (RDS).

Inflammatory response and apoptosis in newborn lungs after meconium aspiration.

An important feature of meconium-instilled newborn lungs is an inflammatory response and apoptotic cell death. It was recently demonstrated by our group and supported by several other investigators in a relatively short period of time. Apoptosis exists also in healthy lungs, but in meconium-instilled lungs its level is usually dramatically higher. Apoptosis is characterized by loss of cell function, decrease in cell size, and its morphology. Apoptosis plays an important role in normal cell life, but increased levels of apoptosis induce great damage for any tissues. Apoptosis in the lungs has been greatly overlooked for the past decade, and meconium-induced apoptosis is a relatively new event and not effectively studied at the present time. This Review summarized current knowledge regarding meconium-induced inflammation and apoptosis in newborn lungs.

The GVK EMRI maternal and neonatal transport system in India: a mega plan for a mammoth problem.

Maternal and infant mortality has been a major concern in India with the Government taking serious efforts to achieve the Millennium Development Goals by 2015. Ganapathy Venkata Krishna Reddy Emergency Management and Research Institute (GVK EMRI) is one such effort and is the country's first emergency service provider working under the public-private partnership model to provide emergency response services and quality pre-hospital care to any sick person, pregnant mothers, and sick neonates. Since the introduction of the emergency medical services, institutional deliveries have increased in all states and union territories where the ambulances have been deployed and the majority of mothers have been provided the required emergency care at the appropriate time. This in turn has helped in considerably reducing the maternal mortality. GVK EMRI has partnered with the government of Tamil Nadu and deployed specialized neonatal ambulances to ensure safe transport of newborns. The safe transport of sick, vulnerable neonates and the improvement in survival of transported neonates over the years advocate scaling up of this program to other states, which would greatly contribute towards reducing infant and neonatal mortality.

Gestational age and indomethacin elimination in the neonate.

The disposition of oral indomethacin was studied in 9 premature infants with significant patent ductus arteriosus (sPDA) with birth weights ranging from 800 to 1,960 gm and gestational ages of 28 to 36 wk. Peak plasma concentrations in most of the subjects were not observed until 3 to 4 hr after administration and ranged from 0.027 to 0.31 microgram/ml. Plasma half-life (t1/2) of indomethacin ranged from 11 to 20 hr and correlated with gestational age. Plasma protein binding studies, in samples from the premature infant using radiolabeled indomethacin, showed no difference in binding from values obtained with adult plasma (greater than 98%). Absorption of orally administered indomethacin appears to be incomplete and plasma clearance much longer than in the adult.

A simple noninvasive technique of measuring intracranial pressure in the newborn.

A noninvasive approach to measuring intracranial pressure in newborns based on optical principles and devoid of electrical hazards is described. This monitoring technique can be used to detail subtle changes in measurements in ill newborns and to predict hydrocephalus. The mean anterior fontanel pressure in normal infants was 10.14 +/- 0.39 cm H2O. Increased pressure was noted in sick neonates and in infants with hydrocephalus. Good correlation was noted between anterior fontanel pressure and CSF pressure. Pediatrics, 59:957-961, 1977, INTRACRANIAL PRESSURE, ANTERIOR FONTANEL PRESSURE, HYDROCEPHALUS, MONITORING DEVICE.

Assisted ventilation in infants with meconium aspiration syndrome.

In a retrospective analysis of infants born with meconium staining over an 18-month period at Cook County Hospital, 32 infants met two of the three criteria for the diagnosis of meconium aspiration syndrome: (1) history of meconium in the oropharynx or trachea; (2) clinical evidence of respiratory distress; and (3) x-ray evidence of aspiration pneumonia. Seventeen infants developed respiratory failure; nine of these infants died. One infant without respiratory failure died of sepsis. Analysis of sequential arterial blood pH and gas tension showed that nonsurviving infants had persistently high PCO2 and A-a gradient in spite of initiation of assisted ventilation. These changes seem to be related to severe right-to-left shunting and ventilation perfusion abnormalities. The data further suggest that asphyxia and acidosis occur well before the infant is born and that intrapartum monitoring to recognize fetal asphyxia may help in improving morbidity and mortality from meconium aspiration syndrome.

Clinical significance of monitoring anterior fontanel pressure in sick neonates and infants.

The intracranial pressure was monitored via the anterior fontanel, using a noninvasive technique, in 78 acutely ill, 39 normal term, and 6 normal preterm infants. In normal term and preterm infants the anterior fontanel pressure (AFP) was 10.2 +/- 0.4 and 9.5 +/- 0.8 cm H2O, respectively. Infants with hyaline membrane disease had elevated pressure (13.3 +/- 0.6 cm H2O), which was higher than that of normal preterm infants. Following an episode of intracranial hemorrhage in four infants, the AFP increased to 26.2 +/- 2.5 cm H2O. Elevated pressure was noted in infants with meconium aspiration syndrome (24.1 +/- 1.8 cm H2O); the pressure decreased during the phase of recovery (15.6 +/- 3.5 cm H2O). Elevated pressure was noted in infants with meningitis and hydrocephalus. Repeated measurements helped to diagnose shunt obstruction in an infant with hydrocephalus.

Early and late surfactant treatments in baboon model of hyaline membrane disease.

Because the issue of optimal time for artificial surfactant therapy for hyaline membrane disease has not been established, the effects of treatment with a reconstituted bovine surfactant (surfactant TA) were compared at two time periods in a hyaline membrane disease model in a premature baboon. The baboons were delivered by cesarean section at 75% of gestation (139.5 +/- 1.5 days, mean +/- SD). One group was treated with surfactant TA within ten minutes after birth (ultraearly), another group was treated at two hours of age (late) and a third (comparison group) did not receive the surfactant. Both treatment groups had significantly higher compliance and ratio of arterial to alveolar Po2 ratio and lower mean airway pressure and oxygen requirement (Fio2) than the comparison group. At autopsy, the largest residual volume and hysteresis in pulmonary pressure-volume curves were noted in the ultraearly group, intermediate values were found in the late group, and least values were found in the comparison group. These data indicate that early surfactant therapy for hyaline membrane disease results in greater improvement in lung mechanics than delaying treatment, even for two hours. Delivery room treatment with surfactant of infants at risk for hyaline membrane disease is perhaps better than therapy for established hyaline membrane disease.

Centronuclear myopathy in the newborn period causing severe respiratory distress.

Centronuclear myopathy can be classified into four clinical varieties based on age, severity at onset, and rapidity of progress. In the severe form with involvement of respiratory muscles at birth, the progress is rapid and fatal before 3 years of age. The case described in this report illustrates rapid progression of muscle paralysis and death in a neonate. However, in a majority of cases the disease is either moderately severe or mild with the affected individuals confined to wheel chair by adolescence or early adult life. Diagnosis of the disease is based on appropriate muscle histopathology and electron microscopic studies.

Bovine surfactant (surfactant TA) therapy in immature baboons with hyaline membrane disease.

As a prelude to clinical trials with a bovine surfactant (surfactant TA), in human infants with hyaline membrane disease, pulmonary and hemodynamic changes following its instillation in premature baboons were investigated. Baboons, delivered by cesarean section at 141 +/- 3.5 days (mean +/- SD, 77% gestation), were provided with intensive care. At 2 hours of age in one group (n = 10), 100 mg/kg of surfactant TA (reconstituted bovine surfactant, Tokyo Tanabe Co., Tokyo) was instilled into the lungs. Sequential measurements and monitoring of pulmonary and hemodynamic variables were carried out in these ten baboons and in a control group of five baboons for 16 hours, at which time the experiments were electively terminated. At birth, the pulmonary compliance, findings of chest radiographs, ratio of arterial PO2 to alveolar PO2, and respirator variables needed to maintain normal blood gas and acid base status were identical in both groups and indicative of severe hyaline membrane disease. Following surfactant instillation, the treated group demonstrated a rapid increase in PO2 with significantly improved ratio of arterial PO2 to alveolar PO2 (from a mean +/- SD pretreatment value of 0.21 +/- 0.11 to 0.45 +/- 0.11 by 16 hours). Pulmonary compliance improved similarly (from pretreatment value of 0.18 +/- 0.06 mL/cm H2O/kg to 0.27 +/- 0.09 mL/cm H2O/kg). Significant reduction in respirator support variables could be achieved in all treated animals; however, in the control animals, the pulmonary status worsened as evidenced by increasing mean airway pressure and respirator variables to keep normal blood gas and acid base status, thus worsening compliance. At autopsy, pulmonary pressure-volume curves were significantly different with large hysteresis obtained in the surfactant-treated group. Although no deleterious effect on hemodynamics was noted in surfactant TA-treated animals, a large patent ductus arteriosus was demonstrated by aortography. Increased lung blood flow, probably due to a large patent ductus arteriosus flow, was demonstrated by radiolabeled microsphere technique. The physiologic significance and clinical relevance of these findings in premature baboons treated with surfactant TA are discussed.

Colloid osmotic pressure in infants with hyaline membrane disease.

Colloid osmotic pressure (COP) was measured serially in 81 critically ill neonates with hyaline membrane disease (HMD) during the first five days of life, and these changes were correlated with the birth weight, gestational age, serum protein level, clinical status, and outcome. Colloid osmotic pressure correlated better with the total protein level (n = 81; r = 0.54) than with birth weight (r = 0.23) and gestational age (r = 0.31; n = 81). Seventy-one of 81 neonates survived. Among the survivors, COP increased significantly by day 5, whereas changes in the total protein level were not significant during the same period. Colloid osmotic pressure decreased significantly in nine of ten nonsurvivors (mean +/- SE, 11 +/- 0.5 to 8 +/- 0.55 mm Hg), whereas the total protein level did not show a similar change. Thus, COP cannot be accurately predicted by measuring serum protein during acute illness. Serial measurement of COP was a better prognostic indicator than the total protein level in infants with HMD.

Transcutaneous oxygen and carbon dioxide monitoring in sick neonates using a combined sensor.

Using a combined O2-CO2 sensor, we evaluated the effect of cathode size and membrane thickness and incorporation of correction factor upon transcutaneous O2-CO2 readings. The present studies were carried out in three phases in newborns less than a week of age. The data from these studies indicate that a combined O2-CO2 sensor with a smaller cathode, Teflon membrane and with a built-in correction factor can accurately reflect arterial O2 and CO2 tension and can replace the present two heated sensors.

A new prenatal cardiac diagnostic device for congenital heart disease.

A unique case of congenital heart disease and complete heart block diagnosed by fetal electrocardiogram (ECG) and phonocardiogram recorded initially at 32 weeks gestation is presented. The slow, regular fetal heart rate of approximately 50 beats/min with bizarre QRS and a diamond-shaped murmur beginning with the fetal QRS complex made a diagnosis of complete heart block (CHB) and associated congenital heart disease highly probable. Direct fetal electrocardiograms (FECG) recorded during labor and vaginal delivery at term confirmed the diagnosis of completel atrioventricular block. Cardiac catheterization at 1 day of age showed multiple congenital heart anomalies. The infant developed signs of congestive heart failure and transvenous pacemaker was successfully placed; however, he died at 9 days of age of sepsis and renal failure.