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Background Historically, adults with relapsed-refractory acute lymphoblastic leukemia (ALL) experienced poor outcomes with intensive chemotherapy. This mature analysis explores the benefit of the addition of sequential blinatumomab to low-intensity mini-Hyper-CVD chemotherapy with inotuzumab ozogamicin in this setting. Methods Mini-Hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 83% dose reduction) was combined with inotuzumab during the first 4 courses. From Patient #68 and onwards, inotuzumab was given in reduced and fractionated doses, and blinatumomab was added sequentially for 4 courses. Maintenance therapy with prednisone, vincristine, 6-mercaptopurine and methotrexate was given for 12 courses, and blinatumomab for 4 additional courses. Results Among 110 patients (median age, 37 years) treated, 91 (83%) responded (complete response, 69 patients, 63%). Measurable residual disease negativity was documented in 75 patients (82% of responders). Fifty-three patients (48%) received allogeneic stem cell transplantation (SCT). Hepatic sinusoidal obstruction syndrome occurred in 9/67 patients (13%) on the original inotuzumab schedule and in 1/43 (2%) on the modified schedule. With a median follow-up of 48 months, the median overall survival (OS) was 17 months, and the 3 year OS was 40%. The 3 year OS was 34% with mini-Hyper-CVD plus inotuzumab and 52% with additional blinatumomab (P = 0.16). By landmark analysis at 4 months, the 3 year OS was 54%, similar between patients who did or did not receive allogeneic SCT. Conclusion Low-intensity mini-Hyper-CVD plus inotuzumab with or without blinatumomab showed efficacy in patients with relapsed-refractory ALL, with better survival after the addition of blinatumomab. Trial registration The trial was registered on clinicaltrials.gov with the identifier NCT01371630. more...

Progress in the research and therapy of adult acute lymphoblastic leukemia (ALL) is accelerating. This analysis summarizes the data derived from the clinical trials conducted at MD Anderson between 1985 and 2022 across ALL subtypes. In Philadelphia chromosome-positive ALL, the addition of BCR::ABL1 tyrosine kinase inhibitors (TKIs) to intensive chemotherapy since 2000, improved outcomes. More recently, a chemotherapy-free regimen with blinatumomab and ponatinib resulted in a complete molecular remission rate of 85% and an estimated 3-year survival rate of 90%, potentially reducing the role of, and need for allogeneic stem cell transplantation (SCT) in remission. In younger patients with pre-B Philadelphia chromosome-negative ALL, the integration of blinatumomab and inotuzumab into the frontline therapy has improved the estimated 3-year survival rate to 85% across all risk categories. Our future strategy is to evaluate the early integration of both immunotherapy agents, inotuzumab and blinatumomab, with low-dose chemotherapy (dose-dense mini-Hyper-CVD-inotuzumab-blinatumomab) into the frontline setting followed by CAR T cells consolidation in high-risk patients, without any further maintenance therapy. In older patients, using less intensive chemotherapy (mini-Hyper-CVD) in combination with inotuzumab and blinatumomab has improved the 5-year survival rate to 50%. Among patients ≥ 65–70 years, the mortality in complete remission (CR) is still high and is multifactorial (old age, death in CR with infections, development of myelodysplastic syndrome or acute myeloid leukemia). A chemotherapy-free regimen with inotuzumab and blinatumomab is being investigated. The assessment of measurable residual disease (MRD) by next-generation sequencing (NGS) is superior to conventional assays, with early MRD negativity by NGS being associated with the best survival. We anticipate that the future therapy in B-ALL will involve less intensive and shorter chemotherapy regimens in combination with agents targeting CD19 (blinatumomab), CD20, and CD22 (inotuzumab). The optimal timing and use of CAR T cells therapy may be in the setting of minimal disease, and future trials will assess the role of CAR T cells as a consolidation among high-risk patients to replace allogeneic SCT. In summary, the management of ALL has witnessed significant progress during the past four decades. Novel combination regimens including newer-generation BCR::ABL1 TKIs and novel antibodies are questioning the need and duration of intensive chemotherapy and allogeneic SCT. more...

Monge’s disease (chronic mountain sickness (CMS)) is a maladaptive condition caused by chronic (years) exposure to high-altitude hypoxia. One of the defining features of CMS is excessive erythrocytosis with extremely high hematocrit levels. In the Andean population, CMS prevalence is vastly different between males and females, being rare in females. Furthermore, there is a sharp increase in CMS incidence in females after menopause. In this study, we assessed the role of sex hormones (testosterone, progesterone, and estrogen) in CMS and non-CMS cells using a well-characterized in vitro erythroid platform. While we found that there was a mild (nonsignificant) increase in RBC production with testosterone, we observed that estrogen, in physiologic concentrations, reduced sharply CD235a+ cells (glycophorin A; a marker of RBC), from 56% in the untreated CMS cells to 10% in the treated CMS cells, in a stage-specific and dose-responsive manner. At the molecular level, we determined that estrogen has a direct effect on GATA1, remarkably decreasing the messenger RNA (mRNA) and protein levels of GATA1 (p, Chronic mountain sickness: Female hormone provides protection The hormone estrogen protects against chronic mountain sickness (CMS) in pre-menopausal women and may prove valuable in treating the condition. People who live for years in high altitude mountain regions are susceptible to CMS because of prolonged oxygen deprivation. One factor in CMS is an over-production of red blood cells, thickening the blood and increasing the risk of strokes and cardiovascular diseases. Men are more likely to suffer CMS than women, although cases spike in females after menopause. Gabriel Haddad at the University of California in San Diego, USA, and co-workers used a cell culture model of CMS to demonstrate that estrogen provides protection against the disease. Estrogen significantly alters the expression and activity of red blood cell-related genes to regulate red blood cell levels by controlling cell death mechanisms. more...

Gap junctions establish direct pathways for cell-to-cell communication, through the assembly of twelve subunits (connexins) that form intercellular channels connecting neighboring cells. Co-assembly of different connexin isoforms produces channels with unique properties, and enables communication across cell-types. To gain access into the structural underpinnings of connexin co-assembly, we used single particle CryoEM to determine the structure of native lens gap junction channels, composed of connexin-46 and connexin-50 (Cx46/50). We provide the first comparative analysis to connexin-26 (Cx26), which together with computational studies elucidates key energetic features governing gap junction perm-selectivity. Cx46/50 adopts an open-state conformation that is unique from the Cx26 crystal structure, yet appears to be stabilized by a conserved set of hydrophobic anchoring residues. ‘Hot spots’ of genetic mutations linked to hereditary cataract formation map to the core structural-functional elements identified in Cx46/50, rationalizing many of the disease-causing effects. more...

Oxygen plays a central role in cardiac energy metabolism. At high altitude where the ambient oxygen level is low, we found EDNRB is associated with human hypoxia adaptation. Our subsequent study in global heterozygous knockout mice (Ednrb−/+) revealed that cardiac function was conserved in these mice when exposed to extreme hypoxia. The major goal of this study was (i) to determine the functional role of cardiomyocyte EdnrB in maintaining cardiac function under hypoxic stress and (ii) to validate the phenotypes we detected in Ednrb−/+ mice using EDNRB blockers. Unlike the global knockouts, cardiac-specific heterozygote (EdnrBflox/+) and homozygote (EdnrBflox/flox) EdnrB knockout mice were phenotypically normal. When treated with graded low levels of oxygen (10% and 5% O2), both EdnrBflox/+ and EdnrBflox/flox were hypoxia tolerant. The cardiac indexes at 10% and 5% O2 for EdnrBflox/+ were significantly higher and lactate levels were significantly lower when compared to the cre-negative controls (P more...

About 1.2 to 33% of high-altitude populations suffer from Monge's disease or chronic mountain sickness (CMS). Number of factors such as age, sex, and population of origin (older, male, Andean) contribute to the percentage reported from a variety of samples. It is estimated that there are around 83 million people who live at altitudes >2500m worldwide and are at risk for CMS. In this review, we focus on a human "experiment in nature" in various high-altitude locations in the world-namely, Andean, Tibetan, and Ethiopian populations that have lived under chronic hypoxia conditions for thousands of years. We discuss the adaptive as well as mal-adaptive changes at the genomic and physiological levels. Although different genes seem to be involved in adaptation in the three populations, we can observe convergence at genetic and signaling, as well as physiological levels. What is important is that we and others have shown that lessons learned from the genes mined at high altitude can be helpful in better understanding and treating diseases that occur at sea level. We discuss two such examples: EDNRB and SENP1 and their role in cardiac tolerance and in the polycythemic response, respectively. more...

An increasing number of genetic variants have been implicated in autism spectrum disorders (ASDs), and the functional study of such variants will be critical for the elucidation of autism pathophysiology. Here, we report a de novo balanced translocation disruption of TRPC6, a cation channel, in a non-syndromic autistic individual. Using multiple models, such as dental pulp cells, induced pluripotent stem cell (iPSC)-derived neuronal cells and mouse models, we demonstrate that TRPC6 reduction or haploinsufficiency leads to altered neuronal development, morphology and function. The observed neuronal phenotypes could then be rescued by TRPC6 complementation and by treatment with insulin-like growth factor-1 or hyperforin, a TRPC6-specific agonist, suggesting that ASD individuals with alterations in this pathway may benefit from these drugs. We also demonstrate that methyl CpG binding protein-2 (MeCP2) levels affect TRPC6 expression. Mutations in MeCP2 cause Rett syndrome, revealing common pathways among ASDs. Genetic sequencing of TRPC6 in 1041 ASD individuals and 2872 controls revealed significantly more nonsynonymous mutations in the ASD population, and identified loss-of-function mutations with incomplete penetrance in two patients. Taken together, these findings suggest that TRPC6 is a novel predisposing gene for ASD that may act in a multiple-hit model. This is the first study to use iPSC-derived human neurons to model non-syndromic ASD and illustrate the potential of modeling genetically complex sporadic diseases using such cells. more...

Reported here are the proceedings of a symposium given in honor of Dr. Henry F. Krous upon his retirement as Clinical Professor of Pathology and Pediatrics at the University of California Schools of Medicine, and as Director of the San Diego SIDS/SUDC Research Project. Dr. Krous' distinguished 37-year-career was dedicated to research into sudden unexpected death in infancy and childhood, notably the sudden infant death syndrome (SIDS) and sudden unexplained death in childhood (SUDC). The presentations were given at the International Conference on Stillbirth, SIDS, and infant survival on October 5, 2012, in Baltimore, MD, USA. Eight colleagues of Dr. Krous whose own professional careers were touched by his efforts discussed forensic issues related to SIDS, tissue banking, animal models in SIDS, brainstem studies in SIDS, genetic studies in SIDS, establishment of a SUDC registry, neuropathologic research in SUDC, and potential shared mechanisms underlying sudden and unexpected death in early life. The wide scope of the presentations crossed the disciplines of forensic pathology, pediatric pathology, neuropathology, neuroscience, physiology, genetics, and bereavement, and attest to Dr. Krous' far-reaching influence upon SIDS and SUDC research. more...

We have previously discovered that the adult Drosophila melanogaster is tolerant to a low O2 environment, withstanding hours of total O2 deprivation without showing any evidence of cell injury. Subsequently, our laboratory embarked on the study of hypoxia tolerance using a mutagenesis and overexpression screens to begin to investigate loss-of-function or gain-of-function phenotypes. Both have given us promising results and, in this article, we detail some of the interesting results. Furthermore, several years ago, we have also started an experimental "Darwinian" selection to generate a fly strain that can perpetuate through all of its life cycle stages in hypoxic environments. Through microarrays and bioinformatic analyses, we have obtained genes (e.g. Notch pathway genes) that play an important role in hypoxia resistance. In addition, we also detail a proof of principle that Drosophila genes that are beneficial in fly resistance to hypoxia can also be as well in mammalian cells. We believe that the mechanisms that we are uncovering in Drosophila will allow us to gain insight regarding susceptibility and tolerance to low O2 and will therefore pave the way to develop better therapies for ailments that afflict humans as a consequence of low O2 delivery or low blood O2 levels. more...

The immature brain is more resistant to hypoxia/ischemia than the mature brain. Although chronic hypoxia can induce adaptive-changes on the developing brain, the mechanisms underlying such adaptive changes are poorly understood. To further elucidate some of the adaptive changes during postnatal hypoxia, we determined the activities of four enzymes of glucose oxidative metabolism in eight brain regions of hypoxic and normoxic rats. Litters of Sprague-Dawley rats were put into the hypoxic chamber (oxygen level maintained at 9.5%) with their dams starting on day 3 postnatal (P3). Age-matched normoxic rats were use as control animals. In P10 hypoxic rats, lactate dehydrogenase (LDH) activity in cerebral cortex, striatum, olfactory bulb, hippocampus, hypothalamus, pons and medulla, and cerebellum was significantly increased (by 100%–370%) compared to those in P10 normoxic rats. In P10 hypoxic rats, hexokinase (HK) activity in hypothalamus, hippocampus, olfactory bulb, midbrain, and cerebral cortex was significantly decreased (by 15%–30%). Neither α-ketoglutarate dehydrogenase complex (KGDHC, which is believed to have an important role in the regulation of the tricarboxylic acid [TCA] cycle flux) nor citrate synthase (CS) activity was significantly decreased in the eight regions of P10 hypoxic rats compared to those in P10 normoxic rats. In P30 hypoxic rats, LDH activity was only increased in striatum (by 19%), whereas HK activity was only significantly decreased (by 30%) in this region. However, KGDHC activity was significantly decreased in olfactory bulb, hippocampus, hypothalamus, cerebral cortex, and cerebellum (by 20%–40%) in P30 hypoxic rats compared to those in P30 normoxic rats. Similarly, CS activity was decreased, but only in olfactory bulb, hypothalamus, and midbrain (by 9%–21%) in P30 hypoxic rats. Our results suggest that at least some of the mechanisms underlying the hypoxia-induced changes in activities of glycolytic enzymes implicate the upregulation of HIF-1. Moreover, our observation that chronic postnatal hypoxia induces differential effects on brain glycolytic and TCA cycle enzymes may have pathophysiological implications (e.g., decreased in energy metabolism) in childhood diseases (e.g., sudden infant death syndrome) in which hypoxia plays a role. more...

Regarding the evolution of financial asset prices governed by an history dependent (path dependent) dynamical system as a prediction mechanism, we provide in this paper the dynamical valuation and management of a portfolio (replicating for instance European, American and other options) depending upon this prediction mechanism (instead of an uncertain evolution of prices, stochastic or tychastic). The problem is actually set in the format of a viability/capturability theory for history dependent control systems and some of their results are then transferred to the specific examples arising in mathematical finance or optimal control. They allow us to provide an explicit formula of the valuation function and to show that it is the solution of a ``Clio Hamilton–Jacobi–Bellman'' equation. For that purpose, we introduce the concept of Clio derivatives of ``history functionals'' in such a way we can give a meaning to such an equation. We then obtain the regulation law governing the evolution of optimal portfolios. more...

Background Mandatory deposit of raw microarray data files for public access, prior to study publication, provides significant opportunities to conduct new bioinformatics analyses within and across multiple datasets. Analysis of raw microarray data files (e.g. Affymetrix CEL files) can be time consuming, complex, and requires fundamental computational and bioinformatics skills. The development of analytical workflows to automate these tasks simplifies the processing of, improves the efficiency of, and serves to standardize multiple and sequential analyses. Once installed, workflows facilitate the tedious steps required to run rapid intra- and inter-dataset comparisons. Results We developed a workflow to facilitate and standardize Meta-Analysis of Affymetrix Microarray Data analysis (MAAMD) in Kepler. Two freely available stand-alone software tools, R and AltAnalyze were embedded in MAAMD. The inputs of MAAMD are user-editable csv files, which contain sample information and parameters describing the locations of input files and required tools. MAAMD was tested by analyzing 4 different GEO datasets from mice and drosophila. MAAMD automates data downloading, data organization, data quality control assesment, differential gene expression analysis, clustering analysis, pathway visualization, gene-set enrichment analysis, and cross-species orthologous-gene comparisons. MAAMD was utilized to identify gene orthologues responding to hypoxia or hyperoxia in both mice and drosophila. The entire set of analyses for 4 datasets (34 total microarrays) finished in ~ one hour. Conclusions MAAMD saves time, minimizes the required computer skills, and offers a standardized procedure for users to analyze microarray datasets and make new intra- and inter-dataset comparisons. more...

A miniaturized torque sensor based on cable brake principle for the measurement of torque-characteristic of minimotors and micromotors has been developed. The first generation torque sensor enables the measurement of torque of minimotors in the range of μNm. Design principles and the production process are described. Experimental results show fair conformity with technical data for minimotors. more...

KATP channels are K+ channels whose activity is inhibited by the presence of and enhanced by the absence of cytosolic ATP. This property allows KATP channels to sense cellular intermediary metabolism and directly couple this information to the modulation of membrane excitability. Indeed, recent studies from our laboratory and others have suggested that activation of KATP channels during anoxia is important in the response and adaptation of central neurons to hypoxia. In order to identify KATP channels from human brain, we performed a polymerase chain reaction (PCR) using human cerebral cortex mRNA and primers derived from the ROMK1 sequence, a cDNA clone encoding an ATP-regulated potassium channel, recently isolated from rat kidney. We thus identified a novel 308-bp PCR product, pKCNJ1, whose expression was found to be restricted to a 3.0-kb band in the kidney by probing a human multiple tissue northern blot, pKCNJ1 was then used to isolate genomic clones and, using fluorescence in situ hybridization (FISH) to human metaphase chromosomes, was mapped to chromosome 11q. more...

Dr. Kaplan concluded the symposium on the complications of Pagets disease by offering a quotation from William Harvey, the discoverer of the circulation of the blood. William Harvey stated, in 1657 that Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows traces of her workings apart from the beaten path. By focusing on a rare complication of Paget's disease (Pagetic sarcoma), as well as common but rarely discussed complications that affect the quality of life (spinal stenosis, hearing loss, and dental problems), the Symposium began to grapple with some of the perplexing basic and clinical problems that previously have received little attention. The oneday workshop accommodated brief presentations followed by broad and robust interdisciplinary discussion that is likely to stimulate new research and collaboration on these important complications of Paget's disease. more...

The regional distribution of blood flow to the brain and to other major organs was studied during wakefulness and sleep in growing piglets. A young group was studied at 6.8 +/- 1.3 d of age and an older group at 33.5 +/- 5.5 d. Two d before the experiments, we instrumented the animals for measurement of blood flow by the microsphere technique. We determined sleep state using EEG and behavioral criteria. Although we did not find significant differences in blood gas tensions and cardiac output with changes in behavioral states, we did note a number of important changes in brain and muscle blood flow with sleep. 1) Although total brain blood flow changed little between wakefulness and sleep at both ages, regional differences existed. Indeed, at both ages, during rapid eye movement sleep (active sleep), blood flow to the thalamus-hypothalamus and brainstem was significantly higher than during wakefulness (p less than 0.025); in older piglets, blood flow to these two regions was significantly lower in quiet sleep than in wakefulness (p less than 0.05). 2) Blood flow to most skeletal muscle groups, and particularly to the diaphragm, was lower during sleep than during wakefulness. 3) Age did not have a significant effect on the regional distribution of blood flow during sleep. We conclude that behavioral states influence the regional distribution of blood flow in early life, but not in an age-dependent fashion. We speculate that, because no difference was observed in other hemodynamic variables, the regional changes in organ blood flow with sleep most probably reflect the differences in local metabolic needs. more...

During hypoxic-ischemic episodes in the brain, the resulting neuronal death is due, in part, to apoptosis, a genetically controlled form of cell death.p53, a tumor suppressor gene, is believed to promote apoptosis.bcl-2, a proto-oncogene, is believed to inhibit apoptosis. However, the role of these two genes in neuronal survival or death during hypoxia is not clear. We hypothesized that: a) neuronal expression of p53 and bcl-2 is altered during hypoxia, b) altered expression of p53 is associated with decreased neuronal survival during hypoxia, and c) altered expression of bcl-2 is associated with prolonged survival during hypoxia. Methods. 7-10 day old cultured rat neocortical neurons were exposed to 0.1,1, or 3% oxygen. Culture dishes were removed at 24-hour intervals for quantitative immunofluorescence staining and immunoblot analyses. Apoptosis was assessed by changes in cell morphology and in situ and genomic DNA fragmentation. To assess the impact of p53 and bcl-2 expression upon neuronal survival during hypoxia, expression of these genes was attenuated by treating selected neuronal culture plates with 3 μM antisense, sense, and nonsense oligonucleotides 24 hours prior to exposure to 0.1% oxygen. Neuronal survival was assessed by Trypan blue exclusion at 24-hour intervals during hypoxic exposure. Results. At each level of hypoxia studied, morphologic changes (cellular shrinkage, nuclear condensation) and in situ and genomic DNA fragmentation consistent with apoptosis was detected. Immunoblot and quantitative immunofluorescence analyses revealed an increase in both neuronal p53 and bcl-2 during hypoxic exposure. After 48 hours at 0.1% oxygen, the proportion of viable neurons was significantly greater in plates treated with p53 antisense oligonucleotide (≈60%) than in untreated plates(35-40%)(n=5;p 0.05). Conclusions.p53 and bcl-2 are increased in neurons during hypoxic exposure. Expression of p53 is, in part, necessary for hypoxia-induced neuronal apoptosis.bcl-2 expression, in part, prolongs neuronal survival during hypoxia. more...

Effects of photoperiod, temperature and food and water availability on body and testicular mass of golden hamsters were investigated. Lack of water or food inhibited body growth. Short photoperiod (LD 8:16) enhanced body growth in males fed 'poor diet' but it had no effect in animals on 'high quality diet'. Cold exposure diminished body growth in animals with access to water but not in those deprived of water. It is suggested that lowered motor activity is mainly responsible for body mass gain of animals kept under the short photoperiod. All stressful factors (water deprivation, 'poor diet' or cold) induced involution of testes. The time course of testicular involution was similar to that induced by short photoperiod. Testicular involution was, after several weeks, followed by spontaneous recrudescence. Combination of stressful external cues speeded up testicular involution. Since the testicular involution induced by water deprivation, "poor diet" and cold also occurred in animals kept in constant light or under long photoperiod (which are known to produce functional pinealectomy) it is concluded that the inhibitory effects of stressful external factors on testes are not mediated by the pineal. The decrease in testosterone production induced by external cues precedes changes in testicular mass. In individuals kept in the cold, testosterone production remains low, in spite of spontaneous recrudescence of the testes. No simple relationship between testosterone concentration in the blood and testicular mass was observed. The mass of the interscapular brown adipose tissue (ISBAT) changes strikingly during the hibernation cycle. Immediately after exposure to cold it decreases and stays at the low level for 40 days.(ABSTRACT TRUNCATED AT 250 WORDS) more...

To examine the interrelationship between the duration of apnea and changes in oxygen saturation, blood pressure, electroencephalogram (EEG), and heart rate, reflex apnea of 10, 20, 40, and 60 s duration was induced by stimulating the superior laryngeal nerves. Pig- lets (n = 11, age 5-14 days) were chronically instrumented for continuous monitoring of SaOz and blood pressure and for sampling arterial blood. Ventilation was recorded using whole body plethysmography and EEG and electrocardi- ogram were measured by acutely placed subcutaneous elec- trodes. Central apnea produced an immediate rise in blood pressure and a decrease in SaOz by 20 s. By 30 s into the apnea, EEG amplitude had already decreased. Major car- diac slowing did not occur until 80 s after the start of apnea. Hyperoxia delayed the start of desaturation, hyper- tension, and EEG attenuation. These data suggest that during superior laryngeal nerve-induced apnea in young piglets: 1) desaturation can reach profound levels rapidly, 2) EEG amplitude decreases substantially and becomes nearly isoelectric within 1 min, and 3) bradycardia is a late manifestation when compared to changes in oxygen satu- ration, blood pressure, and EEG. (Pediatr Res 23:402- 407,1988) Abbreviations SLN, superior laryngeal nerves EEG, electroencephalogram SaOz, arterial oxygen saturation MAP, mean arterial blood pressure EKG, electrocardiogram IVH, intraventricular hemorrhage more...

Twenty-eight premature infants of mean gestation 30.9 +/- 2.5 weeks and mean birth weight 1175 +/- 206 g had repeated serum calcitonin concentrations determined over the first 12 weeks of life. Serum calcitonin concentrations slowly fell but remained elevated even at 12 weeks of age [normal adult = 71 +/- 48, 1 week (N = 15) = 327 +/- 167, 3 week (N = 23) = 270 +/- 129, 6 week (N = 16) = 249 +/- 154, 9 week (N = 13) = 214 +/- 108, 12 week (N = 12) = 174 +/- 11]. Throughout this period, serum total calcium was normal or low (8.4 +/- .8-9.3 +/- 1.0). Serum phosphorus was normal or low (6.0 +/- 1.4-6.5 +/- 1.0), and serum magnesium was normal (1.7 +/- 0.24-1.8 +/- 0.34). The reason for the sustained elevation of serum calcitonin in these very small, sick, premature infants in unclear. more...

Sleep staging has been conventionally performed using neurophysiologic and behavioral criteria. However, these criteria may not always be available. Since it is known that cardiorespiratory variables in rapid eye movement (REM) sleep are different from those in quiet sleep, we asked whether such variables can be used for the determination of sleep state. We studied nine normal fullterm infants at 1 and 4 months of life. Ventilation was measured using barometric plethysmography and the RR interval using a high accuracy R wave detector. Electroencephalogram, electrooculogram, and postural muscle electromyogram were recorded using surface electrodes and behavioral criteria applied. Means of RR interval, respiratory cycle time and tidal volume, and coefficients of variation of the same variables, were obtained for 30-s intervals throughout each sleep study. The Kolmogorov- Smirnov distances between REM and quiet sleep were larger for the coefficients of variation than for the means at both ages for all variables. Moreover, coefficient of variation of respiratory cycle time was found to provide the largest separation between REM and quiet sleep. In view of this result, we developed a statistical decision rule using coefficient of variation of respiratory cycle time for the classification of REM and quiet sleep in blocks of 5-min periods. Each study was divided into 5-min epochs and this rule was applied to each epoch. Of 85 epochs staged as quiet sleep by neurophysiologic and behavioral criteria, 79 epochs (or 93%) were classified correctly as quiet sleep using our decision rule. Of 85 epochs staged as REM sleep, 84 were classified as REM sleep and only one misclassified as quiet sleep. Five additional infants, whose results did not enter into the formulation of the decision rule, were used as a subsequent example to test the rule. The results of these five infants were similar to those of the previous nine others. We conclude that in young infants 1) the variability of cardiorespiratory parameters can separate quiet from nonquiet sleep better than the mean values and 2) sleep staging using a decision rule based on coefficient of variation of respiratory cycle time can be performed with high degree of accuracy. more...

Summary: The QT interval was measured in 12 normal and 7 aborted sudden infant death syndrome (SIDS) infants in rapid eye movement (REM) and quiet sleep at monthly intervals through the age of 4 months. An accuracy of better than 2 msec was assured by high resolution of the digitized signal and calibration of each QT measurement with an accurately generated time code. In contrast to current speculations, the QT index was significantly smaller in the infants with aborted SIDS than in the normal infants in both REM and quiet sleep (P < 0.05). In addition, as in normal infants, the QTC was smaller in REM than in quiet sleep (P < 0.01). Although these results offer no support for the hypothesis that SIDS results from prolongation of the QT interval, they suggest that aborted SIDS infants have a functional abnormality in the autonomic nervous system. Speculation: We suggest that 1) the shortening of the QT interval in the aborted SIDS infants results from a uniform increase in the sympathetic outflow to the cardiac ventricles or an increase in circulating levels of catecholamines; and 2) an imbalance between the left and the right sympathetic outflow to the ventricles of aborted SIDS infants, as has been previously hypothesized, is not likely since the QTc was not larger in REM sleep, a sleep state in which an increase in sympathetic activity occurs. more...

THE antiricketic sterols are both assimilated from the diet and endogenously produced by ultraviolet irradiation of cutaneous 7-dehydrocholesterol1–3. Before the modern practice of supplementing foods with irradiated ergosterol (ergocalciferol, vitamin D2), deficiency states were frequently observed in subjects whose dark skin colour and/or minimal exposure to sunlight minimized the natural endogenous production of cholecalciferol (vitamin D3)4. It has been generally accepted that casual exposure to sunlight and average diets provide enough antiricketic sterol to prevent osteomalacia in the adult (American Academy of Pediatrics, 1963). Infants, however, are recognized to require vitamin D supplementation, for their maternally derived stores wane at a time when their natural foods are a poor source and their exposure to ultraviolet radiation unreliable. Supplementation of foods with vitamin D2 has thus become a widespread and successful practice which has subsequently undergone quantitative revisions in several countries. more...

The thermomechanical stability of organosilane surface treatments for E-glass fibers used in fiber reinforced composites was evaluated. The effect of molecular structure of 40 to 80 namometer coatings on the force transmission across the fiber/matrix interface was measured as a function of temperature and exposure to water using a fiber fragmentation test. It was found that phenyl-substituted amino silanes exhibited better thermal stability, but were less resistant to boiling water, than the commierically available γ-amino propyl silanes. A bis-trimethoxy γ-amino propyl silane showed an increase in both the hydrolytic and thermal stability when compared to the commiercial product. A good balance of thermal and hydrolytic stability was also obtained with a methylaminopropyltrimethoxy silane coating.The strain energy released from the glass fibers upon decoupling from the poxy matrix or silane coating was found to be in the range of 145 to 186 g/m2 and varied no more than 20 percent over a temperature range of 25 to 75°C or when exposed to boiling water and then redried. It also varied very little with the silane coating used. In addition, the average shear stress attained at the fiber-matrix interface in an imbedded single fiber test at 25°C was as much as two times higher than the shear strength of the epoxy matrix and as much as five times higher at elevated temperature. These data lead one to the conclusion that the interphase failure in these composites is controlled by a plane strain fracture in the constrained region of the organic phase, near the fiber surface, rather than by the maximum shear strength in the interphase. more...

RECENT studies1,2 of bone materials have suggested that the fracture behaviour is sensitively dependent on specimen orientation, microstructure, the presence of external notches, temperature and the deformation fate imposed. The deformation properties of bone have been likened to those expected of composite materials2,3. This report provides further information about the strength of bone and helps to define the criteria which must be satisfied by theoretical models of the mechanical properties. more...

Serum human calcitonin (HCT) is highest within the first 48 hrs. of life. In term infants, HCT decreased to a mean ± S.E. of 151 ± 22 pg/ml at 1 week of age. Premature infants, however, had 225 ± 40 pg/ml. Twelve small premature infants were followed for 3 months to see if elevations of HCT persisted. Birth weight and gestation were 1123 ± 218 gm (760-1600 gm) and 30 ± 2.5 weeks (27-34 wks.). As shown below, moderate to severe osteopenia was present at 6 weeks of age. Hypocalcemia, elevations in serum alkaline phosphatase, and elevations in serum PTH with amino aciduria were frequent during the first 9 weeks. Serum HCT slowly fell, but remained elevated in 9/12 infants at 3 months. HCT may play an important role in the mineralization of infant bone and elevated serum HCT persists in the premature. The stimulus to HCT secretion during this period is presently unknown. more...

To examine the maturation of the cardiovascular response to hypoxia (FiO2=.15) during natural sleep, we studied 48 chronically instrumented unanesthetized beagle puppies at 15 and 30 days of age. We measured the RR interval and mean aortic blood pressure (MAP). In addition, in a subset of 10 puppies, we measured cardiac output (CO) by the Fick principle. After baseline measurements, puppies were exposed to hypoxia for 1-2 hrs. During normoxia, at 15 days of age: MAP was lower (mean 10%, p more...

Prolongation of the QT interval has been implicated in the pathogenesis of the Sudden Infant Death Syndrome (SIDS). To test this hypothesis, 31 studies in 12 normal infants and 17 studies in 7 aborted SIDS infants were performed during sleep in the first four months of life. The QT index (QTc) was measured with an accuracy of 2 msec or better. In contrast to recent suggestions, the mean QTc was significantly smaller in the aborted SIDS than in the normal infants in both REM and quiet sleep (p< 0.05, unpaired t-test). Means ± SD are presented: In both the normal and aborted SIDS infants, the mean QTc was significantly smaller in REM than in quiet sleep (p< 0.01, paired t-test). We suggest that 1) the smaller QTc in the aborted SIDS infants results from a uniform increase in the activity of the sympathetic outflow to the ventricles or an increase in circulating levels of catecholamines and 2) the smaller QTc in REM in both groups makes it unlikely that there is an imbalance in the sympathetic innervation of the ventricles in aborted SIDS. Although these studies do not support the hypothesis relating SIDS to prolongation of the QT interval, they may provide a basis for distinguishing normal from aborted SIDS infants. more...

DBP is low in the cord blood of preterm infants (359±24μg/ml) while term infants (558±78μg/ml) have adult concentrations (525±24 μg/ml). To see when preterm infants develop normal concentrations of DBP and to look for any relationship to DBP's major ligand, 25-hydroxyvitamin D (25-OHD), DBP was measured by radial immunodiffusion using a rabbit antiserum in serial serum samples from 28 preterm infants, gestation 29.7±2.5wks and birthweight 1162±344gms. DBP remained low until there was a significant increase at 12wks of age (p more...

We report a new syndrome with the simultaneous failure of control of ventilation (Ondine's Curse), esophageal and intestinal motility (Hirschsprung's disease), and heart rate in three infants, who died in the first few months of life; two were siblings. Detailed physiologic studies were performed in one, and pathologic studies in three. Ventilation was measured by the barometric method or by pneumotachography. Sleep was staged using the EEG, EOG, and EMG. Minute Ventilation (V) and respiratory rate (f) were lower in Quiet sleep (V=315ml, f=18/min) than in both REM sleep (V=477ml, f=22/min) and wakefulness (V=654ml, f= 29/min). Respiratory pauses >5 sec occurred more frequently in Quiet than in REM sleep. V increased by 25% after IV doxapram but not following aminophylline, progesterone or imipramine. Minimal short term (beat to beat) variability of the ECG R-R interval (interquartile ranged more...

The biphasic respiratory response (hyperpnea followed by hypoventilation) of the newborn human has been attributed to central hypoxic depression of the respiratory centers. Recently, we have shown that, in the absence of hypoxia, the excitatory effect of continued carotid sinus nerve (CSN) stimulation fatigues in piglets 4-14 days of age (The Physiologist 23:140, 1980). To study maturation of the excitatory effects of the CSN without confounding blood gas changes, we compared changes in respiratory output (RO=f × neural tidal volume) during electrical CSN stimulation in young and older piglets (7 piglets 4-14 days; 7 piglets 20-34 days). The piglets were anesthetized, vagotomized, paralyzed and ventilated (FIO2=1.0). End-tidal CO2 was kept constant with a servo-controller (mean end-tidal CO2=30.2mmHg). RO was quantified by moving average of the rectified phrenic neurogram. The RO of all piglets increased (p more...

437 SERUM 25-HYDROXY-VITAMIN D (25-OHD) CONCENTRATIONS AND BONE HISTOLOGY IN SUDDEN INFANT DEATH SYNDROME (SIDS)

Heart rate (HR) and HR variability were studied in 15 normal infants and 6 infants with aborted Sudden Infant Death Syndrome (SIDS) during sleep at monthly intervals through 4 months of age. The RR interval (inverse of heart rate) was measured to an accuracy of 0.2 msec. Sleep was staged using EEG, EOG, EMG and behavioral criteria. The median HR was 4 to 10% greater in the aborted SIDS infants at each age in both sleep states and this was significant at 2,3 and 4 months in quiet and at 3 months in REM sleep (p < 0.05, Wilcoxon Rank Sum test). The beat to beat variability of the HR (Δ RR) in the aborted SIDS infants was 6 to 40% smaller than in the normal infants in both REM and quiet sleep at each age studied. The interquartile range of the HR, a measure of overall variability in HR, was the same in the aborted SIDS and normal infants. In both groups, the HR and its interquartile range were greater in REM sleep. These studies indicate that the group of infants with aborted SIDS may be differentiated from the normal infants by their increased heart rate and decreased beat to beat variability, and that these findings may reflect abnormal autonomic regulation of the heart rate. more...

In aminal systems prolactin (HPL) increases 1,25 dihydroxy vitamin D (1,25(OH)2D) and decreases 24,25 dihydroxy vitamin D (24,25(OH)2D) synthesis. 24,25(OH)2D is low during pregnancy with normal serum PTH. During pregnancy, serum HPL and other hormones are increased, but during lactation only HPL remains elevated. We studied lactating mothers and non-lactating controls for 24,25(OH)2D, 250HD, PTH, HPL, calcium and magnesium at 6 weeks post partum. In nursing mother 24,25(OH)2D was significantly lower than normal or post partum controls. During lactation only there was an inverse correlation between HPL and 24,25(OH)2D (R=-.51) and PTH and 24,25(OH)2D (R=-.47). During lactation there was no correlation between 24,25(OH)2D and 250HD (R=.18). Thus, changes in vitamin D metabolism probably mediated by HPL and PTH may enable the lactating woman to maintain normal serum calcium and magnesium while providing for milk production. more...

Increased Parathyroid hormone serum concentrations, [PTH] enhance 1,25-(OH)2D and decrease 24,25-(OH)2D synthesis from 25-hydroxy vitamin D (25-OHD). At term, pregnant women have elevated PTH and infants have low [PTH]. 16 pairs of maternal (M) and umbilical cord (C) venous sera were analyzed for 24,25-(OH)2D, 25-OHD, calcium, magnesium and PTH. Both M 24,25-(OH)2D (2.6±0.5 ng/ml) and C 24,25-(OH)2D (3.0±1.2 ng/ml) were lower than 29 adult normals (5.0±0.6 ng/ml). Normal adult 24,25-(OH)2D is correlated with 25-OHD (R=.40 P more...