Transient Neonatal Zinc Deficiency Caused by a Heterozygous G87R Mutation in the Zinc Transporter ZnT-2 (SLC30A2) Gene in the Mother Highlighting the Importance of Zn (2+) for Normal Growth and Development

Suboptimal dietary zinc (Zn(2+)) intake is increasingly appreciated as an important public health issue. Zn(2+) is an essential mineral, and infants are particularly vulnerable to Zn(2+) deficiency, as they require large amounts of Zn(2+) for their normal growth and development. Although term infants are born with an important hepatic Zn(2+) storage, adequate Zn(2+) nutrition of infants mostly depends on breast milk or formula feeding, which contains an adequate amount of Zn(2+) to meet the infants' requirements. An exclusively breast-fed 6 months old infant suffering from Zn(2+) deficiency caused by an autosomal dominant negative G87R mutation in the Slc30a2 gene (encoding for the zinc transporter 2 (ZnT-2)) in the mother is reported. More than 20 zinc transporters characterized up to date, classified into two families (Slc30a/ZnT and Slc39a/Zip), reflect the complexity and importance of maintaining cellular Zn(2+) homeostasis and dynamics. The role of ZnTs is to reduce intracellular Zn(2+) by transporting it from the cytoplasm into various intracellular organelles and by moving Zn(2+) into extracellular space. Zips increase intracellular Zn(2+) by transporting it in the opposite direction. Thus the coordinated action of both is essential for the maintenance of Zn(2+) homeostasis in the cytoplasm, and accumulating evidence suggests that this is also true for the secretory pathway of growth hormone.

Neonatal Fc receptor expression in dendritic cells mediates protective immunity against colorectal cancer

Cancers arising in mucosal tissues account for a disproportionately large fraction of malignancies. Immunoglobulin G (IgG) and the neonatal Fc receptor for IgG (FcRn) have an important function in the mucosal immune system that we have now shown extends to the induction of CD8(+) T cell-mediated antitumor immunity. We demonstrate that FcRn within dendritic cells (DCs) was critical for homeostatic activation of mucosal CD8(+) T cells that drove protection against the development of colorectal cancers and lung metastases. FcRn-mediated tumor protection was driven by DCs activation of endogenous tumor-reactive CD8(+) T cells via the cross-presentation of IgG complexed antigens (IgG IC), as well as the induction of cytotoxicity-promoting cytokine secretion, particularly interleukin-12, both of which were independently triggered by the FcRn-IgG IC interaction in murine and human DCs. FcRn thus has a primary role within mucosal tissues in activating local immune responses that are critical for priming efficient anti-tumor immunosurveillance.

Multiple major morbidities and increased mortality during long-term follow-up after recovery from thrombotic thrombocytopenic purpura

Recovery from acute episodes of thrombotic thrombocytopenic purpura (TTP) appears complete except for minor cognitive abnormalities and risk for relapse. The Oklahoma TTP-HUS (hemolytic uremic syndrome) Registry enrolled 70 consecutive patients from 1995 to 2011 with ADAMTS13 activity <10% at their initial episode; 57 survived, with follow-up through 2012. The prevalence of body mass index (BMI), glomerular filtration rate (GFR), urine albumin/creatinine ratio (ACR), hypertension, major depression, systemic lupus erythematosus (SLE), and risk of death were compared with expected values based on the US reference population. At initial diagnosis, 57 survivors had a median age of 39 years; 45 (79%) were women; 21 (37%) were black; BMI and prevalence of SLE (7%) were greater (P < .001) than expected; prevalence of hypertension (19%; P = .463) was not different. GFR (P = .397) and ACR (P = .793) were not different from expected values. In 2011-2012, prevalence of hypertension (40% vs 23%; P = .013) and major depression (19% vs 6%; P = .005) was greater than expected values. Eleven patients (19%) have died, a proportion greater than expected compared with US and Oklahoma reference populations (P < .05). TTP survivors may have greater risk for poor health and premature death.

Neonatal dexamethasone induces premature microvascular maturation of the alveolar capillary network.

Postnatal glucocorticoid treatment of preterm infants was mimicked by treating newborn rats with dexamethasone (0.1-0.01 microg/g, days 1-4). This regimen has been shown to cause delayed alveolarization. Knowing that microvascular maturation (transformation of double- to single-layered capillary networks in alveolar septa) and septal thinning prevent further alveolarization, we measured septal maturation on electron photomicrographs in treated and control animals. In treated rats and before day 10, we observed a premature nonreversing microvascular maturation and a transient septal thinning, which both appeared focally. In vascular casts of both groups, we observed contacts between the two capillary layers of immature alveolar septa, which were predictive for capillary fusions. Studying serial electron microscopic sections of human lungs, we were able to confirm the postulated fusion process for the first time. We conclude that alveolar microvascular maturation indeed occurs by capillary fusion and that the dexamethasone-induced impairment of alveolarization is associated with focal premature capillary fusion.

The Swiss Neonatal Quality Cycle, a monitor for clinical performance and tool for quality improvement

BACKGROUND We describe the setup of a neonatal quality improvement tool and list which peer-reviewed requirements it fulfils and which it does not. We report on the so-far observed effects, how the units can identify quality improvement potential, and how they can measure the effect of changes made to improve quality. METHODS Application of a prospective longitudinal national cohort data collection that uses algorithms to ensure high data quality (i.e. checks for completeness, plausibility and reliability), and to perform data imaging (Plsek's p-charts and standardized mortality or morbidity ratio SMR charts). The collected data allows monitoring a study collective of very low birth-weight infants born from 2009 to 2011 by applying a quality cycle following the steps 'guideline - perform - falsify - reform'. RESULTS 2025 VLBW live-births from 2009 to 2011 representing 96.1% of all VLBW live-births in Switzerland display a similar mortality rate but better morbidity rates when compared to other networks. Data quality in general is high but subject to improvement in some units. Seven measurements display quality improvement potential in individual units. The methods used fulfil several international recommendations. CONCLUSIONS The Quality Cycle of the Swiss Neonatal Network is a helpful instrument to monitor and gradually help improve the quality of care in a region with high quality standards and low statistical discrimination capacity.

Intracisternal application of endotoxin enhances the susceptibility to subsequent hypoxic-ischemic brain damage in neonatal rats.

Perinatal brain damage is associated not only with hypoxic-ischemic insults but also with intrauterine inflammation. A combination of antenatal inflammation and asphyxia increases the risk of cerebral palsy >70 times. The aim of the present study was to determine the effect of intracisternal (i.c.) administration of endotoxin [lipopolysaccharides (LPS)] on subsequent hypoxic-ischemic brain damage in neonatal rats. Seven-day-old Wistar rats were subjected to i.c. application of NaCl or LPS (5 microg/pup). One hour later, the left common carotid artery was exposed through a midline neck incision and ligated with 6-0 surgical silk. After another hour of recovery, the pups were subjected to a hypoxic gas mixture (8% oxygen/92% nitrogen) for 60 min. The animals were randomized to four experimental groups: 1) sham control group, left common carotid artery exposed but not ligated (n = 5); 2) LPS group, subjected to i.c. application of LPS (n = 7); 3) hypoxic-ischemic study group, i.c. injection of NaCl and exposure to hypoxia after ligation of the left carotid artery (n = 17); or 4) hypoxic-ischemic/LPS study group, i.c. injection of LPS and exposure to hypoxia after ligation of the left carotid artery (n = 19). Seven days later, neonatal brains were assessed for neuronal cell damage. In a second set of experiments, rat pups received an i.c. injection of LPS (5 microg/pup) and were evaluated for tumor necrosis factor-alpha expression by immunohistochemistry. Neuronal cell damage could not be observed in the sham control or in the LPS group. In the hypoxic-ischemic/LPS group, neuronal injury in the cerebral cortex was significantly higher than in animals that were subjected to hypoxia/ischemia after i.c. application of NaCl. Injecting LPS intracisternally caused a marked expression of tumor necrosis factor-alpha in the leptomeninges. Applying LPS intracisternally sensitizes the immature rat brain to a subsequent hypoxic-ischemic insult.

Gammaglobulin and selenium status in healthy neonatal dairy calves in Switzerland

Serum samples from 142 calves and their dams were analyzed for gammaglobulins (gammaG, calves) and selenium concentrations (Se, calves and dams). A questionnaire provided information about birth and colostrum management. The calves and their dams were distributed into two groups according the calves' gammaG concentration (< 10 and >= 10 g/L), Se concentrations were compared between groups. The correlation between gammaG and Se concentrations in the calves and their dams was analyzed. Risk factors for failure of passive transfer and Se deficiency were assessed based on the questionnaire. The gammaG concentration of 42.9 % of the calves was < 10 g/L (median: 10.9). Calves showed significantly higher gammaG values after optimized colostrum administration than calves with suboptimal colostrum administration (p < 0.004). The median Se concentration was 26.8 and 36.5 microg/L for the calves and dams, respectively. A high correlation was observed between the Se concentration of the dam and her calf (r = 0.72, p < 0.001). The calves' Se and gammaG concentrations were not significantly correlated. These results demonstrate that further efforts toward better information of farmers regarding colostrum management and Se supply are warranted.

The use of bougie-guided insertion of a laryngeal mask airway device in neonatal piglets after unexpected complications

After marked airway obstruction with laryngeal mask (LM) placement in neonate piglets, anatomical observations in cadavers revealed a large epiglottis advancing markedly over the soft palate. CT imaging in vivo confirmed that the LM pushes the epiglottis caudally thereby obstructing the larynx. As a new approach, in 20 piglets a flexible PVC bougie placed under laryngoscopy was used to guide the LM to the correct position at the larynx. Placement of the bougie was easy and the LM was positioned successfully in all piglets at first attempt. In 14 piglets, the epiglottis was positioned dorsal to the soft palate before LM insertion and had to be pushed downwards to advance the bougie. In case of failure of LM placement with potential airway obstruction, the use of a bougie to guide the LM over the epiglottis was simple, rapid, and improved the success rate without complication.

The value of susceptibility-weighted imaging (SWI) in patients with non-neonatal hypoxic-ischemic encephalopathy

OBJECTIVE In susceptibility-weighted imaging (SWI) in the normal brain, cortical veins appear hypointense due to paramagnetic properties of deoxy-hemoglobin. Global cerebral anoxia decreases cerebral oxygen metabolism, thereby increasing oxy-hemoglobin levels in cerebral veins. We hypothesized that a lower cerebral oxygen extraction fraction in comatose patients with non-neonatal hypoxic ischemic encephalopathy (IHE) produce a pattern of global rarefied or pseudo-diminished cortical veins due to higher oxy-hemoglobin. PURPOSE 1. To investigate the topographic relationship between susceptibility effects in cortical veins and related diffusion restrictions on diffusion-weighted imaging (DWI) in patients with IHE. 2. To relate imaging findings to patterns of altered resting activity on surface EEG. METHODS Twenty-three IHE patients underwent MRI. EEG patterns were used to classify the depth of coma. Regional vs. global susceptibility changes on SWI and patterns of DWI restrictions were compared with the depth of coma. RESULTS All patients exhibited areas of restricted cortical diffusion and SWI abnormalities. The dominant DWI restrictions encompassed widespread areas along the precuneus, frontal and parietal association cortices and basal ganglia. For SWI, nineteen patients had generalized bi-hemispherical patterns, the EEG patterns correlated with coma grades III to V. Four patients had focal decreases of deoxy-hemoglobin following DWI restrictions; associated with normal EEGs. CONCLUSION Focal patterns of diamagnetic effects on SWI according to relative decreases in deoxy-hemoglobin due to reduced metabolic demand are associated with normal EEG in IHE patients. Global patterns indicated increased depth of coma and widespread cortical damage. CLINICAL RELEVANCE The results indicate a potential diagnostic value of SWI in patients with IHE.

Polycystic Kidneys and GM2 Gangliosidosis-Like Disease in Neonatal Springboks (Antidorcas marsupialis)

Clinical, gross, histopathologic, electron microscopic findings and enzymatic analysis of 4 captive, juvenile springboks (Antidorcas marsupialis) showing both polycystic kidneys and a storage disease are described. Springbok offspring (4 of 34; 12%) were affected by either one or both disorders in a German zoo within a period of 5 years (2008-2013). Macroscopic findings included bilaterally severely enlarged kidneys displaying numerous cysts in 4 animals and superior brachygnathism in 2 animals. Histopathologically, kidneys of 4 animals displayed cystic dilation of the renal tubules. In addition, abundant cytoplasmic vacuoles with a diameter ranging from 2 to 10 μm in neurons of the central and peripheral nervous system, hepatocytes, thyroid follicular epithelial cells, pancreatic islets of Langerhans and renal tubular cells were found in 2 springbok neonates indicative of an additional storage disease. Ultrastructurally, round electron-lucent vacuoles, up to 4 μm in diameter, were present in neurons. Enzymatic analysis of liver and kidney tissue of 1 affected springbok revealed a reduced activity of total hexosaminidase (Hex) with relatively increased HexA activity at the same level of total Hex, suggesting a hexosaminidase defect. Pedigree analysis suggested a monogenic autosomal recessive inheritance for both diseases. In summary, related springboks showed 2 different changes resembling both polycystic kidney and a GM2 gangliosidosis similar to the human Sandhoff disease. Whether the simultaneous occurrence of these 2 entities represents an incidental finding or has a genetic link needs to be investigated in future studies.

Effects of colostrum versus formula feeding on hepatic glucocorticoid and α1- and β2-adrenergic receptors in neonatal calves and their effect on glucose and lipid metabolism

Neonatal energy metabolism in calves has to adapt to extrauterine life and depends on colostrum feeding. The adrenergic and glucocorticoid systems are involved in postnatal maturation of pathways related to energy metabolism and calves show elevated plasma concentrations of cortisol and catecholamines during perinatal life. We tested the hypothesis that hepatic glucocorticoid receptors (GR) and α₁- and β₂-adrenergic receptors (AR) in neonatal calves are involved in adaptation of postnatal energy metabolism and that respective binding capacities depend on colostrum feeding. Calves were fed colostrum (CF; n=7) or a milk-based formula (FF; n=7) with similar nutrient content up to d 4 of life. Blood samples were taken daily before feeding and 2h after feeding on d 4 of life to measure metabolites and hormones related to energy metabolism in blood plasma. Liver tissue was obtained 2 h after feeding on d 4 to measure hepatic fat content and binding capacity of AR and GR. Maximal binding capacity and binding affinity were calculated by saturation binding assays using [(3)H]-prazosin and [(3)H]-CGP-12177 for determination of α₁- and β₂-AR and [(3)H]-dexamethasone for determination of GR in liver. Additional liver samples were taken to measure mRNA abundance of AR and GR, and of key enzymes related to hepatic glucose and lipid metabolism. Plasma concentrations of albumin, triacylglycerides, insulin-like growth factor I, leptin, and thyroid hormones changed until d 4 and all these variables except leptin and thyroid hormones responded to feed intake on d 4. Diet effects were determined for albumin, insulin-like growth factor I, leptin, and thyroid hormones. Binding capacity for GR was greater and for α₁-AR tended to be greater in CF than in FF calves. Binding affinities were in the same range for each receptor type. Gene expression of α₁-AR (ADRA1) tended to be lower in CF than FF calves. Binding capacity of GR was related to parameters of glucose and lipid metabolism, whereas β₂-AR binding capacity was negatively associated with glucose metabolism. In conclusion, our results indicate a dependence of GR and α₁-AR on milk feeding immediately after birth and point to an involvement of hepatic GR and AR in postnatal adaptation of glucose and lipid metabolism in calves.

Can stable isotope analysis and tooth histology assist in detecting stillbirth? An approach using neonatal remains from the Roman settlement Studen Petinesca

Infant burials in Roman settlements are a common observation. Even though ancient authors provide information many questions remain uncertain. For instance, the burial ritual for stillbirth and infanticide neonates is not specifically mentioned. This study therefore aimed to investigate the application of stable nitrogen (δ15N) and carbon (δ13C) isotopes from neonatal bone collagen in differentiating between a breastfeeding signal and stillbirth or a short survival of less than ten days. For this purpose collagen of 11 human and 14 non-human bones from the Roman settlement Petinesca (1st - 3rd century AD, Switzerland) was extracted and analysed for δ15N and δ13C. Tooth histology was performed for the central incisor and canine of the right mandible in order to investigate the presence of a neonatal line. According to the length of the long bones the age varied between 8.5 lunar months to 2 months ex utero. The stable isotope results provided a breastfeeding signal for all except one individual where the breastfeeding signal was absent. The tooth histological analysis of this individual exhibited no neonatal line. It is concluded that stable isotope analysis could indicate stillbirth or a short survival after birth. The tooth histology confirmed the stable isotope results. Furthermore, this might indicate that the burial ritual did not differentiate between stillbirth and neonates, who died within the time span stated by ancient authors of up to 40 days of age or the appearance of teeth. However, for further justifications additional research is going to be conducted.