Timing of antenatal corticosteroid administration and survival in extremely preterm infants: a national population-based cohort study.

OBJECTIVE: To explore the association between administration-to-birth interval of antenatal corticosteroids (ACS) and survival in extremely preterm infants. DESIGN: Population-based prospective cohort study. SETTING: All obstetric and neonatal units in Sweden from 1 April 2004 to 31 March 2007. POPULATION: All live-born infants (n = 707) born at 22-26 completed weeks of gestation. METHODS: The relationship between time from first administration of ACS to delivery and survival was investigated using Cox proportional hazards regression analysis. MAIN OUTCOME MEASURES: Neonatal (0-27 days) and infant (0-365 days) survival, and infant survival without major neonatal morbidity (intraventricular haemorrhage grade ≥ 3, retinopathy of prematurity stage ≥ 3, periventricular leukomalacia, necrotising enterocolitis, or severe bronchopulmonary dysplasia). RESULTS: Five-hundred and ninety-one (84%) infants were exposed to ACS. In the final adjusted model, infant survival was lower in infants unexposed to ACS [hazard ratio (HR) = 0.26; 95% confidence interval 0.15-0.43], in infants born <24 h [HR = 0.53 (0.33-0.87)] and >7 days after ACS [HR = 0.56 (0.32-0.97)], but not in infants born 24-47 h after ACS [HR = 1.60 (0.73-3.50)], as compared with infants born 48 h to 7 days after administration. The findings were similar for neonatal survival. Survival without major neonatal morbidity among live-born infants was 14% in unexposed infants and 30-39% in steroid-exposed groups, indicating that any ACS exposure was valuable. CONCLUSIONS: Administration of ACS 24 h to 7 days before extremely preterm birth was associated with significantly higher survival than in unexposed infants and in infants exposed to ACS at shorter or longer administration-to-birth intervals. TWEETABLE ABSTRACT: Timing of antenatal corticosteroids is important for extremely preterm infants' survival.

Brown bear attacks on humans: a worldwide perspective.

The increasing trend of large carnivore attacks on humans not only raises human safety concerns but may also undermine large carnivore conservation efforts. Although rare, attacks by brown bears Ursus arctos are also on the rise and, although several studies have addressed this issue at local scales, information is lacking on a worldwide scale. Here, we investigated brown bear attacks (n = 664) on humans between 2000 and 2015 across most of the range inhabited by the species: North America (n = 183), Europe (n = 291), and East (n = 190). When the attacks occurred, half of the people were engaged in leisure activities and the main scenario was an encounter with a female with cubs. Attacks have increased significantly over time and were more frequent at high bear and low human population densities. There was no significant difference in the number of attacks between continents or between countries with different hunting practices. Understanding global patterns of bear attacks can help reduce dangerous encounters and, consequently, is crucial for informing wildlife managers and the public about appropriate measures to reduce this kind of conflicts in bear country.

Activity and heart rate in semi-domesticated reindeer during adaptation to emergency feeding.

Although reindeer are well adapted to limited food resources during winter, semi-domesticated reindeer are regularly fed when snow conditions are bad in order to prevent starvation. Feeding sometimes results in health problems and loss of animals. This study was made to assess if activity pattern in reindeer could be used as a tool for the reindeer herder in early detection of animals that are not adapting to feeding. The frequency of 10 behavioural categories was recorded in five groups of penned, eight-month-old, female semi-domesticated reindeer. Three reindeer per group were fitted with heart rate monitors. Lying was the most frequent behaviour, whilst there were few cases of agonistic behaviour. Heart rate varied during the day, with peaks during feeding and low heart rates in the early morning. Restricted feed intake resulted in more locomotion and seeking but less ruminating compared to feeding ad libitum. This was followed by a generally lower heart rate in reindeer in the restricted groups compared to controls. Subsequent feeding with different combinations of lichens, silage and pellets ad libitum resulted initially in significantly more of the animals lying curled up, compared to controls, combined with increased heart rates. As the experiment continued the general activity pattern, as well as the heart rate, gradually became more similar in all groups. Lying curled was the behavioural indicator most consistently affected by feed deprivation and adaptation to feeding and may thus be a useful indicator to distinguish individual reindeer that are not adjusting to feeding.

Increased parathyroid hormone secretion and hypocalcemia in experimental pancreatitis: necessity for an intact thyroid gland.

Elevated concentrations of serum parathyroid hormone and hypocalcemia occur following the induction of experimental pancreatitis in the pig, but only when the thyroid gland is present. Prior thyroidectomy completely eliminates these changes. Serum magnesium concentrations remained normal throughout the experiments despite the occurrence of hypocalcemia. These data support the hypothesis that calcitonin or another thyroid-related substance plays a role in the mechanism of the hypocalcemia which accompanies experimental pancreatitis in the pig.

Substernal goiter with superior vena caval obstruction.

Substernal goiter with vena caval obstruction remains an interesting diagnostic and therapeutic problem. Since 85 to 90 percent of superior vena caval obstructions are due to a malignant disease, an intrathoracic goiter represents one of the benign, curable causes of this syndrome. This report describes the clinical course of a 44-year-old woman who presented with this entity and was successfully corrected by surgical intervention. A discussion of diagnostic, operative, and prognostic considerations is presented.

Histamine-induced hypocalcemia in the rat.

The effect of histamine and betazole hydrochloride (Histalog) on serum calcium homeostasis in the rat was studied in these experiments. Either histamine base, histamine phosphate, betazole, or the appropriate control solution was injected intravenously into fasted, anesthetized 80-100 g male rats. Venous blood was collected before and at 30 and 60 min postinjection. Histamine base in doses of 0.5-2.0 mg/rat induced a significant hypocalcemic response 30 min postinjection which returned to baseline by 60 min. Likewise, the administration of 1.375 mg/rat of histamine phosphate (equivalent to 0.5 mg histamine base) also resulted in a significant fall in serum calcium concentration. However, betazole administration, in doses as high as 10 mg/rat, did not lower the serum calcium concentration. In the histamine experiments neither total protein nor hematocrit values differed from control at the time of hypocalcemia. Therefore the changes in serum calcium concentration cannot be explained by hemodilution. These experiments demonstrate that in the rat the administration of histamine results in a hypocalcemic response similar to that previously observed with gastrin.

The importance of the stomach in mediating histamine-induced hypocalcemia in the rat.

The effect of histamine on serum calcium homeostasis was studied in the rat. After the intravenous administration of 0.5-1.0 mg histamine base to fasted Holtzman rats weighing 80-100 g, a significant lowering of serum calcium (Ca) level occurred 30 min after injection (decrease in Ca, 1.4-1.9 mg/100 ml), but normocalcemia returned at 60 min. Repeat intravenous injections of histamine 1.0 mg resulted in repeated lowering of the serum Ca level. Hypophosphatemia did not accompany the hypocalcemia. Thyroparathyroidectomy (TPTX) did not eliminate the calcium-lowering effect of histamine in acute TPTX animals but did so in more chronic TPTX animals in which the mean serum Ca was 7.6 mg/100 ml or less. Gastrectomy, however, completely eliminated the calcium-lowering effect of histamine given in doses of up to 2 mg/rat (20 mg/kg of body weight), despite the presence of an intact thyroid gland. These studies support the role of a gastric factor and not the thyroid secretion of calcitonin in mediating this response in the rat.

Complications of ornamental Christmas bulb ingestion. Case report and review of the literature.

Unusual complications ensued when a 14-month-old boy ingested an ornamental Christmas bulb. Profuse rectal bleeding, a large ischiorectal abscess, and an acute condition of the abdomen necessiated a sigmoid colostomy with drainage of the ischiorectal abscess. Following this, repeated episodes of hemorrhage via the colostomy and rectum required multiple operative procedures. The last of these was a total colectomy with an ileostomy and rectal mucous fistula. The patient subsequently developed intestinal obstruction that required lysis of adhesions and drainage of a chronic subhepatic abscess, due to perforation of the terminal part of the ileum. The patient required five months of hospitalization and further surgery to reconstruct gastrointestinal continuity. Hemorrhage is an infrequent complication of foreign body ingestion, as reported in the literature. We theorize that the problems in this case were the result of the extreme thinness (0.033 cm) and the brittleness of the glass fragments.

Ivermectin treatment did not increase slaughter weight of first-year reindeer calves.

To investigate if antiparasitic treatment of reindeer calves during the summer could increase their carcass weight during the slaughter period in autumn and winter, 529 reindeer calves were allocated to three groups, weighed, and marked with individually numbered plastic ear tags in early July, 1995. One of the groups was left untreated, another was treated with ivermectin injection at 200 micrograms/kg, and the third with pour-on ivermectin at 500 micrograms/kg. Following slaughter, carcass weights were received from 231 animals, and there was no difference between the treatment groups.

Clinical technique and success of the esophageal stent to prevent corrosive strictures.

The Reyes technique for the management of severe, acute corrosive injuries of the esophagus has been modified and successfully applied to two children and one adult whose cases are reported. None developed stricture and two were uncomplicated. Esophagomegaly, motility dysfunction, upper gastrointestinal bleeding, and pneumonitis complicated the hospitalization of one child whose subsequent course has been asymptomatic. Until more experience can be recorded, widespread use is not yet recommended.

Influence of route of administration on the plasma concentrations of ivermectin in reindeer.

The concentration of ivermectin in the plasma of reindeer was measured after it was administered either topically as a pour-on preparation at 500 micrograms kg-1 bodyweight at different seasons to animals of different ages, or after subcutaneous and oral doses of 200 micrograms kg-1 bodyweight. The plasma concentrations of ivermectin were highest and least variable after it was administered subcutaneously.

Individually coded telemetry: a tool for studying heart rate and behaviour in reindeer calves.

The aim of the study was to test the performance of a silver wire modified version of the coded telemetric heart rate monitor Polar Vantage NV (PVNV) and to measure heart rate (HR) in a group of captive reindeer calves during different behaviour. The technical performance of PVNV HR monitors was tested in cold conditions (-30 degrees C) using a pulse generator and the correlation between generated pulse and PVNV values was high (r=0.9957). The accuracy was tested by comparing the HR obtained with the PVNV monitor with the standard ECG, and the correlation was significant (r=0.9965). Both circadian HR and HR related to behavioural pattern were recorded. A circadian rhythm was observed in the HR in reindeer with a minimum during night and early morning hours and maximum at noon and during the afternoon, the average HR of the reindeer calves studied being 42.5 beats/min in February. The behaviour was recorded by focal individual observations and the data was synchronized with the output of the HR monitors. Running differed from all other behavioural categories in HR. Inter-individual differences were seen expressing individual responses to external and internal stimuli. The silver wire modified Polar Vantage NV provides a suitable and reliable tool for measuring heart rate in reindeer, also in natural conditions.

Caspase-2 promotes cytoskeleton protein degradation during apoptotic cell death.

The caspase family of proteases cleaves large number of proteins resulting in major morphological and biochemical changes during apoptosis. Yet, only a few of these proteins have been reported to selectively cleaved by caspase-2. Numerous observations link caspase-2 to the disruption of the cytoskeleton, although it remains elusive whether any of the cytoskeleton proteins serve as bona fide substrates for caspase-2. Here, we undertook an unbiased proteomic approach to address this question. By differential proteome analysis using two-dimensional gel electrophoresis, we identified four cytoskeleton proteins that were degraded upon treatment with active recombinant caspase-2 in vitro. These proteins were degraded in a caspase-2-dependent manner during apoptosis induced by DNA damage, cytoskeleton disruption or endoplasmic reticulum stress. Hence, degradation of these cytoskeleton proteins was blunted by siRNA targeting of caspase-2 and when caspase-2 activity was pharmacologically inhibited. However, none of these proteins was cleaved directly by caspase-2. Instead, we provide evidence that in cells exposed to apoptotic stimuli, caspase-2 probed these proteins for proteasomal degradation. Taken together, our results depict a new role for caspase-2 in the regulation of the level of cytoskeleton proteins during apoptosis.

Allele-specific programming of Npy and epigenetic effects of physical activity in a genetic model of depression.

Neuropeptide Y (NPY) has been implicated in depression, emotional processing and stress response. Part of this evidence originates from human single-nucleotide polymorphism (SNP) studies. In the present study, we report that a SNP in the rat Npy promoter (C/T; rs105431668) affects in vitro transcription and DNA-protein interactions. Genotyping studies showed that the C-allele of rs105431668 is present in a genetic rat model of depression (Flinders sensitive line; FSL), while the SNP's T-allele is present in its controls (Flinders resistant line; FRL). In vivo experiments revealed binding of a transcription factor (CREB2) and a histone acetyltransferase (Ep300) only at the SNP locus of the FRL. Accordingly, the FRL had increased hippocampal levels of Npy mRNA and H3K18 acetylation; a gene-activating histone modification maintained by Ep300. Next, based on previous studies showing antidepressant-like effects of physical activity in the FSL, we hypothesized that physical activity may affect Npy's epigenetic status. In line with this assumption, physical activity was associated with increased levels of Npy mRNA and H3K18 acetylation. Physical activity was also associated with reduced mRNA levels of a histone deacetylase (Hdac5). Conclusively, the rat rs105431668 appears to be a functional Npy SNP that may underlie depression-like characteristics. In addition, the achieved epigenetic reprogramming of Npy provides molecular support for the putative effectiveness of physical activity as a non-pharmacological antidepressant.

Integration of apoptosis and metabolism.

Apoptotic resistance is a hallmark of human cancers. Recent advances have contributed to our understanding of the molecular mechanisms that intimately integrate cell metabolism and apoptosis. Coordinated activation of the proapoptotic Bcl-2 family and the caspase family during apoptosis often leads to permeabilization of the mitochondrial outer membrane and release of multiple enzymes that normally function in regulating energy production and metabolism. The roles of these metabolic enzymes in promoting caspase activation demonstrate a primordial need to couple apoptotic cell death and metabolic catastrophe during cellular destruction. The Bcl-2 family also directly interacts with the multiple metabolic regulators to protect or promote mitochondrial damage during apoptosis. However, the integration of metabolism and apoptosis is not simply limited to the maintenance of mitochondrial integrity. A recent study demonstrates that the NatA complex, a protein N-α-acetyltransferase complex, is required for DNA damage-mediated apoptosis and suggests that regulation of protein acetylation might provide an important mechanism for regulating apoptotic sensitivity. Since acetyl-CoA (coenzyme A) is a key cofactor for the NatA complex, protein acetylation is subject to the availability of acetyl-CoA and, thus, under metabolic regulation. The revelation that protein N-α-acetylation is regulated by Bcl-xL, a major antiapoptotic mitochondrial protein, demonstrates a mechanism by which metabolism can regulate the activation of multiple key apoptotic factors simultaneously.

Small-molecule inhibitors specifically targeting type III secretion.

The type III secretion (TTS) system is used by several animal and plant pathogens to deliver effector proteins into the cytosol of the eukaryotic target cell as a strategy to evade the defense reactions elicited by the infected organism. The fact that these systems are highly homologous implies that novel antibacterial agents that chemically attenuate the pathogens via a specific interaction with the type III secretion mechanism can be identified. A number of small organic molecules having this potential have recently been identified (A. M. Kauppi, R. Nordfelth, H. Uvell, H. Wolf-Watz, and M. Elofsson, Chem. Biol. 10:241-249, 2003). Using different reporter gene constructs, we showed that compounds that belong to a class of acylated hydrazones of different salicylaldehydes target the TTS system of Yersinia pseudotuberculosis. One of these compounds, compound 1, was studied in detail and was found to specifically block Yop effector secretion under in vitro conditions by targeting the TTS system. In this respect the drug mimics the well-known effect of calcium on Yop secretion. In addition, compound 1 inhibits Yop effector translocation after infection of HeLa cells without affecting the eukaryotic cells or the bacteria. A HeLa cell model that mimics in vivo conditions showed that compound 1 chemically attenuates the pathogen to the advantage of the eukaryotic cell. Thus, our results show proof of concept, i.e., that small compounds targeting the TTS system can be identified, and they point to the possible use of TTS inhibitors as a novel class of antibacterial agents.

Lethal cerebrospinal elaphostrongylosis in a reindeer calf.

Lethal elaphostrongylosis in a reindeer calf is described. The calf showed signs of abnormal behaviour, mental confusion and reduced vision due to lesions in the brain parenchyma caused by migrating mature Elaphostrongylus rangiferi. Traumatically caused malacia and secondary axon degeneration were observed in all brain areas. Nematodes were found in the skeletal muscles, epidural space of the spinal cord, and in the subdural spaces and leptomeninges of the cord and brain. Developing nematode ova were sectioned along migratory tracks in the brain, in the subdural space of the cord, epidural adipose tissue, perineurium of the spinal nerve roots and in the lungs.

Cost analysis and ethical aspects of hospital-based home-care for terminal cancer patients.

A study was undertaken to measure the costs of caring for 20 terminally ill/dying cancer patients at home, within a hospital-based home-care system. A new method was used, by which all staff expenses were registered and the work costs per minute were calculated for each personnel category (e.g. nurses, physicians). The total number of care days amounted to 857. The average daily cost was 509 Skr. (range 87-2999), but it was higher for patients with the shortest periods of home-care ( = the dying patients). Comparisons were made between the costs of hospital-based home-care and those of hospital care in 1) a geriatric unit, 2) other somatic departments, and 3) those departments from which the patients had been referred. The costs of hospital-based home-care were 40%, 55%, and 67% lower than the three different forms of hospital care, respectively. All the patients had relatives at home and were intensely dependent on their families. The important part played by the relatives contributed to the relatively low costs. The ethical aspects of caring for dying cancer patients at home are discussed.