Examination of the effect of procalcitonin on human leucocytes and the porcine isolated coronary artery

Background: The aim of this study was to investigate the effects of procalcitoninon the lipopolysaccharide (LPS)-induced changes in human leucocytesand porcine isolated coronary artery. Methods: Using flow cytometry, changes in forward scatter and intracellularcalcium in human neutrophils and monocytes were determined afterexposure to procalcitonin, calcitonin gene-related peptide (CGRP),LPS, and the known chemoattractants formylated methionine-leucine-phenylalanine(fMLP) and interleukin-8 (IL-8). In porcine isolated coronaryartery, the effects of procalcitonin were evaluated using thecontractile function change and the release of TNF. Results: In human neutrophils and monocytes, procalcitonin (100 nM),but not CGRP, increased forward scatter and the expression ofsurface markers (CD16 and CD14, respectively) in a similar mannerto 10 µg ml^–1 LPS. Procalcitonin, but not CGRP,also increased the proportion of cells exhibiting an increasein intracellular calcium ions similar to that produced by fMLPand IL-8. Acute exposure of the coronary artery to procalcitoninproduced a small, endothelium-independent relaxation (approximately15% of constrictor tone), but failed to modify subsequent relaxationsto CGRP. After 16 h exposure, procalcitonin (100 nM) increasedTNF release from the coronary artery equivalent to 70% of thatproduced by LPS, but did not modify the inhibitory effect ofLPS (100 µg ml^–1) on contractile responses. Conclusions: Procalcitonin has a proinflammatory effect on human leucocytesand porcine coronary artery, but it is not capable of modulatingLPS-induced changes in vascular responsiveness in vitro.     

The United Kingdom Infantile Spasms Study (UKISS) comparing hormone treatment with vigabatrin on developmental and epilepsy outcomes to age 14 months: a multicentre randomised trial

BACKGROUND: Infantile spasms is a severe infantile seizure disorder that is difficult to treat and has a high morbidity. Absence of spasms on days 13 and 14 after randomisation is more common in infants allocated hormone treatments than in those allocated vigabatrin. We sought to assess whether early control of spasms is associated with improved developmental or epilepsy outcomes. METHODS: Infants enrolled in the United Kingdom Infantile Spasms Study (UKISS) were randomly assigned hormone treatment (n=55) or vigabatrin (n=52) and were followed up until clinical assessment at 12-14 months of age. We assessed neurodevelopment with the Vineland adaptive behaviour scales (VABS) at 14 months of age on an intention to treat basis. FINDINGS: Of 107 infants enrolled, five died and 101 survivors reached both follow-up assessments. Absence of spasms at final clinical assessment (hormone 41/55 [75%] vs vigabatrin 39/51 [76%]) was similar in each treatment group (difference 1.9%, 95% CI -18.3% to 14.4%; chi(2)=0.05; p=0.82). Mean VABS score did not differ significantly (hormone 78.6 [SD 16.8] vs vigabatrin 77.5 [SD 12.7]; difference 1.0, 95% CI -4.9 to 7.0; t(99)=0.35, p=0.73). In infants with no identified underlying aetiology, the mean VABS score was higher in those allocated hormone treatment than in those allocated vigabatrin (88.2 [17.3] vs 78.9 [14.3]; difference 9.3, 95% CI 1.2 to 17.3; t(95)=2.28, p=0.025). INTERPRETATION: Hormone treatment controls spasms better than does vigabatrin initially, but not at 12-14 months of age. Better initial control of spasms by hormone treatment in those with no identified underlying aetiology may lead to improved developmental outcome.     

Banking sperm is only the first of many decisions for men: what healthcare professionals and men need to know

Sperm banking is recommended for all males prior to cancer treatment where there are risks of infertility. Subsequent decisions about monitoring fertility, use of banked sperm or disposal are less well understood, with adverse consequences for men and cost implications. We review the literature around key decision points: Diagnosis of cancer, monitoring fertility, use of banked sperm and sperm disposal. The results suggest that decisions about banking are compromised by concerns to initiate treatment quickly; subsequent decisions about monitoring fertility, use of banked sperm or disposal are coloured by the views of family members, men's failure to understand the longer-term implications and their reluctance to avail themselves of health care generally. Methodological limitations of current research include low response rates, increased focus on germ cell cancers and a lack of research outside North America. There is evidence that men and oncologists could use sperm banks more "wisely". Lack of longitudinal work means it is not possible to determine the long-term consequences of banking for men's general health and well-being, or identify barriers to fertility monitoring or disposal. We argue that sperm banking should be considered as a series of decisions, all involving implications for fertility, contraception and social and psychological adjustment to cancer.     

Cross-border reproductive care: a review of the literature

Cross-border reproductive care (CBRC) has attracted considerable attention in media and professional publications. The aim of this review is to present a critical narrative overview of the published evidence on CBRC. A systematic search of key academic databases was undertaken with no time restrictions set for publication. This was supplemented by additional searches of key websites, reference chaining and enquiries to people working in the field. A total of 54 items are included in the review, including both empirical research studies (18) and debate papers (36). The key themes discussed are: terminology and definitions; incidence; experiences; explanations; implications; and policy responses. Significant methodological limitations and gaps in the literature are identified. Evidence on incidence is scant, though it suggests that CBRC is increasing. The literature suggests legal, social and political drivers, which vary in importance geographically and between individuals. Limited findings on patient perceptions suggest a broadly positive patient experience. Suggested policy responses include prohibition, regulatory harmonization and harm minimization. There is a need for better international data collection tools and both quantitative and qualitative work which encompasses views of patients, donors, surrogates and professionals and which explores the implications for healthcare services in sending countries.     

Effects of neonatal hypothyroidism on cerebral and cerebellar synaptosome development.

The effect of hypothyroidism on cerebral and cerebellar synaptosome development has been studied. Neonatal hypothyroidism was induced following addition of 0.3% propylthiouracil to the diet of nursing mothers. Maturation profiles of total synaptosome fraction and specific activities of lactate dehydrogenase, Na+K ATPase, cytochrome c oxidase, and protein were obtained from days 6 to 32 on synaptosomes isolated from Ficoll-sucrose gradients. The greatest changes were found in the total activities of enzymes isolated from the cerebellum. Hypothyroidism induced a retardation of LDH and cytochrome c oxidase in cerebellar synaptosomes, but no change in corresponding specific activities. Maximum rates of 14C-leucine incorporation into cerebellar synaptosome protein was found at 16-20 days, after which a rapid decline occurred to adult levels at 32 days. In neonatal hypothyroidism, synthesis was significantly reduced at 8 and 14 days, but reached control levels or above at 21--32 days. In the cerebrum, maximum rates of 14C-leucine incorporation into synaptosome protein were identified at 8--12 days in normal with a rapid drop to adult levels at approximately 20 days. In neonatal hypothyroidism, peak activities were identified at 14 days and increased activities over control were noted at 14, 20 and 30 days. These observations demonstrate the sensitivity of the developing cerebellar synaptic apparatus to neonatal hypothyroidism, with a protraction in the peak levels of synaptosome protein synthesis in cerebrum and cerebellum.     

Structural diversity in twin-arginine signal peptide-binding proteins

The twin-arginine transport (Tat) system is dedicated to the translocation of folded proteins across the bacterial cytoplasmic membrane. Proteins are targeted to the Tat system by signal peptides containing a twin-arginine motif. In Escherichia coli, many Tat substrates bind redox-active cofactors in the cytoplasm before transport. Coordination of cofactor insertion with protein export involves a "Tat proofreading" process in which chaperones bind twin-arginine signal peptides, thus preventing premature export. The initial Tat signal-binding proteins described belonged to the TorD family, which are required for assembly of N- and S-oxide reductases. Here, we report that E. coli NapD is a Tat signal peptide-binding chaperone involved in biosynthesis of the Tat-dependent nitrate reductase NapA. NapD binds tightly and specifically to the NapA twin-arginine signal peptide and suppresses signal peptide translocation activity such that transport via the Tat pathway is retarded. High-resolution, heteronuclear, multidimensional NMR spectroscopy reveals the 3D solution structure of NapD. The chaperone adopts a ferredoxin-type fold, which is completely distinct from the TorD family. Thus, NapD represents a new family of twin-arginine signal-peptide-binding proteins.     

Pathways to drug development for autism spectrum disorders

Autism spectrum disorders (ASDs) are neurodevelopmental disorders whose prevalence has risen over the past two decades. Current drug treatments for ASDs and the related disorders--fragile X syndrome (FXS) and Rett syndrome--target specific symptoms but do not address the basic underlying etiologies. However, based partly on an improved understanding of the neurochemical underpinnings of FXS, pharmacotherapy for this syndrome has progressed to the point of clinical trials of several novel drug treatments. By contrast, our overall understanding of the neuropathophysiology of ASDs is still rudimentary. There is hope in the field that knowledge and experience gained in the study of fragile X and Rett syndromes may be applicable to the larger autism patient population. In this review, we discuss how recent advances in our understanding of the biochemistry and neuropathology of these disorders could lead to new more effective treatments for ASDs.