High versus "low" dose corticosteroids in recipients of cadaveric kidneys: prospective controlled trial.

Corticosteroids have the major role in the immunosuppressive treatment of patients who have received renal transplants. Despite their extensive use there is still debate about the appropriate dose that will prevent rejection of the renal allograft with the least morbidity. From March 1979 to November 1981 a randomised controlled trial of high (33 patients) v low oral dose (34 patients) of prednisolone along with azathioprine was conducted in recipients of first cadaveric transplants who had received a blood transfusion within six months of transplantation. The main difference in outcome between the two groups was a high incidence of some infections in the high dose group. Patient mortality, graft survival, transplant function, and number of rejection episodes were indistinguishable in the two groups, but rejection episodes tended to occur later in the high dose group. These findings suggest that the use of lower doses of corticosteroids soon after cadaveric renal transplantation does not jeopardise graft survival and results in lower patient morbidity.     

Genomic structure and chromosomal localization of the mouse persyn gene

Synucleins are a family of small intracellular proteins expressed mainly in the nervous system. The involvement of synucleins in neurodegeneration and malignancy has been demonstrated, but the physiological functions of these proteins remain elusive. Further studies including generation of animals with modified persyn expression are necessary to clarify the functions of these proteins and the mechanisms of their involvement in human diseases. We cloned and determined the organization and chromosomal localization of the mouse gene coding for persyn, a member of the synuclein family. The gene is composed of five exons, and its general structure is very similar to that of the human persyn gene. Using fluorescence in situ hybridization, we assigned the persyn gene to the boundary of bands B and C on mouse chromosome 14. We found a fragment of the gene that directs expression of the persyn protein in sensory neurons and could be used for generation of transgenic animals.     

Mycobacterium kansasii infection diagnosed by pleural fluid cytology: a case report

BACKGROUND: Identification of disseminated nontuberculous Mycobacterium infection is a challenge, especially when it occurs in patients without a known cause of immunosuppression. Acid-fast organisms in the pleural fluid are rare and easily missed, especially when they occur in patients without a clinical suspicion of infection. The classical cytologic picture of tuberculous pleural fluid with lymphocytosis and paucity of mesothelial cells is not seen. CASE: A 57-year-old man presented with chronic neutrophilia of unknown etiology together with chest pain and bilateral pleural effusions. Pleural fluid cytology revealed organisms seen in the cytoplasm of numerous macrophages and neutrophils, creating a "negative image" on Diff-Quik smears. Acid-fast stains demonstrated intracellular acid-fast bacilli consistent with mycobacteria. Microbiologic studies with DNA probe technology resulted in identification of the mycobacterial organism as Mycobacterium kansasii. CONCLUSION: Nontuberculous Mycobacterium should be included in the differential diagnosis in patients with inflammatory, exudative pleural effusions.     

Fc Gamma Receptor IIIB (FcγRIIIB) Polymorphisms Are Associated with Clinical Malaria in Ghanaian Children

Plasmodium falciparum malaria kills nearly a million people annually. Over 90% of these deaths occur in children under five years of age in sub-Saharan Africa. A neutrophil mediated mechanism, the antibody dependent respiratory burst (ADRB), was recently shown to correlate with protection from clinical malaria. Human neutrophils constitutively express Fc gamma receptor-FcγRIIA and FcγRIIIB by which they interact with immunoglobulin (Ig) G (IgG)-subclass antibodies. Polymorphisms in exon 4 of FCGR2A and exon 3 of FCGR3B genes encoding FcγRIIA and FcγRIIIB respectively have been described to alter the affinities of both receptors for IgG. Here, associations between specific polymorphisms, encoding FcγRIIA p.H166R and FcγRIIIB-NA1/NA2/SH variants with clinical malaria were investigated in a longitudinal malaria cohort study. FcγRIIA-p.166H/R was genotyped by gene specific polymerase chain reaction followed by allele specific restriction enzyme digestion. FCGR3B-exon 3 was sequenced in 585 children, aged 1 to 12 years living in a malaria endemic region of Ghana. Multivariate logistic regression analysis found no association between FcγRIIA-166H/R polymorphism and clinical malaria. The A-allele of FCGR3B-c.233C>A (rs5030738) was significantly associated with protection from clinical malaria under two out of three genetic models (additive: p = 0.0061; recessive: p = 0.097; dominant: p = 0.0076) of inheritance. The FcγRIIIB-SH allotype (CTGAAA) containing the 233A-allele (in bold) was associated with protection from malaria (p = 0.049). The FcγRIIIB-NA2*03 allotype (CTGCGA), a variant of the classical FcγRIIIB-NA2 (CTGCAA) was associated with susceptibility to clinical malaria (p = 0.0092). The present study is the first to report an association between a variant of FcγRIIIB-NA2 and susceptibility to clinical malaria and provides justification for further functional characterization of variants of the classical FcγRIIIB allotypes. This would be crucial to the improvement of neutrophil mediated functional assays such as the ADRB assay aimed at assessing the functionality of antibodies induced by candidate malaria vaccines.     

Molecular Mechanism for Human Sperm Chemotaxis Mediated by Progesterone

Sperm chemotaxis is a chemical guiding mechanism that may orient spermatozoa to the egg surface. A picomolar concentration gradient of Progesterone (P), the main steroidal component secreted by the cumulus cells that surround the egg, attracts human spermatozoa. In order to elucidate the molecular mechanism of sperm chemotaxis mediated by P, we combine the application of different strategies: pharmacological inhibition of signaling molecules, measurements of the concentrations of second messengers and activation of the chemotactic signaling. Our data implicate a number of classic signal transduction pathways in the response and provide a model for the sequence of events, where the tmAC-cAMP-PKA pathway is activated first, followed by protein tyrosine phosphorylation (equatorial band and flagellum) and calcium mobilization (through IP₃R and SOC channels), whereas the sGC-cGMP-PKG cascade, is activated later. These events lead to sperm orientation towards the source of the chemoattractant. The finding proposes a molecular mechanism which contributes to the understanding of the signal transduction pathway that takes place in a physiological process as chemotaxis.     

Forest biomass,productivity and carbon cycling along a rainfall gradient in West Africa

Net Primary Productivity (NPP) is one of the most important parameters in describing the functioning of any ecosystem and yet it arguably remains a poorly quantified and understood component of carbon cycling in tropical forests, especially outside of the Americas. We provide the first comprehensive analysis of NPP and its carbon allocation to woody, canopy and root growth components at contrasting lowland West African forests spanning a rainfall gradient. Using a standardized methodology to study evergreen (EF), semi‐deciduous (SDF), dry forests (DF) and woody savanna (WS), we find that (i) climate is more closely related with above and belowground C stocks than with NPP (ii) total NPP is highest in the SDF site, then the EF followed by the DF and WS and that (iii) different forest types have distinct carbon allocation patterns whereby SDF allocate in excess of 50% to canopy production and the DF and WS sites allocate 40%–50% to woody production. Furthermore, we find that (iv) compared with canopy and root growth rates the woody growth rate of these forests is a poor proxy for their overall productivity and that (v) residence time is the primary driver in the productivity‐allocation‐turnover chain for the observed spatial differences in woody, leaf and root biomass across the rainfall gradient. Through a systematic assessment of forest productivity we demonstrate the importance of directly measuring the main components of above and belowground NPP and encourage the establishment of more permanent carbon intensive monitoring plots across the tropics.     

Waiving in vivo studies for monoclonal antibody biosimilar development: National and global challenges

Biosimilars are biological medicinal products that contain a version of the active substance of an already authorised original biological medicinal product (the innovator or reference product). The first approved biosimilar medicines were small proteins, and more recently biosimilar versions of innovator monoclonal antibody (mAb) drugs have entered development as patents on these more complex proteins expire. In September 2013, the first biosimilar mAb, infliximab, was authorised in Europe. In March 2015, the first biosimilar (Zarxio?, filgrastim-sndz, Sandoz) was approved by the US Food and Drug Administration; however, to date no mAb biosimilars have been approved in the US. There are currently major differences between how biosimilars are regulated in different parts of the world, leading to substantial variability in the amount of in vivo nonclinical toxicity testing required to support clinical development and marketing of biosimilars. There are approximately 30 national and international guidelines on biosimilar development and this number is growing. The European Union's guidance describes an approach that enables biosimilars to enter clinical trials based on robust in vitro data alone; in contrast, the World Health Organization's guidance is interpreted globally to mean in vivo toxicity studies are mandatory.

We reviewed our own experience working in the global regulatory environment, surveyed current practice, determined drivers for nonclinical in vivo studies with biosimilar mAbs and shared data on practice and study design for 25 marketed and as yet unmarketed biosimilar mAbs that have been in development in the past 5y. These data showed a variety of nonclinical in vivo approaches, and also demonstrated the practical challenges faced in obtaining regulatory approval for clinical trials based on in vitro data alone. The majority of reasons for carrying out nonclinical in vivo studies were not based on scientific rationale, and therefore the authors have made recommendations for a data-driven approach to the toxicological assessment of mAb biosimilars that minimises unnecessary use of animals and can be used across all regions of the world.