ANNALS EXPRESS: Late Diagnosis of Hypophosphatasia in a case with Unverricht-Lundborg disease

A significant increase in the activity of serum alkaline phosphatase is commonly reported in patients on long-term antiepileptic treatment or after any uncomplicated fracture. We report a case of a 35-year old male patient on five different anticonvulsant medications for treatment of the rare autosomal recessive neurodegenerative disorder, Unverricht-Lundborg disease. He presented with bilateral metatarsal fractures: however, his serum alkaline phosphatase activity remained below the lower limit of reference interval. Biochemical laboratory investigations revealed a long standing low serum alkaline phosphatase and raised plasma pyridoxal-5'-phosphate level. Sequencing of genomic DNA revealed that he is heterozygous for a mutation in the ALPL gene which is consistent with the diagnosis of hypophosphatasia. Keywords: Hypophosphatasia, Unverricht-Lundborg disease, Alkaline phosphatase enzyme

Opportunities for topical antimicrobial therapy: permeation of canine skin by fusidic acid

BACKGROUND: Staphylococcal infection of the canine epidermis and hair follicle is amongst the commonest reasons for antimicrobial prescribing in small animal veterinary practice. Topical therapy with fusidic acid (FA) is an attractive alternative to systemic therapy based on low minimum inhibitory concentrations (MICs, commonly <0.03 mg/l) documented in canine pathogenic staphylococci, including strains of MRSA and MRSP (methicillin-resistant Staphylococcus aureus and S. pseudintermedius). However, permeation of canine skin by FA has not been evaluated in detail. This study aimed to define the degree and extent of FA permeation in canine skin in vitro from two sites with different hair follicle density following application of a licensed ophthalmic formulation that shares the same vehicle as an FA-betamethasone combination product approved for dermal application in dogs. Topical FA application was modelled using skin held in Franz-type diffusion cells. Concentrations of FA in surface swabs, receptor fluid, and transverse skin sections of defined anatomical depth were determined using high-performance liquid chromatography and ultraviolet (HPLC-UV) analysis. RESULTS: The majority of FA was recovered by surface swabs after 24 h, as expected (mean ± SEM: 76.0 ± 17.0%). FA was detected within 424/470 (90%) groups of serial sections of transversely cryotomed skin containing follicular infundibula, but never in 48/48 (100%) groups of sections containing only deeper follicular structures, nor in receptor fluid, suggesting that FA does not permeate beyond the infundibulum. The FA concentration (mean ± SEM) in the most superficial 240 μm of skin was 2000 ± 815 μg/g. CONCLUSIONS: Topically applied FA can greatly exceed MICs for canine pathogenic staphylococci at the most common sites of infection. Topical FA therapy should now be evaluated using available formulations in vivo as an alternative to systemic therapy for canine superficial bacterial folliculitis.Peer reviewedFinal Published versio

A Decline in the Incidence of Invasive Non-Typhoidal Salmonella Infection in the Gambia Temporally Associated with a Decline in Malaria Infection

BACKGROUND: Malaria is a risk factor for invasive non-typhoidal Salmonella (NTS) infection in children. In the last 10 years, indices of malaria infection in The Gambia have fallen substantially. METHODS: We compared temporal trends of childhood malaria and NTS infection in two Gambian locations. In Fajara, on the coast, the incidence of NTS infection at three time points between 1979 and 2005 was compared to the percentage of malaria positive outpatient thick blood films and the percentage of admissions associated with malaria over time. In Basse, in the eastern part of the country, the incidence of NTS infection at three time points between 1989 and 2008 was compared to the prevalence of malaria parasitaemia at four time points between 1992 and 2008. RESULTS: The estimated incidence of NTS infection in Fajara fell from 60 (1979-1984) to 10 (2003-05) cases per 100,000 person years. The proportion of outpatients in Fajara with suspected malaria who were parasitaemic fell from 33% (1999) to 6% (2007) while the proportion of admissions associated with malaria fell from 14.5% (1999) to 5% (2007). In Basse, the estimated incidence of NTS infection fell from 105 (1989-1991) to 29 (2008) cases per 100,000 person years while the prevalence of malaria parasitaemia fell from 45% (1992) to 10% (2008). The incidence of pneumococcal bacteraemia in Fajara and Basse did not fall over the study period. CONCLUSIONS: These data support an association between malaria and NTS infection. Reductions in malaria infection may be associated with reduced rates of invasive childhood NTS infection

The Osteology of the Basal Archosauromorph Tasmaniosaurus triassicus from the Lower Triassic of Tasmania, Australia

Proterosuchidae are the most taxonomically diverse archosauromorph reptiles sampled in the immediate aftermath of the Permo-Triassic mass extinction and represent the earliest radiation of Archosauriformes (archosaurs and closely related species). Proterosuchids are potentially represented by approximately 15 nominal species collected from South Africa, China, Russia, Australia and India, but the taxonomic content of the group is currently in a state of flux because of the poor anatomic and systematic information available for several of its putative members. Here, the putative proterosuchid Tasmaniosaurus triassicus from the Lower Triassic of Hobart, Tasmania (Australia),is redescribed. The holotype and currently only known specimen includes cranial and postcranial remains and the revision of this material sheds new light on the anatomy of the animal, including new data on the cranial endocast. Several bones are re-identified or reinterpreted, contrasting with the descriptions of previous authors. The new information provided here shows that Tasmaniosaurus closely resembles the South African proterosuchid Proterosuchus, but it differed in the presence of, for example, a slightly downturned premaxilla, a shorter anterior process of maxilla, and a diamond-shaped anterior end of interclavicle. Previous claims for the presence of gut contents in the holotype of Tasmaniosaurus are considered ambiguous. The description of the cranial endocast of Tasmaniosaurus provides for the first time information about the anatomy of this region in proterosuchids. The cranial endocast preserves possibly part of the vomero-nasal (= Jacobson's) system laterally to the olfactory bulbs. Previous claims of the absence of the vomero-nasal organs in archosaurs, which is suggested by the extant phylogenetic bracket, are questioned because its absence in both clades of extant archosaurs seems to be directly related with the independent acquisition of a non-ground living mode of life

Preliminary clinical study of left ventricular myocardial strain in patients with non-ischemic dilated cardiomyopathy by three-dimensional speckle tracking imaging

<p>Abstract</p> <p>Background</p> <p>Non-ischemic dilated cardiomyopathy (DCM) is the most common cardiomyopathy worldwide, with significant mortality. Correct evaluation of the patient's myocardial function has important clinical significance in the diagnosis, therapeutic effect assessment and prognosis in non-ischemic DCM patients. This study evaluated the feasibility of three-dimensional speckle tracking imaging (3D-STE) for assessment of the left ventricular myocardial strain in patients with non-ischemic dilated cardiomyopathy (DCM).</p> <p>Methods</p> <p>Apical full-volume images were acquired from 65 patients with non-ischemic DCM (DCM group) and 59 age-matched normal controls (NC group), respectively. The following parameters were measured by 3D-STE: the peak systolic radial strain (RS), circumferential strain (CS), longitudinal strain (LS) of each segment. Then all the parameters were compared between the two groups.</p> <p>Results</p> <p>The peak systolic strain in different planes had certain regularities in normal groups, radial strain (RS) was the largest in the mid region, the smallest in the apical region, while circumferential strain (CS) and longitudinal strain (LS) increased from the basal to the apical region. In contrast, the regularity could not be applied to the DCM group. RS, CS, LS were significantly decreased in DCM group as compared with NC group (<it>P </it>< 0.001 for all). The interobserver, intraobserver and test-retest reliability were acceptable.</p> <p>Conclusions</p> <p>3D-STE is a reliable tool for evaluation of left ventricular myocardial strain in patients with non-ischemic DCM, with huge advantage in clinical application.</p

Reversal of stress fibre formation by Nitric Oxide mediated RhoA inhibition leads to reduction in the height of preformed thrombi

Evidence has emerged to suggest that thrombi are dynamic structures with distinct areas of differing platelet activation and inhibition. We hypothesised that Nitric oxide (NO), a platelet inhibitor, can modulate the actin cytoskeleton reversing platelet spreading, and therefore reduce the capability of thrombi to withstand a high shear environment. Our data demonstrates that GSNO, DEANONOate, and a PKG-activating cGMP analogue reversed stress fibre formation and increased actin nodule formation in adherent platelets. This effect is sGC dependent and independent of ADP and thromboxanes. Stress fibre formation is a RhoA dependent process and NO induced RhoA inhibition, however, it did not phosphorylate RhoA at ser188 in spread platelets. Interestingly NO and PGI2 synergise to reverse stress fibre formation at physiologically relevant concentrations. Analysis of high shear conditions indicated that platelets activated on fibrinogen, induced stress fibre formation, which was reversed by GSNO treatment. Furthermore, preformed thrombi on collagen post perfused with GSNO had a 30% reduction in thrombus height in comparison to the control. This study demonstrates that NO can reverse key platelet functions after their initial activation and identifies a novel mechanism for controlling excessive thrombosis

Acute-Phase-HDL Remodeling by Heparan Sulfate Generates a Novel Lipoprotein with Exceptional Cholesterol Efflux Activity from Macrophages

During episodes of acute-inflammation high-density lipoproteins (HDL), the carrier of so-called good cholesterol, experiences a major change in apolipoprotein composition and becomes acute-phase HDL (AP-HDL). This altered, but physiologically important, HDL has an increased binding affinity for macrophages that is dependent on cell surface heparan sulfate (HS). While exploring the properties of AP-HDL∶HS interactions we discovered that HS caused significant remodeling of AP-HDL. The physical nature of this change in structure and its potential importance for cholesterol efflux from cholesterol-loaded macrophages was therefore investigated. In the presence of heparin, or HS, AP-HDL solutions at pH 5.2 became turbid within minutes. Analysis by centrifugation and gel electrophoresis indicated that AP-HDL was remodeled generating novel lipid poor particles composed only of apolipoprotein AI, which we designate β2. This remodeling is dependent on pH, glycosaminoglycan type, is promoted by Ca2+ and is independent of protease or lipase activity. Compared to HDL and AP-HDL, remodeled AP-HDL (S-HDL-SAA), containing β2 particles, demonstrated a 3-fold greater cholesterol efflux activity from cholesterol-loaded macrophage. Because the identified conditions causing this change in AP-HDL structure and function can exist physiologically at the surface of the macrophage, or in its endosomes, we postulate that AP-HDL contains latent functionalities that become apparent and active when it associates with macrophage cell surface/endosomal HS. In this way initial steps in the reverse cholesterol transport pathway are focused at sites of injury to mobilize cholesterol from macrophages that are actively participating in the phagocytosis of damaged membranes rich in cholesterol. The mechanism may also be of relevance to aspects of atherogenesis

Pre-agricultural plant management in the uplands of the central Zagros: the archaeobotanical evidence from Sheikh-e Abad

Prior to the emergence of agriculture in southwest Asia, sedentarising human communities were experimenting with a diverse range of wild plant species over a prolonged period. In some cases, this involved the cultivation of species that would go on to be domesticated and form the foundation of future agricultural economies. However, many forms of plant use did not follow this trajectory, and in multiple places farming was only taken up later as an established ‘package’. In this paper, we present new archaeobotanical evidence from the Early Neolithic site of Sheikh-e Abad in the central Zagros of western Iran. Sheikh-e Abad is unique in being the only settlement known to date within southwest Asia that lies at an altitude above 1000m and which has occupation spanning the agricultural transition. Thus, it provides a rare opportunity to examine pre-agricultural plant management strategies in an upland zone. Our analyses of the plant remains from Sheikh-e Abad suggest that from its earliest occupation inhabitants were unconsciously ‘auditioning’ a suite of locally available wild grasses which ultimately were never domesticated. We discuss the possible reasons for this from a socio-ecological perspective, considering both the biology and ecology of the plant species in question, as well as the ways in which they were potentially managed