Filaggrin repeat number polymorphism is associated with a dry skin phenotype

Profilaggrin is a key epidermal protein, critical for the generation and maintenance of the stratum corneum barrier. It is encoded by a gene located in the epidermal differentiation complex of Chromosome 1q21 and is composed of multiple filaggrin repeats connected by highly conserved linker peptides. Within the human population the number of filaggrin repeats encoded by this gene varies between 10, 11 or 12 repeats. Using a PCR-based approach we have determined individual profilaggrin allelotypes in a group of 113 subjects and identified preliminary evidence of an inverse association between the 12 repeat allele and self-perceived frequent dry skin (P=0.0293). This is the first demonstration of a potential association between a genetic marker and cosmetic skin condition and suggests that cosmetic skin dryness may in part be genetically determined and associated with specific profilaggrin allelotypes.     

The causes of musculoskeletal chest pain in patients admitted to hospital with suspected myocardial infarction

BACKGROUND: We wished to investigate the causes and characteristics of musculoskeletal chest pain leading to acute medical admission. METHODS: We studied patients admitted to Queen Elizabeth Hospital, Gateshead, over a 10-week period. Patients with chest pain for which no acute cardiorespiratory cause was evident were identified and only included if they were tender on anteroposterior chest compression, thoracic spine rotation or firm sternal pressure. A detailed clinical history, anxiety and depression scale and a focussed physical examination were done to define the nature of musculoskeletal disease and their therapeutic requirements. RESULTS: Fifty patients satisfying the inclusion criteria were admitted in the 10-week period and comprised 54% females with a mean age of 57 years (S.D.=13.48). Chest pain lasted for 1 h or less in 24 patients and was mostly anterior. Three distinct groups of patients were identified. Twelve patients had evidence of inflammatory joint disease, thirteen had fibromyalgia and half had regional syndromes with pain arising from the shoulder, neck, thoracic spine or sternocostal areas. Visual analogue scores were highest in fibromyalgia for pain, and highest in inflammatory arthritis for impaired mobility. Anxiety and depression scores were highest in fibromyalgia and lowest among patients with regional syndromes. CONCLUSIONS: Musculoskeletal causes for acute chest pain are common and varied. Most patients have an identifiable cause of pain, but accurate diagnosis is needed to select the most appropriate intervention. Anxiety and depression are frequent, with much self-reported pain and dysfunction. However, all patients in this study had a disorder that was amenable to treatment and diagnosis. Management needs to be actively pursued in all patients.     

t-Tubules and sarcoplasmic reticulum function in cardiac ventricular myocytes

Although the existence of t-tubules in mammalian cardiac ventricular myocytes has been recognized for a long time, it now appears that their structure and function are more complex than previously believed. Recent work has provided evidence that many of the key proteins underlying excitation-contraction coupling are located predominantly at the t-tubules. L-type Ca(2+) current (I(Ca)) flowing across the t-tubule membrane provides a rapidly inactivating Ca(2+) influx that triggers Ca(2+) release from the sarcoplasmic reticulum (SR), thereby allowing rapid and synchronous Ca(2+) release throughout the cell; I(Ca) at the t-tubules also appears to be more sensitive than that at the surface membrane to regulation by beta-adrenergic stimulation and intracellular Ca(2+). In contrast, although its density is lower, I(Ca) flowing across the surface membrane inactivates slowly, and thus may help load the SR with Ca(2+). There is also increasing evidence that many of the mechanisms that remove Ca(2+) from the cytoplasm are located predominantly at the t-tubules, which therefore play an important role in determining cellular, and hence SR, Ca(2+) content. Thus, the t-tubules appear to play a central role in the increase and subsequent decrease of Ca(2+) during the systolic Ca(2+) transient. Remodelling of the t-tubules has been reported in cardiac pathologies, and may play a role in the altered cellular, and hence cardiac, function observed in such conditions.     

A stretch-activated anion channel is up-regulated by the malaria parasite plasmodium falciparum

A recent study on malaria-infected human red blood cells (RBCs) has shown induced ion channel activity in the host cell membrane, but the questions of whether they are host- or parasite-derived and their molecular nature have not been resolved. Here we report a comparison of a malaria-induced anion channel with an endogenous anion channel in Plasmodium falciparum -infected human RBCs. Ion channel activity was measured using the whole-cell, cell-attached and excised inside-out configurations of the patch-clamp method. Parasitised RBCs were cultured in vitro , using co-cultured uninfected RBCs as controls. Unstimulated uninfected RBCs possessed negligible numbers of active anion channels. However, anion channels could be activated in the presence of protein kinase A (PKA) and ATP in the pipette solution or by membrane deformation. These channels displayed linear conductance (∼15 pS), were blocked by known anion channel inhibitors and showed the permeability sequence I⁻ > Br⁻ > Cl⁻. In addition, in less than 5 % of excised patches, an outwardly rectifying anion channel (∼80 pS, outward conductance) was spontaneously active. The host membrane of malaria-infected RBCs possessed spontaneously active anion channel activity, with identical conductances, pharmacology and selectivity to the linear conductance channel measured in stimulated uninfected RBCs. Furthermore, the channels measured in malaria-infected RBCs were shown to have a low open-state probability ( P _o) at positive potentials, which explains the inward rectification of membrane conductance observed when using the whole-cell configuration. The data are consistent with the presence of two endogenous anion channels in human RBCs, of which one (the linear conductance channel) is up-regulated by the malaria parasite P. falciparum .     

A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome

Many patients with the antiphospholipid antibody syndrome and recurrent thrombosis receive doses of warfarin adjusted to achieve an international normalized ratio (INR) of more than 3.0. However, there are no prospective data to support this approach to thromboprophylaxis.     

Massively parallel signature sequencing profiling of fetal human neural precursor cells

We have examined gene expression in multipotent neural precursor cells (NPCs) derived from human fetal (f) brain tissue and compared its expression profiles with embryonic stem (ESC) cells, embryoid body cell (EBC), and astrocyte precursors using the technique of massively parallel signature sequencing (MPSS). Gene expression profiles show that fNPCs express core neural stem cells markers and share expression profiles with astrocyte precursor cells (APCs) rather than ESC or EBC. Gene expression analysis shows that fNPCs differ from other adult stem and progenitor cells in their marker expression and activation of specific functional networks such as the transforming growth factorbeta (TGFbeta) and Notch signaling pathways. In addition, our results allow us to identify novel genes expressed in fNPCs and provide a detailed profile of fNPCs.