A case of unprovoked venous thromboembolism in a marathon athlete presenting atypical sequelae: What are the chances?

Marathon runners are exposed to multiple thrombogenic risk factors including dehydration and hemoconcentration, injury and inflammation, long-distance travel between events, and contraceptive usage. However, despite awareness about thromboembolism and several case reports detailing life-threatening hypercoagulopathies in athletes, the prevalence of venous thromboembolism in marathon runners remains uncharted. There is a lack of data and evidence-based guidelines for these athletes and for healthcare providers, including general medical practitioners and sports physicians. We present an episode of unprovoked deep vein thrombosis (DVT) and pulmonary embolism (PE) in a female marathon athlete who presented with atypical sequelae over the course of 8 months, and identify some "easy-to-miss" warning signs and symptoms. Through dialogue with the patient regarding their personal questions and anxieties surrounding idiopathic DVT-PE, we identify a clear need for more accessible information and comprehensive research concerning the detection, prevalence, and long-term management of venous thromboembolism in athletes. We discuss the possibility that being an athlete might constitute a more significant risk factor for venous thromboembolism than is currently estimated by commonly used diagnostic protocols and conclude that there is quite possibly a need for more specific clinical guidelines for athletes in this area.

The clinical candidate VT-1161 is a highly potent inhibitor of Candida albicans CYP51 but fails to bind the human enzyme.

The binding and cytochrome P45051 (CYP51) inhibition properties of a novel antifungal compound, VT-1161, against purified recombinant Candida albicans CYP51 (ERG11) and Homo sapiens CYP51 were compared with those of clotrimazole, fluconazole, itraconazole, and voriconazole. VT-1161 produced a type II binding spectrum with Candida albicans CYP51, characteristic of heme iron coordination. The binding affinity of VT-1161 for Candida albicans CYP51 was high (dissociation constant [Kd], ≤ 39 nM) and similar to that of the pharmaceutical azole antifungals (Kd, ≤ 50 nM). In stark contrast, VT-1161 at concentrations up to 86 µM did not perturb the spectrum of recombinant human CYP51, whereas all the pharmaceutical azoles bound to human CYP51. In reconstitution assays, VT-1161 inhibited Candida albicans CYP51 activity in a tight-binding fashion with a potency similar to that of the pharmaceutical azoles but failed to inhibit the human enzyme at the highest concentration tested (50 µM). In addition, VT-1161 (MIC = 0.002 µg ml(-1)) had a more pronounced fungal sterol disruption profile (increased levels of methylated sterols and decreased levels of ergosterol) than the known CYP51 inhibitor voriconazole (MIC = 0.004 µg ml(-1)). Furthermore, VT-1161 weakly inhibited human CYP2C9, CYP2C19, and CYP3A4, suggesting a low drug-drug interaction potential. In summary, VT-1161 potently inhibited Candida albicans CYP51 and culture growth but did not inhibit human CYP51, demonstrating a >2,000-fold selectivity. This degree of potency and selectivity strongly supports the potential utility of VT-1161 in the treatment of Candida infections.

Pimecrolimus 1% cream for oral erosive lichen planus: a 6-week randomized, double-blind, vehicle-controlled study with a 6-week open-label extension to assess efficacy and safety.

OBJECTIVE: To assess the efficacy and safety of topical pimecrolimus 1% cream in the treatment of oral erosive lichen planus. DESIGN: A 6-week randomized, double-blind, vehicle-controlled phase followed by a 6-week open-label phase. SETTING: Outpatients of the Department of Dermatology, University of Utah. PATIENTS: Twenty-one patients with oral erosive lichen planus were randomized and treated with either pimecrolimus 1% cream or vehicle cream. INTERVENTION: Pimecrolimus 1% cream, or its vehicle, were applied twice daily for 6 weeks to each side of the mouth with a 2×2 inch gauze pad folded in half and placed directly on the erosive lesion. MAIN OUTCOME MEASURES: Efficacy was based on clinical evaluation of Investigator's Global Assessment (IGA) of the overall severity of the disease, erythema, measurement of the size of any target erosion in millimetres, and assessment of spontaneous pain. Blood levels of pimecrolimus were monitored in all subjects on day 0 and repeated on day 7. RESULTS: Pimecrolimus 1% cream was superior to vehicle cream in reducing mean IGA, pain, and erosion size. For the vehicle group that entered the open-label phase, pimecrolimus 1% cream improved the mean IGA, pain, erosion size, and erythema. Pimecrolimus levels were detected in nine out of 10 of the pimecrolimus-treated subjects. These levels were consistently low. The pimecrolimus cream was well-tolerated. No clinically relevant, drug-related adverse events were reported. CONCLUSION: Pimecrolimus 1% cream was superior to vehicle in reducing pain, erythema, decreasing erosion size, and improving overall severity of disease when compared with vehicle treatment.

Elevation of IgA anti-epidermal transglutaminase antibodies in dermatitis herpetiformis.

BACKGROUND: Dermatitis herpetiformis (DH) is a papulovesicular eruption caused by ingestion of gluten. It is characterized by the deposition of IgA in the dermal papillae. IgA antibodies directed at tissue transglutaminase (TG2) are elevated in gluten-sensitive diseases including DH and coeliac disease (CD). More recently, antibodies directed at epidermal transglutaminase (TG3) were identified in patients with DH, and this may be the dominant autoantigen in this disease. OBJECTIVES: To measure IgA antibodies to TG3 and TG2 in patients with DH and CD, and control populations. METHODS: Serum IgA antibodies against TG2 and TG3 were measured from adults with DH, adults and children with CD, patients with psoriasis, adult Red Cross blood donors, and paediatric controls. RESULTS: Patients with DH and CD had elevated levels of IgA anti-TG2 antibodies compared with control populations. The levels in the patients with DH and adults with CD were similar. IgA anti-TG2 antibodies were higher in the children with CD compared with adults with DH and CD, and with control populations. Patients with DH and adults with CD had elevated levels of IgA anti-TG3 antibodies compared with children with CD and control populations. There was a trend towards higher levels in the patients with DH compared with adults with CD. CONCLUSIONS: IgA antibodies to TG3 are elevated in patients with DH and adults with CD. The progressive expansion of the epitope-binding profile of IgA antitransglutaminase antibodies in patients with CD may explain the development of DH in patients with undiagnosed CD during their adult life.

Evidence for mating of the "asexual" yeast Candida albicans in a mammalian host.

Since its classification nearly 80 years ago, the human pathogen Candida albicans has been designated as an asexual yeast. In this report, we describe the construction of C. albicans strains that were subtly altered at the mating-type-like (MTL) locus, a cluster of genes that resembles the mating-type loci of other fungi. These derivatives were capable of mating after inoculation into a mammalian host. C. albicans is a diploid organism, but most of the mating products isolated from a mouse host were tetrasomic for the two chromosomes that could be rigorously monitored and, overall, exhibited substantially higher than 2n DNA content. These observations demonstrated that C. albicans can recombine sexually.

A familial case of P-ANCA glomerulonephritis presenting in a father and daughter.

Antineutrophil cytoplasmic antibodies (ANCA) have proved to be useful serological markers for a subset of vasculitic diseases, including Wegener's granulomatosis, microscopic polyangiitis, and the Churg-Strauss syndrome. The pathogenesis of the ANCA vasculitides remains less clear, including what role, if any, genetic factors play in the expression of ANCA-associated diseases. Familial cases of systemic vasculitis have been reported, and a number of studies have addressed HLA associations of Wegener's and microscopic polyangiitis, but the results have been confusing and inconsistent. We report the first case of P-ANCA-positive vasculitis presenting in a Native American father and daughter. Both patients had systemic vasculitis and were P-ANCA positive with anti-myeloperoxidase (MPO) antibodies.

Identification of a mating type-like locus in the asexual pathogenic yeast Candida albicans.

Candida albicans, the most prevalent fungal pathogen in humans, is thought to lack a sexual cycle. A set of C. albicans genes has been identified that corresponds to the master sexual cycle regulators a1, alpha1, and alpha2 of the Saccharomyces cerevisiae mating-type (MAT) locus. The C. albicans genes are arranged in a way that suggests that these genes are part of a mating type-like locus that is similar to the mating-type loci of other fungi. In addition to the transcriptional regulators a1, alpha1, and alpha2, the C. albicans mating type-like locus contains several genes not seen in other fungal MAT loci, including those encoding proteins similar to poly(A) polymerases, oxysterol binding proteins, and phosphatidylinositol kinases.

Vasoactive agonists do not change the caliber of retinal capillaries of the rat.

The pericytes of the retinal capillaries are considered to be contractile cells, based on indirect evidence. We attempted to detect pericyte contractility directly using a morphometric method following intravitreal injection of vasoconstricting (endothelin-1, norepinephrine) and vasodilating (forskolin, prostaglandin E1) agonists in rats. The technique involved measuring changes in the ratio of the (lumenal perimeter x mean lumenal radius) to the lumenal area (rP/A ratio, which we defined as "caliber"). Following intravitreal injection of endothelin-1 or norepinephrine there is an ophthalmoscopically visible constriction of the larger retinal arterioles. This constriction is also clearly demonstrable morphometrically (P = 0.001 for endothelin-1 and P = 0.047 for norepinephrine). However, neither for the vasoconstricting nor for the vasodilating agonists is there evidence of a significant change of the caliber of the capillaries. At least in the retina of the rat, therefore, we have no evidence that the pericytes perform a contractile function that alters flow in the capillaries.