Two sporadic infected cardiac myxomas in 1 patient

Infected cardiac myxoma is a rare cause of endocarditis. The finding of coexisting infected cardiac myxomas is highly unusual. Herein, we present the case of a 58-year-old woman with a low-grade fever. Laboratory findings strongly indicated inflammation, and blood cultures detected Staphylococcus species. Echocardiograms revealed mobile masses in the area of the mitral valve. Transesophageal echocardiograms showed 2 formations that arose from opposite sides of the mitral annulus and protruded into the left ventricle during systole. During emergency surgery, 2 abnormal growths with numerous vegetations were completely excised. The diagnosis of myxoma was confirmed upon histologic evaluation. Microbiological and polymerase chain reaction analysis of the myxomas detected the bacterial strain Enterococcus faecalis. Five months postoperatively, the patient showed no signs of recurrent infection and had a normal echocardiographic appearance.This report is the first of an infected cardiac myxoma in the Czech population and one of approximately 60 reports in the medical literature from 1956 to the present. In addition to the case of our patient, we discuss the discrepancy between the bacteriologic findings.     

Changes of patient-reported outcomes and protein fingerprint biomarkers after exercise therapy for axial spondyloarthritis

Clinical Rheumatology - The objective of this study was to investigate the patient-reported outcomes (PROs) and matrix metalloproteinase (MMP) derived extracellular matrix (ECM) biomarkers in...     

Prognostic significance of anti-apoptosis proteins survivin and bcl-2 in non-small cell lung carcinomas: a clinicopathologic study of 102 cases.

Inhibitors of apoptosis, including bcl-2 and survivin (a novel gene encoding a unique apoptosis inhibitor), regulate cell proliferation by promoting cell survival. Although survivin has been detected in several human cancers, its prognostic significance and relationship to bcl-2 are not well characterized in lung cancer. Tissue sections from 102 non-small cell lung carcinomas (NSCLC) were immunostained using antibodies against survivin and bcl-2. Staining results were correlated with prognostic variables. Immunoreactivity for survivin and bcl-2 was observed in 53% and 21% of NSCLCs, respectively. Fifty-two percent of the 50 squamous cell carcinomas and 54% of the 52 adenocarcinomas expressed survivin. Survivin positivity correlated with tumor stage in squamous cell carcinoma. On univariate analysis, survivin expression correlated with decreased patient survival in NSCLC and in the subset of squamous cell carcinomas, but not in adenocarcinomas. On multivariate analysis, survivin was an independent predictor, along with distant metastasis and large tumor size. Eighteen percent of squamous cell carcinomas and 24% of adenocarcinomas expressed bcl-2. On univariate analysis, bcl-2 expression correlated with increased patient survival in NSCLC and in the subset of squamous cell carcinomas. An inverse correlation between the expression of survivin and bcl-2 was noted. Survivin immunoreactivity is an independent predictor of shortened survival in NSCLC, while bcl-2 protein expression correlated with prolonged patient survival. These findings indicate an inverse relationship between survivin and bcl-2 expression and suggest that these two inhibitors of apoptosis function through different pathways in the regulation of tumorigenesis in NSCLC.     

Mycophenolate mofetil in low doses stabilizes and improves antineutrophil cytoplasmic antibody-associated vasculitis and lupus nephritis

BACKGROUND: Clinical experience with mycophenolate mofetil (MMF) in glomerulonephritis still remains limited. METHODS: In order to assess the experience of one center with the efficacy and tolerability of MMF in patients with glomerulonephritis, we performed a retrospective 6-year analysis of 68 patients treated by MMF for glomerular disease, mainly anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV: n=34) and systemic lupus erythematosus and lupus nephritis (SLE: n=24). Indications were maintenance treatment in 40% of patients, induction treatment in patients not tolerating cyclophosphamide in 27%, and disease relapse in 33%. Mean treatment duration was 11.5 months. RESULTS: Efficacy endpoints were serum creatinine, urinary protein excretion, and steroid dose. In AAV patients, MMF was associated with significant improvement in 18%, partial improvement in 26%, stabilization in 29%, and disease progression in 12%; adverse event dropouts totalled 15%. In SLE, the respective figures were 30, 22, 9, and 22%, with 17% adverse event dropouts. The most frequent side effects were gastrointestinal events (n=7) and infections (n=3). None was life-threatening and there were no deaths. CONCLUSIONS: MMF, in the relatively low doses used, was safe and effective, stabilizing or improving AAV in 73% of patients and SLE in 61%. Further prospective randomized controlled trials with MMF in renal vasculitis and lupus nephritis are clearly warranted.     

The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer

Phosphatidylinositol-3-kinase (PI3K) is an important target in cancer due to the deregulation of the PI3K/ Akt signaling pathway in a wide variety of tumors. A series of thieno[3,2-d]pyrimidine derivatives were prepared and evaluated as inhibitors of PI3 kinase p110alpha. The synthesis, biological activity, and further profiling of these compounds are described. This work resulted in the discovery of 17, GDC-0941, which is a potent, selective, orally bioavailable inhibitor of PI3K and is currently being evaluated in human clinical trials for the treatment of cancer.     

Cryptochrome 2 mediates directional magnetoreception in cockroaches

The ability to perceive geomagnetic fields (GMFs) represents a fascinating biological phenomenon. Studies on transgenic flies have provided evidence that photosensitive Cryptochromes (Cry) are involved in the response to magnetic fields (MFs). However, none of the studies tackled the problem of whether the Cry-dependent magnetosensitivity is coupled to the sole MF presence or to the direction of MF vector. In this study, we used gene silencing and a directional MF to show that mammalian-like Cry2 is necessary for a genuine directional response to periodic rotations of the GMF vector in two insect species. Longer wavelengths of light required higher photon fluxes for a detectable behavioral response, and a sharp detection border was present in the cyan/green spectral region. Both observations are consistent with involvement of the FADox, FAD^•− and FADH^– redox forms of flavin. The response was lost upon covering the eyes, demonstrating that the signal is perceived in the eye region. Immunohistochemical staining detected Cry2 in the hemispherical layer of laminal glia cells underneath the retina. Together, these findings identified the eye-localized Cry2 as an indispensable component and a likely photoreceptor of the directional GMF response. Our study is thus a clear step forward in deciphering the in vivo effects of GMF and supports the interaction of underlying mechanism with the visual system.Behavioral evidence for sensitivity to geomagnetic fields (GMFs) has been found in numerous vertebrate and invertebrate taxa (1); however, the underlying mechanisms remain a biological and biophysical enigma. In the late 1970s, the effect of light on the orientation of birds inspired Schulten and colleagues (2) to suggest that reactions of radical pairs (RPs) formed by photosensitive biological processes may be susceptive to external magnetic fields (MFs), and thus provide the basis for in vivo chemical magnetoreception. Since then, ample studies have supported this hypothesis (reviewed, e.g., in refs. 3 and 4).In the past decade, proteins from the Cryptochrome/Photolyase family (CPF) have been widely discussed as being relevant to the light-dependent biological compass relying on the RP mechanism (5–7). Plant Crys mediate sensitivity to blue ∕ UVA light (8), and this sensitivity was reported to be influenced by a MF (9), although later verification failed (10). Crys are essential for circadian clock function in mammals, but are likely not directly involved in light reception (11). In the fruit fly, Drosophila melanogaster, Cry mediates the light entrainment of the circadian clock (12). Both fly circadian rhythmicity and geotaxis turned out to be Cry-dependent and were also affected by a MF (13–15). Curiously, some insect species have only a Drosophila-type of Cry (Cry1 or animal type I Cry), whereas others have a mammalian-type of Cry (Cry2 or animal type II Cry) or both (16).The validity of the RP mechanism was proven in the carotenoid–porphyrin–fullerene triad (17). In CPF proteins, the change in redox state of their flavin adenine dinucleotide (FAD) cofactor can result in magnetosensitive RPs (18). Although the RPs studied in two CPF proteins were magnetosensitive (19, 20), RP-based GMF effects and anisotropic MF effects have not been shown in CPF proteins. In contrast, ultrafast GMF effects on transient FAD fluorescence in an apparently purified Cry from birds was reported in a recent study (21), suggesting the existence of a GMF-sensitive reaction that differs from spin-selective RP recombination.The biological output of the RP–GMF interaction might hypothetically be generated when a particular redox status of a FAD cofactor is reached, changing the configuration of the Cry protein (22) or its C terminus, which switches the Cry to a signaling state (23). Concerning possible downstream effects, Cry activation was shown to control permeability of potassium channels in Drosophila (24).In terms of Cry-mediated in vivo chemical magnetoreception in general, an organism’s sensitivity to the presence of GMF should be considered separate from its sensitivity to the GMF’s orientation (25). Although the sole detection of the presence or intensity of a GMF can be accomplished in vitro via a disordered RP system (17), a number of additional critical requirements should be met to function as a sensor of magnetic direction, from the anisotropy of electron–nucleus interactions to the anatomy of a sensory organ (see Discussion).The most convincing evidence of Cry-dependent magnetosensitivity was provided on Drosophila (26, 27). The ability to recognize the presence of a MF relies on functional Cry1, and this magnetoreception in Cry-deficient fruit fly mutants could be rescued using mammalian-like Cry2 (28). The flies were trained to recognize the local magnetic anomaly up to 10 times stronger than the natural GMF in T-shape maze experiments. Although the choice of one of two arms involved orientation, the actual physiological effect was consistent with nondirectional magnetic sensitivity (29), as was discussed for plants (9, 10), fruit fly geotaxis (14), and the fruit fly circadian clock (13, 15). Therefore, rather than demonstrating a genuine directional sensor serving as a GMF compass, these studies proved that Cry mediated detection of a rather intense, artificial magnetic anomaly.Here, we have taken advantage of an assay enabling us to test directional magnetic sensitivity in insects at naturally occurring GMF intensities (30) and functionally confirmed that mammalian-like Cry2 is necessary for sensing the directional component of MFs of natural intensities by two different species of cockroaches.     

Unique presentation of LHON/MELAS overlap syndrome caused by m.13046T>C in MTND5

Background: Leber hereditary optic neuropathy (LHON) and mitochondrial encephalopathy, myopathy, lactic acidosis and stroke-like episodes (MELAS) syndromes are mitochondrially inherited disorders characterized by acute visual failure and variable multiorgan system presentation, respectively.

Materials and methods: A 12-year-old girl with otherwise unremarkable medical history presented with abrupt, painless loss of vision. Over the next few months, she developed moderate sensorineural hearing loss, vertigo, migraines, anhedonia and thyroiditis. Ocular examination confirmed bilateral optic nerve atrophy. Metabolic workup documented elevated cerebrospinal fluid lactate. Initial genetic analyses excluded the three most common LHON mutations. Subsequently, Sanger sequencing of the entire mitochondrial DNA (mtDNA) genome was performed.

Results: Whole mtDNA sequencing revealed a pathogenic heteroplasmic mutation m.13046T>C in MTND5 encoding the ND5 subunit of complex I. This particular variant has previously been described in a single case report of MELAS/Leigh syndrome (subacute necrotizing encephalopathy). Based on the constellation of clinical symptoms in our patient, we diagnose the condition as LHON/MELAS overlap syndrome.

Conclusions: We describe a unique presentation of LHON/MELAS overlap syndrome resulting from a m.13046T>C mutation in a 12-year-old girl. In patients with sudden vision loss in which three of the most prevalent LHON mitochondrial mutations have been ruled out, molecular genetic examination should be extended to other mtDNA-encoded subunits of MTND5 complex I. Furthermore, atypical clinical presentations must be considered, even in well-described phenotypes.