Exome sequencing reveals a novel COL2A1 mutation implicated in multiple epiphyseal dysplasia

Mutations in the COMP, COL9A1, COL9A2, COL9A3, MATN3, and SLC26A2 genes cause approximately 70% of multiple epiphyseal dysplasia (MED) cases. The genetic changes involved in the etiology of the remaining cases are still unknown, suggesting that other genes contribute to MED development. Our goal was to identify a mutation causing an autosomal dominant form of MED in a large multigenerational family. Initially, we excluded all genes known to be associated with autosomal dominant MED by using microsatellite and SNP markers. Follow‐up with whole‐exome sequencing analysis revealed a mutation c.2032G>A (p.Gly678Arg) in the COL2A1 gene (NCBI Reference Sequence: NM_001844.4), which co‐segregated with the disease phenotype in this family, manifested by severe hip dysplasia and osteoarthritis. One of the affected family members had a double‐layered patella, which is frequently seen in patients with autosomal recessive MED caused by DTDST mutations and sporadically in the dominant form of MED caused by COL9A2 defect.     

Mixed epithelial and stromal tumors of the kidney. A report of 22 cases

Mixed epithelial and stromal tumor of the kidney (MESTK) is a recently described subset of renal neoplasm that tends to occur in middle-aged and older women and is characterized by a distinctive histological appearance. To further characterize this lesion, we report the clinicopathological and immunohistochemical features of 22 additional cases from our institutional files. Grossly, the tumors ranged in size from 1 cm to 14 cm (mean 6.7 cm), were well circumscribed but unencapsulated, and showed a cystic cut surface. The tumors were composed of a spindle cell proliferation that resembled ovarian stroma, as well as an epithelial component lining the cystic structures, which usually consisted of flat to hobnailed cells typical of collecting-duct epithelium. Areas displaying features of Müllerian differentiation were also documented in 6 cases, including epithelium of endometrioid, tubal, clear cell and squamous cell type as well as one case showing an architecture that closely resembled Müllerian adenofibroma and adenosarcoma. Follow-up in 14 patients (average 4.4 years) showed no evidence of recurrence or metastasis. We believe these tumors represent the renal counterpart of similar mixed epithelial and stromal neoplasms occurring in the biliary tract and pancreas, which is also characterized by cystic structures lined by epithelium, admixed with ovarian-type stroma. The differential diagnosis for these tumors includes cystic nephroma and cystic partially differentiated nephroblastoma, which we believe to represent clinically and morphologically distinct entities from MESTK. In particular, the distinction from cystic nephroma in adult male patients is emphasized, and two cases of this entity are included in the study for comparison.     

Risk factors for Epstein–Barr virus reactivation after renal transplantation: Results of a large,multi-centre study

Epstein–Barr virus (EBV) reactivation is a very common and potentially lethal complication of renal transplantation. However, its risk factors and effects on transplant outcome are not well known. Here, we have analysed a large, multi-centre cohort (N = 512) in which 18.4% of the patients experienced EBV reactivation during the first post-transplant year. The patients were characterized pre-transplant and two weeks post-transplant by a multi-level biomarker panel. EBV reactivation was episodic for most patients, only 12 patients showed prolonged viraemia for over four months. Pre-transplant EBV shedding and male sex were associated with significantly increased incidence of post-transplant EBV reactivation. Importantly, we also identified a significant association of post-transplant EBV with acute rejection and with decreased haemoglobin levels. No further severe complications associated with EBV, either episodic or chronic, could be detected. Our data suggest that despite relatively frequent EBV reactivation, it had no association with serious complications during the first post-transplantation year. EBV shedding prior to transplantation could be employed as biomarkers for personalized immunosuppressive therapy. In summary, our results support the employed immunosuppressive regimes as relatively safe with regard to EBV. However, long-term studies are paramount to support these conclusions.     

Patients undergoing surgery for lumbar degenerative spinal disorders favor smartphone-based objective self-assessment over paper-based patient-reported outcome measures

Background ContextSmartphone-based applications enable new prospects to monitor symptoms and assess functional outcome in patients with lumbar degenerative spinal disorders. However, little is known regarding patient acceptance and preference towards new modes of digital objective outcome assessment.PurposeTo assess patient preference of an objective smartphone-based outcome measure compared to conventional paper-based subjective methods of outcome assessment.Study designProspective observational cohort study.Patient sampleFourty-nine consecutive patients undergoing surgery for lumbar degenerative spinal disorder.Outcome measuresPatients completed a preference survey to assess different methods of outcome assessment. A 5-level Likert scale ranged from strong disagreement (2 points) over neutral (6 points) to strong agreement (10 points) was used.MethodsPatients self-determined their objective functional impairment using the 6-minute Walking Test application (6WT-app) and completed a set of paper-based patient-reported outcome measures (PROMs) before and 6 weeks after surgery. Patients were then asked to rate the methods of outcome assessment in terms of suitability, convenience, and responsiveness to their symptoms.ResultsThe majority of patients considered the 6WT-app a suitable instrument (median 8.0, interquartile range [IQR] 4.0). Patients found the 6WT more convenient (median 10.0, IQR 2.0) than the Zurich Claudication Questionnaire (ZCQ; median 8.0, IQR 4.0, p=.019) and Core Outcome Measure Index (COMI; median 8.0, IQR 4.0, p=.007). There was good agreement that the 6WT-app detects change in physical performance (8.0, IQR 4.0). 78 % of patients considered the 6WT superior in detecting differences in symptoms (vs. 22% for PROMs). Seventy-six percent of patients would select the 6WT over the other, 18% the ZCQ and 6% the COMI. Eighty-two percent of patients indicated their preference to use a smartphone app for the assessment and monitoring of their spine-related symptoms in the future.ConclusionsPatients included in this study favored the smartphone-based evaluation of objective functional impairment over paper-based PROMs. Involving patients more actively by means of digital technology may increase patient compliance and satisfaction as well as diagnostic accuracy.     

Concentrating stroke care provision in the Czech Republic: The establishment of Stroke Centres in 2011 has led to improved outcomes

This article describes policy processes that have led to the re-organisation of stroke care in the Czech Republic since 2011, which has been part of a broader process of care concentration in several medical fields. Currently, stroke care is provided by 13 Comprehensive and 32 Primary Stroke Centres. The paper explains factors that supported the reform implementation, reviews implications, and discusses future challenges.Mandatory reporting of quality indicators, the introduction of a benchmarking system, integration with pre-hospital emergency care, and the introduction of countrywide patient triage have supported more timely treatment for stroke patients and better quality of care. Data from the Stroke Care Quality Indicators of the Czech Stroke Society show positive trends in many areas: the number of patients treated with intravenous thrombolysis quadrupled in eight years, with 26.4 % of all acute stroke patients receiving thrombolysis in 2018. Czech Republic now ranks third in Europe in the number of thrombolysis per population and second in the number of mechanical thrombectomies per population. The Czech experience provides an example of positive outcomes of concentrated stroke care, while highlighting the importance of proper implementation processes. In particular, it is essential to involve stakeholders and to provide reputational incentives through continuous benchmarking.     

Phalloarteriography in the diagnosis of erectile impotence

An angiographic method has been developed for x-ray visualization of the arteries supplying the cavernous bodies of the penis, namely, the internal iliac, internal pudendal, and penile artery and its branches (dorsal, deep, and bulbocavernous arteries). Under normal conditions the technique makes pulsations in both dorsal penile arteries palpable, and the flow rate of fluid into the cavernous bodies necessary to produce and maintain erection can be determined. The principle of the method involves artificial passive erection or semierection, during which we perform selective or semiselective arteriography of the bed supplied by the internal iliac artery, or retrograde arteriography by puncture of the dorsal artery of the penis. Thirty males complaining of more than 1 year of impotence (including 12 diabetics) were investigated, 29 by our standard technique and 1 by translumbar pelvic arteriography with retrograde arteriography of the dorsal penile artery. All patients showed severe stenosis or obliteration of the vessels supplying the cavernous bodies. There was agreement between absence of pulsation in the dorsal penile arteries and the angiographic findings. Flow rates necessary to produce erection varied from 45 to 160 ml/min, with a mean of 90 ml/min. For controls, angiographic studies were performed in 4 men with clearly psychogenic impotence, all of whom were found to have normal-appearing arteries supplying the cavernous bodies. On the basis of these findings and previously reported histological investigations, we believe that most impotence is the symptomatic and functional result of arterial disease. The arteriographic technique described allows a precise anatomical diagnosis to be made, and can indicate surgical and microsurgical correction.

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Résumé Nous avons mis au point une technique d'angiographic qui visualise la vascularisatioh artérielle des corps caverneux, soit les artères iliaques internes, honteuses internes, péniennes et leurs branches dorsales, profondes et bulbocaverneuses. Dans les conditions normales, la technique permet de palper le pouls dans les artères dorsales de la verge et de mesurer, dans les corps caverneux, le débit nécessaire pour produire et maintenir une érection. Le principe de la méthode repose sur une érection ou semi-érection artificielle passive associée, soit à une artériographie sélective ou semi-sélective du territoire de l'iliaque interne, soit à une artériographie rétrograde par ponction de l'artère dorsale de la verge.Trente hommes (dont 12 diabétiques) ont été étudiés: ils présentaient tous une impuissance depuis plus d'un an. L'investigation a été faite, dans 29 cas avec notre technique standard, dans un cas par aortographie translombaire et arteriographie rétrograde de l'artère dorsale de la verge. Il existait dans tous les cas des sténoses serrées ou des oblitérations de l'arbre artériel allant aux corps caverneux. Les lésions mises en évidence par l'artériographie concordaient avec l'absence de pulsations dans les artères dorsales de la verge. Les débits nécessaires pour produire l'érection ont varié entre 45 et 160 ml/min, avec une moyenne de 90 ml/min. A titre de contrôle, des artériographies ont été faites chez 4 hommes atteints d'impuissance manifestement psychogène: chez tous, l'irrigation artérielle des corps caverneux était normale.Ces résultats, et des études histologiques antérieures, nous amènent à penser que, dans la plupart des cas, l'impuissance est la manifestation symptomatique et fonctionnelle d'une maladie artérielle. La technique d'angiographic que nous avons décrite donne un diagnostic anatomique précis et permet de poser les indications de la chirurgie ou de la microchirurgie correctrice.

     

Fibrous hamartoma of infancy. A study of eight cases with immunohistochemical and electron microscopical findings.

Eight cases of fibrous hamartomas of infancy are presented. Actin positivity and desmin negativity in collagen forming spindle-shaped cells and electron microscopical findings point to the myofibroblastic nature of this entity. "Dark cells" which spread regularly in all but one of our tumors were immunohistochemically determined to be a mixture of B and T cell lymphocytes. Their selective location and possible role are discussed.     

The renal cytochrome P-450 arachidonic acid system

In addition to cyclooxygenase and lipoxygenase, arachidonic acid (AA) is metabolized by the cytochrome P-450 monooxygenase system. The kidney is one of the major extrahepatic tissues that display cytochrome P-450 enzyme activities, in particular the cortex, specifically the proximal tubule demonstrate the highest concentration. AA is metabolized by the renal cytochrome P-450 epoxygenase and /-1 hydroxylases to epoxyeicosatrienoic acids and /-1 alcohols (20- and 19-mono-hydroxyeicosatetraenoic acids), respectively. These metabolites possess a broad spectrum of biological and renal effects which include: vasodilation, vasoconstriction, inhibition and stimulation of Na⁺–K⁺-ATPase, inhibition of ion transport mechanisms, natriuresis, inhibition of renin release and stimulation of cell growth. These metabolites are endogenous constituents of the kidney and are present in urine with increasing concentration under pathological conditions such as pregnancy-induced hypertension. The cytochrome P-450-dependent metabolism of AA is specifically localized to the proximal tubule and exhibits developmental changes, i.e., renal production of metabolites is very low in the fetus, newborn and up to 3 weeks of age, after which a remarkable increase in enzyme activities is observed. These characteristics call attention to the importance of this enzyme system in producing cellular mediators for regulating renal function in normal and diseased states.