Mitochondrial tRNA(Leu(UUR)) mutation m.3302A > G presenting as childhood-onset severe myopathy: threshold determination through segregation study.

Mitochondrial tRNA(Leu(UUR)) mutation m.3302A > G is associated with respiratory chain complex I deficiency and has been described as a rare cause of mostly adult-onset slowly progressive myopathy. Five families with 11 patients have been described so far; 5 of them died young due to cardiorespiratory failure. Here, we report on a segregation study in a family with an index patient who already presented at the age of 18 months with proximal muscular hypotonia, abnormal fatigability, and lactic acidosis. This early-onset myopathy was rapidly progressive. At 8 years, the patient is wheel-chair bound, requires nocturnal assisted ventilation, and suffers from recurrent respiratory infections. Severe complex I deficiency and nearly homoplasmy for m.3302A > G were found in muscle. We collected blood, hair, buccal swabs and muscle biopsies from asymptomatic adults in this pedigree and determined heteroplasmy levels in these tissues as well as OXPHOS activities in muscle. All participating asymptomatic adults had normal OXPHOS activities. In contrast to earlier reports, we found surprisingly little variation of heteroplasmy levels in different tissues of the same individual. Up to 45% mutation load in muscle and up to 38% mutation load in other tissues were found in non-affected adults. The phenotypic spectrum of tRNA(Leu(UUR)) m.3302A > G mutation seems to be wider than previously described. A threshold of more than 45% heteroplasmy in muscle seems to be necessary to alter complex I activity leading to clinical manifestation. The presented data may be helpful for prognostic considerations and counseling in affected families.

Intracranial arterial and arteriovenous malformations presenting with infarction. Lausanne Stroke Registry study.

Cerebral aneurysms and arteriovenous malformations (AVMs) are well-known sources of intracranial hemorrhage, but can also manifest as other clinical symptoms or remain clinically asymptomatic. The aim was to document and analyze cases of aneurysm or AVM with brain infarction. Survey on 4804 stroke patients treated at the Department of Neurology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland between 1978 and 2000 using the Lausanne Stroke Registry. Twenty patients presented with cerebral aneurysm and 21 with cerebral AVM. Hemorrhage was present in 100% of the AVM and in 75% of the aneurysm patients; in one (5%) of the remaining aneurysm patients, aneurysm and infarction were located in different territories. Infarction associated with Sylvian artery aneurysm was found in three (15%), vertebrobasilar ischemia because of fusiform left vertebral artery aneurysm in one (5%), and dural fistula draining to the distal transversal and left sigmoid sinus associated with a stroke in the territory of the left anterior inferior cerebellar artery in one patient. Ischemic stroke is infrequent, but important, complication in unruptured intracranial aneurysms and AVMs. The early recognition and therapy of these vascular malformations in selected patients can avoid a major neurological deficit or death caused by their rupture.

Anterior segment granuloma and optic nerve involvement as the presenting signs of systemic sarcoidosis.

PURPOSE: To report a case with anterior and posterior nodules associated with systemic sarcoidosis. METHODS: A patient with decreased vision underwent complete ophthalmologic examination, ultrasound biomicroscopy, fluorescein and indocyanine green (ICG) angiography. RESULTS: The patient presented a nodule of the iris of the OS and of the optic nerves of both eyes. Chest computed tomography and tissue biopsy established the diagnosis. CONCLUSIONS: Fluorescein and ICG angiography are the only objective exams to demonstrate the extent of ocular involvement in a patient with sarcoidosis.

Clinical characteristics and outcome of patients admitted to a medico- surgical ICU requiring non invasive ventilation (NIV) for hypercapnic respiratory failure

Introduction Because it decreases intubation rate and mortality, NIV has become first-line treatment in case of hypercapnic acute respiratory failure (HARF). Whether this approach is equally successful for all categories of HARF patients is however debated. We assessed if any clinical characteristics of HARF patients were associated with NIV intensity, success, and outcome, in order to identify prognostic factors. Methods Retrospective analysis of the clinical database (clinical information system and MDSi) of patients consecutively admitted to our medico-surgical ICU, presenting with HARF (defined as PaCO2 > 50 mmHg), and receiving NIV between May 2008 and December 2010. Demographic data, medical diagnoses (including documented chronic lung disease), reason for ICU hospitalization, recent surgical interventions, SAPS II and McCabe scores were extracted from the database. Total duration of NIV and the need for tracheal intubation during the 5 days following the first hypercapnia documentation, as well as ICU, hospital and one year mortality were recorded. Results are reported as median [IQR]. Comparisons were carried out with Chi2 or Kruskal-Wallis tests, p<0.05 (*). Results Two hundred and twenty patients were included. NIV successful patients received 16 [9-31] hours of NIV for up to 5 days. Fifty patients (22.7%) were intubated 11 [2-34] hours after HARF occurence, after having receiving 10 [5-21] hours of NIV. Intubation was correlated with increased ICU (18% vs. 6%, p<0.05) and hospital (42% vs. 31%, p>0.05) mortality. SAPS II score was related to increasing ICU (51 [29-74] vs. 23 [12-41]%, p<0.05), hospital (37% [20-59] vs 20% [12-37], p<0.05) and one year mortality (35% vs 20%, p<0.05). Surgical patients were less frequent among hospital fatalities (28.8% vs. 46.3%, p<0.05, RR 0.8 [0-6-0.9]). Nineteen patients (8.6%) died in the ICU, 73 (33.2%) during their hospital stay and 108 (49.1%) were dead one year after HARF. Conclusion The practice to start NIV in all suitable patients suffering from HARF is appropriate. NIV can safely and appropriately be used in patients suffering from HARF from an origin different from COPD exacerbation. Beside usual predictors of severity such as severity score (SAPS II) appear to be associated with increased mortality. Although ICU mortality was low in our patients, hospital and one year mortality were substantial. Surgical patients, although undergoing a similar ICU course, had a better hospital and one year outcome.

Further observations on clinical, histopathological, and immunological features of borderline disseminated cutaneous leishmaniasis caused by Leishmania (Leishmania) amazonensis

Leishmania (Leishmania) amazonensis has for some time been considered as the causative agent of two distinct forms of American cutaneous leishmaniasis (ACL): localized cutaneous leishmaniasis (LCL), and anergic diffuse cutaneous leishmaniasis (ADCL). Recently, a new intermediate form of disease, borderline disseminated cutaneous leishmaniasis (BDCL), was introduced into the clinical spectrum of ACL caused by this parasite, and in this paper we record the clinical, histopathological, and immunological features of eight more BDCL patients from Brazilian Amazonia, who acquired the disease in the Pará state, North Brazil. Seven of them had infections of one to two years' evolution and presented with primary skin lesions and the occurrence of metastases at periods varying from six to 12 months following appearance of the first lesion. Primary skin lesions ranged from 1-3 in number, and all had the aspect of an erythematous, infiltrated plaque, variously located on the head, arms or legs. There was lymphatic dissemination of infection, with lymph node enlargement in seven of the cases, and the delayed hypersensitivity skin-test (DTH) was negative in all eight patients prior to their treatment. After that, there was a conversion of DTH to positive in five cases re-examined. The major histopathological feature was a dermal mononuclear infiltration, with a predominance of heavily parasitized and vacuolated macrophages, together with lymphocytes and plasma cells. In one case, with similar histopathology, the patient had acquired his infection seven years previously and he presented with the largest number of disseminated cutaneous lesions. BDCL shows clinical and histopathological features which are different from those of both LCL and ADCL, and there is a good prognosis of cure which is generally not so in the case of frank ADCL.

Deep accidental hypothermia with core temperature below 24°c presenting with vital signs.

Abstract Pasquier, Mathieu, Noemi Zurron, Barbara Weith, Pierre Turini, Fabrice Dami, Pierre-Nicolas Carron, and Peter Paal. Deep accidental hypothermia with core temperature below 24°C presenting with vital signs. High Alt Med Biol. 15:58-63, 2014.-Background: According to the Swiss hypothermia clinical staging, patients with stage III are unconscious with preserved vital signs, with core temperature usually between 24° and 28°C. With stage IV, vital signs are absent with core temperature <24°C. Aims: To describe a patient presenting with HT stage III with vital signs but a core temperature of <24°C, and to search for similar patients in the medical literature. Materials and methods: MEDLINE was used to search for cases of deep accidental hypothermia (<24°C) and preserved vital signs. Results: We found 22 cases in addition to our case (n=23). Median age was 44 years (IQR 36; range 4-83) and median core temperature 22°C (IQR 1.7; 17-23.8). Vital signs were often minimal. Seven patients developed ventricular fibrillation (VF). Twenty patients survived with excellent neurological outcome. Conclusions: Vital signs can be present in hypothermic patients with core temperature <24°C. In deeply hypothermic patients, a careful check and prolonged check of vital functions should be made, as vital signs may be minimal. The clinical Swiss staging remains valuable in the prehospital evaluation of hypothermic patients; its correlation with core temperature should be better defined.

Patients presenting with somatic complaints in general practice: depression, anxiety and somatoform disorders are frequent and associated with psychosocial stressors.

BACKGROUND: Mental disorders in primary care patients are frequently associated with physical complaints that can mask the disorder. There is insufficient knowledge concerning the role of anxiety, depression, and somatoform disorders in patients presenting with physical symptoms. Our primary objective was to determine the prevalence of depression, anxiety, and somatoform disorders among primary care patients with a physical complaint. We also investigated the relationship between cumulated psychosocial stressors and mental disorders. METHODS: We conducted a multicentre cross-sectional study in twenty-one private practices and in one academic primary care centre in Western Switzerland. Randomly selected patients presenting with a spontaneous physical complaint were asked to complete the self-administered Patient Health Questionnaire (PHQ) between November 2004 and July 2005. The validated French version of the PHQ allowed the diagnosis of mental disorders (DSM-IV criteria) and the analyses of exposure to psychosocial stressors. RESULTS: There were 917 patients exhibiting at least one physical symptom included. The rate of depression, anxiety, and somatoform disorders was 20.0% (95% confidence interval [CI] = 17.4% to 22.7%), 15.5% (95% CI = 13.2% to 18.0%), and 15.1% (95% CI = 12.8% to 17.5%), respectively. Psychosocial stressors were significantly associated with mental disorders. Patients with an accumulation of psychosocial stressors were more likely to present anxiety, depression, or somatoform disorders, with an increase of 2.2 fold (95% CI = 2.0 to 2.5) for each additional stressor. CONCLUSIONS: The investigation of mental disorders and psychosocial stressors among patients with physical complaints is relevant in primary care. Psychosocial stressors should be explored as potential epidemiological causes of mental disorders.

Clinical presentation and time-course of postoperative venous thromboembolism: Results from the RIETE Registry

There is little literature about the clinical presentation and time-course of postoperative venous thromboembolism (VTE) in different surgical procedures. RIETE is an ongoing, prospective registry of consecutive patients with objectively confirmed, symptomatic acute VTE. In this analysis, we analysed the baseline characteristics, thromboprophylaxis and therapeutic patterns, time-course, and three-month outcome of all patients with postoperative VTE. As of January 2006, there were 1,602 patients with postoperative VTE in RIETE: 393 (25%) after major orthopaedic surgery (145 elective hip arthroplasty, 126 knee arthroplasty, 122 hip fracture); 207 (13%) after cancer surgery; 1,002 (63%) after other procedures. The percentage of patients presenting with clinically overt pulmonary embolism (PE) (48%, 48%, and 50% respectively), the average time elapsed from surgery to VTE (22 +/- 16, 24 +/- 16, and 21 +/- 15 days, respectively), and the three-month incidence of fatal PE (1.3%, 1.4%, and 0.8%, respectively), fatal bleeding (0.8%, 1.0%, and 0.2%, respectively), or major bleeding (2.3%, 2.9%, and 2.8%, respectively) were similar in the three groups. However, the percentage of patients who had received thromboprophylaxis (96%, 76% and 52%, respectively), the duration of prophylaxis (17 +/- 9.6, 13 +/- 8.9, and 12 +/- 11 days, respectively) and the mean daily doses of low-molecular-weight heparin (4,252 +/- 1,016, 3,260 +/- 1,141, and 3,769 +/- 1,650 IU, respectively), were significantly lower in those undergoing cancer surgery or other procedures. In conclusion, the clinical presentation, time-course, and three-month outcome of VTE was similar among the different subgroups of patients, but the use of prophylaxis in patients undergoing cancer surgery or other procedures was suboptimal.

Clinical predictors for fatal pulmonary embolism in 15520 patients with venous thromboembolism - Findings from the Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) registry

BACKGROUND Clinical predictors for fatal pulmonary embolism (PE) in patients with venous thromboembolism have never been studied. METHODS AND RESULTS Using data from the international prospective Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) registry about patients with objectively confirmed symptomatic acute venous thromboembolism, we determined independent predictive factors for fatal PE. Between March 2001 and July 2006, 15520 consecutive patients (mean age+/-SD, 66.3+/-16.9 years; 49.7% men) with acute venous thromboembolism were included. Symptomatic deep-vein thrombosis without symptomatic PE was observed in 58.0% (n=9008) of patients, symptomatic nonmassive PE in 40.4% (n=6264), and symptomatic massive PE in 1.6% (n=248). At 3 months, the cumulative rates of overall mortality and fatal PE were 8.65% and 1.68%, respectively. On multivariable analysis, patients with symptomatic nonmassive PE at presentation exhibited a 5.42-fold higher risk of fatal PE compared with patients with deep-vein thrombosis without symptomatic PE (P<0.001). The risk of fatal PE was multiplied by 17.5 in patients presenting with a symptomatic massive PE. Other clinical factors independently associated with an increased risk of fatal PE were immobilization for neurological disease, age >75 years, and cancer. CONCLUSIONS PE remains a potentially fatal disease. The clinical predictors identified in the present study should be included in any clinical risk stratification scheme to optimally adapt the treatment of PE to the risk of the fatal outcome.

Opposite clinical phenotypes of glucokinase disease: Description of a novel activating mutation and contiguous inactivating mutations in human glucokinase (GCK) gene.

Glucokinase is essential for glucose-stimulated insulin release from the pancreatic beta-cell, serving as glucose sensor in humans. Inactivating or activating mutations of glucokinase lead to different forms of glucokinase disease, i.e. GCK-monogenic diabetes of youth, permanent neonatal diabetes (inactivating mutations), and congenital hyperinsulinism, respectively. Here we present a novel glucokinase gene (GCK)-activating mutation (p.E442K) found in an infant with neonatal hypoglycemia (1.5 mmol/liter) and in two other family members suffering from recurrent hypoglycemic episodes in their childhood and adult life. In contrast to the severe clinical presentation in the index case, functional studies showed only a slight activation of the protein (relative activity index of 3.3). We also report on functional studies of two inactivating mutations of the GCK (p.E440G and p.S441W), contiguous to the activating one, that lead to monogenic diabetes of youth. Interestingly, adult family members carrying the GCK pE440G mutation show an unusually heterogeneous and progressive diabetic phenotype, a feature not typical of GCK-monogenic diabetes of youth. In summary, we identified a novel activating GCK mutation that although being associated with severe neonatal hypoglycemia is characterized by the mildest activation of the glucokinase enzyme of all previously reported.

Detection of human herpesvirus 7 infection in young children presenting with exanthema subitum

In this study, we assessed the prevalence of human herpesvirus-7 (HHV-7) in 141 serum samples from children less than four years of age with exanthematic disease. All samples were negative for measles, rubella, dengue fever and parvovirus B19 infection. Testing for the presence of human herpesvirus-6 (HHV-6)-specific high avidity IgG antibodies by indirect immunofluorescence assay (IFA) revealed two main groups: one composed of 57 patients with recent primary HHV-6 infection and another group of 68 patients showing signs of past HHV-6 infection. Another 16 samples had indeterminate primary HHV-6 infection, by both IgG IFA and IgM IFA. Serum samples were subjected to a nested polymerase chain reaction to detect the presence of HHV-7 DNA. Among patients with a recent primary HHV-6 infection, HHV-7 DNA was present in 1.7% of individuals; however, 5.8% of individuals tested positive for HHV-7 DNA in the group with past primary HHV-6 infection. Among the 16 samples with indeterminate diagnosis, 25% (4/16) had HHV-7 DNA (p < 0.002). We hypothesise that HHV-7 might be the agent that causes exanthema. However, a relationship between clinical manifestations and the detection of virus DNA does not always exist. Therefore, a careful interpretation is necessary to diagnose a primary infection or a virus-associated disease. In conclusion, we detected HHV-7 DNA in young children from the state of Rio de Janeiro, Brazil.

Genotyping of human parvovirus B19 in clinical samples from Brazil and Paraguay using heteroduplex mobility assay, single-stranded conformation polymorphism and nucleotide sequencing

Heteroduplex mobility assay, single-stranded conformation polymorphism and nucleotide sequencing were utilised to genotype human parvovirus B19 samples from Brazil and Paraguay. Ninety-seven serum samples were collected from individuals presenting with abortion or erythema infectiosum, arthropathies, severe anaemia and transient aplastic crisis; two additional skin samples were collected by biopsy. After the procedure, all clinical samples were classified as genotype 1.

Sociodemographic factors and clinical conditions associated to hospitalization in influenza A (H1N1) 2009 virus infected patients in Spain, 2009-2010.

The emergence and pandemic spread of a new strain of influenza A (H1N1) virus in 2009 resulted in a serious alarm in clinical and public health services all over the world. One distinguishing feature of this new influenza pandemic was the different profile of hospitalized patients compared to those from traditional seasonal influenza infections. Our goal was to analyze sociodemographic and clinical factors associated to hospitalization following infection by influenza A(H1N1) virus. We report the results of a Spanish nationwide study with laboratory confirmed infection by the new pandemic virus in a case-control design based on hospitalized patients. The main risk factors for hospitalization of influenza A (H1N1) 2009 were determined to be obesity (BMI≥40, with an odds-ratio [OR] 14.27), hematological neoplasia (OR 10.71), chronic heart disease, COPD (OR 5.16) and neurological disease, among the clinical conditions, whereas low education level and some ethnic backgrounds (Gypsies and Amerinds) were the sociodemographic variables found associated to hospitalization. The presence of any clinical condition of moderate risk almost triples the risk of hospitalization (OR 2.88) and high risk conditions raise this value markedly (OR 6.43). The risk of hospitalization increased proportionally when for two (OR 2.08) or for three or more (OR 4.86) risk factors were simultaneously present in the same patient. These findings should be considered when a new influenza virus appears in the human population.

Cellular characterisation of Candida tropicalis presenting fluconazole-related trailing growth

We assessed fluconazole susceptibility in 52 Candida tropicalis clinical strains using seven antifungal susceptibility methods, including broth microdilution (BMD) [standard M27 A3 (with neutral and acid pH), ATB Fungus 3, Vitek 2 system and flow cytometric analysis] and agar-based methods (disk diffusion and E-test). Trailing growth, detection of cell-associated secreted aspartic proteases (Saps) and morphological and ultrastructural traits of these clinical strains were also examined. The ranges of fluconazole 24 h-minimum inhibitory concentration (MIC) values were similar among all methods. The essential agreement among the methods used for MIC determinations was excellent and all methods categorised all strains as susceptible, except for one strain that showed a minor error. The presence of the trailing effect was assessed by six methods. Trailing positivity was observed for 86.5-100% of the strains. The exception was the BMD-Ac method where trailing growth was not observed. Morphological and ultrastructural alterations were detected in C. tropicalis trailing cells, including mitochondrial swelling and cell walls with irregular shapes. We tested the production of Saps in 13 C. tropicalis strains expressing trailing growth through flow cytometry. Our results showed that all of the C. tropicalis strains up-regulated surface Sap expression after 24 h or 48 h of exposure to fluconazole, which was not observed in untreated yeast strains. We concluded that C. tropicalis strains expressing trailing growth presented some particular features on both biological and ultrastructural levels.

Complete genome sequence of a clinical Bordetella pertussis isolate from Brazil

There has been a resurgence in the number of pertussis cases in Brazil and around the world. Here, the genome of a clinical Bordetella pertussis strain (Bz181) that was recently isolated in Brazil is reported. Analysis of the virulence-associated genes defining the pre- and post-vaccination lineages revealed the presence of the prn2-ptxS1A-fim3B-ptxP3 allelic profile in Bz181, which is characteristic of the current pandemic lineage. A putative metallo-β-lactamase gene presenting all of the conserved zinc-binding motifs that characterise the catalytic site was identified, in addition to a multidrug efflux pump of the RND family that could confer resistance to erythromycin, which is the antibiotic of choice for treating pertussis disease.