Molecular and phenotypic characterization of a mouse model of oculopharyngeal muscular dystrophy reveals severe muscular atrophy restricted to fast glycolytic fibres

Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disorder characterized by ptosis, dysphagia and proximal limb weakness. Autosomal-dominant OPMD is caused by a short (GCG)8–13 expansions within the first exon of the poly(A)-binding protein nuclear 1 gene (PABPN1), leading to an expanded polyalanine tract in the mutated protein. Expanded PABPN1 forms insoluble aggregates in the nuclei of skeletal muscle fibres. In order to gain insight into the different physiological processes affected in OPMD muscles, we have used a transgenic mouse model of OPMD (A17.1) and performed transcriptomic studies combined with a detailed phenotypic characterization of this model at three time points. The transcriptomic analysis revealed a massive gene deregulation in the A17.1 mice, among which we identified a significant deregulation of pathways associated with muscle atrophy. Using a mathematical model for progression, we have identified that one-third of the progressive genes were also associated with muscle atrophy. Functional and histological analysis of the skeletal muscle of this mouse model confirmed a severe and progressive muscular atrophy associated with a reduction in muscle strength. Moreover, muscle atrophy in the A17.1 mice was restricted to fast glycolytic fibres, containing a large number of intranuclear inclusions (INIs). The soleus muscle and, in particular, oxidative fibres were spared, even though they contained INIs albeit to a lesser degree. These results demonstrate a fibre-type specificity of muscle atrophy in this OPMD model. This study improves our understanding of the biological pathways modified in OPMD to identify potential biomarkers and new therapeutic targets.

Combined use of satellite estimates and rain gauge observations to generate high-quality historical rainfall time series over Ethiopia

Climate data are used in a number of applications including climate risk management and adaptation to climate change. However, the availability of climate data, particularly throughout rural Africa, is very limited. Available weather stations are unevenly distributed and mainly located along main roads in cities and towns. This imposes severe limitations to the availability of climate information and services for the rural community where, arguably, these services are needed most. Weather station data also suffer from gaps in the time series. Satellite proxies, particularly satellite rainfall estimate, have been used as alternatives because of their availability even over remote parts of the world. However, satellite rainfall estimates also suffer from a number of critical shortcomings that include heterogeneous time series, short time period of observation, and poor accuracy particularly at higher temporal and spatial resolutions. An attempt is made here to alleviate these problems by combining station measurements with the complete spatial coverage of satellite rainfall estimates. Rain gauge observations are merged with a locally calibrated version of the TAMSAT satellite rainfall estimates to produce over 30-years (1983-todate) of rainfall estimates over Ethiopia at a spatial resolution of 10 km and a ten-daily time scale. This involves quality control of rain gauge data, generating locally calibrated version of the TAMSAT rainfall estimates, and combining these with rain gauge observations from national station network. The infrared-only satellite rainfall estimates produced using a relatively simple TAMSAT algorithm performed as good as or even better than other satellite rainfall products that use passive microwave inputs and more sophisticated algorithms. There is no substantial difference between the gridded-gauge and combined gauge-satellite products over the test area in Ethiopia having a dense station network; however, the combined product exhibits better quality over parts of the country where stations are sparsely distributed.

Combined periodontal, orthodontic, and restorative treatment of pathologic migration of anterior teeth: A case report

Pathologic tooth migration related to periodontal disease is a common chief complaint of periodontal patients. This paper describes the treatment of a case of severe periodontal disease and disfiguring pathologic migration of maxillary central incisors, which required a multidisciplinary approach. After conventional pert. odontal treatment was performed, the anterior diastema was closed using a combination of orthodontic therapy and restorative treatment. A 6-month follow-up examination of this case revealed resolution of the anterior pathologic migration, with gains in clinical attachment levels and a successful esthetic and functional final result.

Morphological evaluation of combined effects of cyclosporin and nifedipine on gingival overgrowth in rats

It has previously been shown that, while cyclosporin A (CsA) and nifedipine both cause gingival overgrowth in the rat. the combined use of these drugs increases the severity of overgrowth. The aim of this study was to describe the histometry and densities of fibroblasts, collagen fibers and vessels in the gingival tissue of rats that were treated with CsA and nifedipine, either alone or in combination. Rats were treated for 60 days with a daily subcutaneous injection of 10 mg/kg body weight of CsA and/or with 50 mg/kg body weight of nifedipine added to the chow. The results confirmed that CsA causes a more severe overgrowth than nifedipine, and that the combined use of these drugs increases the overgrowth severity. All the rat groups that were studied showed that, as the severity of overgrowth increased, there was a parallel increase in fibroblasts and collagen, and a decrease in vessel content. Therefore, independently of whether the gingival overgrowth was caused by CsA alone, nifedipine alone, or both treatments in combination, the fibroblast and collagen density increased in parallel with the severity of the overgrowth. © Blackwell Munksgaard, 2002.

Epidemiology of human immunodeficiency virus-visceral leishmaniasis-co-infection

In Brazil, the rates of mother-to-child-transmission (MTCT) of human immunodeficiency virus (HIV) decreased from 20% to 1-2% in some regions. However, the country contains 90% of individuals infected with visceral leishmaniasis (VL) in Latin America, and the west region of São Paulo state faces an alarming expansion of the disease. We describe the epidemiological aspects of the expanding infection of VL and a case report of an HIV-VL-co-infected child from the west region of São Paulo state. The patient was an AIDS-C3 with low levels of CD4, high viral load, severe diarrhea, oral and perineal candidiasis, severe thrombocytopenia, and protein-caloric malnourishment. She evolved with sepsis, renal and cardiac failure. An rK rapid diagnosis test, indirect fluorescent antibody test (IFAT), and bone marrow aspirate were performed for VL. Her symptoms improved significantly after liposomal amphotericin B administration. From the 45 municipalities that compose the Regional Health Department of Presidente Prudente, Lutzomyia longipalpis vectors were found in 58% of them. VL infected dogs were found in 33% of those municipalities, infected dogs and humans were found in 29%, 20% are starting and 33% of the municipalities are preparing VL investigation. It is likely, in this patient, that VL advanced the clinical progression of the HIV disease and the development of AIDS severity. Supported by favorable conditions, the region becomes a new frontier of VL in Brazil. © 2013.

Oral live attenuated human rotavirus vaccine (RotarixTM) offers sustained high protection against severe G9P[8] rotavirus gastroenteritis during the first two years of life in Brazilian children

In a large Phase III trial conducted in 10 Latin American countries, the safety and efficacy of the live attenuated monovalent rotavirus vaccine RIX4414 was evaluated in 15,183 healthy infants followed up during the first two years of life. Belém was the only site in Brazil included in this multicentre trial. The study in Belém included a subset of 653 infants who were followed up until 24 months of age for protection against severe rotavirus gastroenteritis. These subjects were randomly assigned in a 1:1 ratio to receive two doses of vaccine (n = 328) or two doses of placebo (n = 325) at approximately two and four months of age. Of the 653 enrolled infants, 23 dropped out during the study period. For the combined two-year period, the efficacy of RIX4414 was 72.3% [95% confidence interval (CI) 37.5-89.1%] against severe rotavirus-related gastroenteritis, reaching a protection rate of 81.8% (95% CI 36.4-96.6%) against circulating wild-type G9 rotavirus strains. It is concluded that two doses of RIX4414 are highly efficacious against severe rotavirus gastroenteritis in Belém during the first two years of life and provide high protection against the worldwide emergence and spread of G9P[8] strains.

Surgical Treatment of Severe Frontal Bone Fracture

Craniofacial trauma can lead to several complications. The combined fractures of anterior and posterior walls of the frontal bone are almost always followed by lesions in nasofrontal orifices and disruption of nasofrontal ostia or ducts, a significant factor for the development of early and late complications after sinus fractures. This article reports a case of trauma patient, who underwent neurological evaluation and at first showed good general condition. Computed tomography noted fracture of the anterior and posterior walls of the frontal sinus and small foci of pneumocephalus in the cerebral cortex. The patient was monitored periodically and 9 days after trauma showed increased areas of pneumocephalus in prefrontal cortex, cerebrospinal fluid draining, and large dura mater lesion, with signs of necrosis and inflammation (meningitis). The necrotic tissues were removed, and dura mater was repaired through the approximation with resorbable wire polyglactin 910 5-0, oxidized cellulose application, and bonding with human fibrin sealant (fibrinogen, thrombin, and calcium chloride). Sinusectomy, frontal sinus, and nasofrontal duct obliteration with pedicled pericranium flap were performed. Tomographically, a reanatomization was noted in frontal region, and a 12-month follow-up showed no complication. The use of fibrin glue to repair dura mater lacerations, as well as the pedicle pericranium flap for frontal sinus and nasofrontal duct obliteration, is an efficient method for treating fractures of the frontal bone.

Combined low initial DNA damage and high radiation-induced apoptosis confers clinical resistance to long-term toxicity in breast cancer patients treated with high-dose radiotherapy

[EN] Background: Either higher levels of initial DNA damage or lower levels of radiation-induced apoptosis in peripheral blood lymphocytes have been associated to increased risk for develop late radiation-induced toxicity. It has been recently published that these two predictive tests are inversely related. The aim of the present study was to investigate the combined role of both tests in relation to clinical radiation-induced toxicity in a set of breast cancer patients treated with high dose hyperfractionated radical radiotherapy. Methods: Peripheral blood lymphocytes were taken from 26 consecutive patients with locally advanced breast carcinoma treated with high-dose hyperfractioned radical radiotherapy. Acute and late cutaneous and subcutaneous toxicity was evaluated using the Radiation Therapy Oncology Group morbidity scoring schema. The mean follow-up of survivors (n = 13) was 197.23 months. Radiosensitivity of lymphocytes was quantified as the initial number of DNA double-strand breaks induced per Gy and per DNA unit (200 Mbp). Radiation-induced apoptosis (RIA) at 1, 2 and 8 Gy was measured by flow cytometry using annexin V/propidium iodide. Results: Mean DSB/Gy/DNA unit obtained was 1.70 ± 0.83 (range 0.63-4.08; median, 1.46). Radiation-induced apoptosis increased with radiation dose (median 12.36, 17.79 and 24.83 for 1, 2, and 8 Gy respectively). We observed that those "expected resistant patients" (DSB values lower than 1.78 DSB/Gy per 200 Mbp and RIA values over 9.58, 14.40 or 24.83 for 1, 2 and 8 Gy respectively) were at low risk of suffer severe subcutaneous late toxicity (HR 0.223, 95%CI 0.073-0.678, P = 0.008; HR 0.206, 95%CI 0.063-0.677, P = 0.009; HR 0.239, 95%CI 0.062-0.929, P = 0.039, for RIA at 1, 2 and 8 Gy respectively) in multivariate analysis. Conclusions: A radiation-resistant profile is proposed, where those patients who presented lower levels of initial DNA damage and higher levels of radiation induced apoptosis were at low risk of suffer severe subcutaneous late toxicity after clinical treatment at high radiation doses in our series. However, due to the small sample size, other prospective studies with higher number of patients are needed to validate these results.

Combined Evaluation of ST-segment Elevation in lead AVR and ST-segment Depression in other Leads Enhances Prediction of in-hospital Cardiovascular Death in Patients with Non ST-segment Elevation Acute Coronary Syndrome

Objective: To investigate the prognostic significance of ST-segment elevation (STE) in aVR associated with ST-segment depression (STD) in other leads in patients with non-STE acute coronary syndrome (NSTE-ACS). Background: In NSTE-ACS patients, STD has been extensively associated with severe coronary lesions and poor outcomes. The prognostic role of STE in aVR is uncertain. Methods: We enrolled 888 consecutive patients with NSTE-ACS. They were divided into two groups according to the presence or not on admission ECG of aVR STE≥ 1mm and STD (defined as high risk ECG pattern). The primary and secondary endpoints were: in-hospital cardiovascular (CV) death and the rate of culprit left main disease (LMD). Results: Patients with high risk ECG pattern (n=121) disclosed a worse clinical profile compared to patients (n=575) without [median GRACE (Global-Registry-of-Acute-Coronary-Events) risk score =142 vs. 182, respectively]. A total of 75% of patients underwent coronary angiography. The rate of in-hospital CV death was 3.9%. On multivariable analysis patients who had the high risk ECG pattern showed an increased risk of CV death (OR=2.88, 95%CI 1.05-7.88) and culprit LMD (OR=4.67,95%CI 1.86-11.74) compared to patients who had not. The prognostic significance of the high risk ECG pattern was maintained even after adjustment for the GRACE risk score (OR = 2.28, 95%CI:1.06-4.93 and OR = 4.13, 95%CI:2.13-8.01, for primary and secondary endpoint, respectively). Conclusions: STE in aVR associated with STD in other leads predicts in-hospital CV death and culprit LMD. This pattern may add prognostic information in patients with NSTE-ACS on top of recommended scoring system.

The "Orthoplastic" combined surgical approach to open tibia fractures: a multicentric prospective outcome study

Introduction: Open fractures of the leg represent a severe trauma. The combined approach, shared between plastic and orthopaedic surgeons, is considered to be important, although this multidisciplinary treatment is not routinely performed. Aim of this study was to verify whether the orthoplastic treatment is of any advantage over the traditional simply orthopedic treatment, through a multicentric inclusion of these unfrequent injuries into a prospective study. Material and methods: The following trauma centres were involved: Rizzoli Orthopaedic Institute/University of Bologna (leading centre) and Maggiore Hospital (Bologna, Italy), Frenchay Hospital (Bristol, United Kingdom), Jinnah Hospital (Lahore, Pakistan). All patients consecutively hospitalized in the mentioned centres between January 2012 and December 2013 due to tibial open fractures were included in the study and prospectively followed up to December 2014. Demographics and other clinical features were recorded, including the type of treatment (orthopaedic or orthoplastic). The considered outcome measures included duration of hospitalization, time for bone union and soft tissue closure, Enneking score at 3, 6 and 12 months, the incidence of osteomyelitis and other complications. Results: A total of 164 patients were included in the study. Out of them 68% were treated with an orthoplastic approach, whereas 32% received a purely orthopedic treatment. All considered outcome measures showed to be improved by the orthoplastic approach, compared to the orthopaedic one: time for soft tissue closure (2 versus 25 weeks), duration of hospital stay (22 versus 55 days), time for bone union (6 versus 8.5 months) , number of additional operations (0.6 versus 1.2) and functional recovery of the limb at 12 months (27 versus 19, Enneking’s score). All results were statistically significant. Conclusion: The combined orthoplastic approach to the treatment of open tibia fractures, in particular for high grade injuries (Gustilo 3B), is proven to improve the outcome of these severe injuries.

Multidrug strategies are effective in the treatment of severe experimental pancreatitis

Trypsinogen activation, oxygen radicals, cytokines, leukocyte infiltration, and pancreatic ischemia are important steps in the pathogenesis of necrotizing pancreatitis and associated systemic complications. Several drugs that inhibit those pathogenetic steps attenuated biochemical and histologic changes, while survival remained low. The aim of the present study was to evaluate the benefit of multidrug approaches compared to monotherapies on organ injury and survival in acute experimental pancreatitis in the rat model of retrograde bile injection combined with intravenous cerulein.

Clinical outcome of high-risk patients with severe aortic stenosis and reduced left ventricular ejection fraction undergoing medical treatment or TAVI

Introduction Reduced left ventricular function in patients with severe symptomatic valvular aortic stenosis is associated with impaired clinical outcome in patients undergoing surgical aortic valve replacement (SAVR). Transcatheter Aortic Valve Implantation (TAVI) has been shown non-inferior to SAVR in high-risk patients with respect to mortality and may result in faster left ventricular recovery. Methods We investigated clinical outcomes of high-risk patients with severe aortic stenosis undergoing medical treatment (n = 71) or TAVI (n = 256) stratified by left ventricular ejection fraction (LVEF) in a prospective single center registry. Results Twenty-five patients (35%) among the medical cohort were found to have an LVEF≤30% (mean 26.7±4.1%) and 37 patients (14%) among the TAVI patients (mean 25.2±4.4%). Estimated peri-interventional risk as assessed by logistic EuroSCORE was significantly higher in patients with severely impaired LVEF as compared to patients with LVEF>30% (medical/TAVI 38.5±13.8%/40.6±16.4% versus medical/TAVI 22.5±10.8%/22.1±12.8%, p <0.001). In patients undergoing TAVI, there was no significant difference in the combined endpoint of death, myocardial infarction, major stroke, life-threatening bleeding, major access-site complications, valvular re-intervention, or renal failure at 30 days between the two groups (21.0% versus 27.0%, p = 0.40). After TAVI, patients with LVEF≤30% experienced a rapid improvement in LVEF (from 25±4% to 34±10% at discharge, p = 0.002) associated with improved NYHA functional class at 30 days (decrease ≥1 NYHA class in 95%). During long-term follow-up no difference in survival was observed in patients undergoing TAVI irrespective of baseline LVEF (p = 0.29), whereas there was a significantly higher mortality in medically treated patients with severely reduced LVEF (log rank p = 0.001). Conclusion TAVI in patients with severely reduced left ventricular function may be performed safely and is associated with rapid recovery of systolic left ventricular function and heart failure symptoms.

Treatment of advanced soft-tissue sarcomas using a combined strategy of high-dose ifosfamide, high-dose doxorubicin and salvage therapies

Having determined in a phase I study the maximum tolerated dose of high-dose ifosfamide combined with high-dose doxorubicin, we now report the long-term results of a phase II trial in advanced soft-tissue sarcomas. Forty-six patients with locally advanced or metastatic soft-tissue sarcomas were included, with age <60 years and all except one in good performance status (0 or 1). The chemotherapy treatment consisted of ifosfamide 10 g m(-2) (continuous infusion for 5 days), doxorubicin 30 mg m(-2) day(-1) x 3 (total dose 90 mg m(-2)), mesna and granulocyte-colony stimulating factor. Cycles were repeated every 21 days. A median of 4 (1-6) cycles per patient was administered. Twenty-two patients responded to therapy, including three complete responders and 19 partial responders for an overall response rate of 48% (95% CI: 33-63%). The response rate was not different between localised and metastatic diseases or between histological types, but was higher in grade 3 tumours. Median overall survival was 19 months. Salvage therapies (surgery and/or radiotherapy) were performed in 43% of patients and found to be the most significant predictor for favourable survival (exploratory multivariate analysis). Haematological toxicity was severe, including grade > or =3 neutropenia in 59%, thrombopenia in 39% and anaemia in 27% of cycles. Three patients experienced grade 3 neurotoxicity and one patient died of septic shock. This high-dose regimen is toxic but nonetheless feasible in multicentre settings in non elderly patients with good performance status. A high response rate was obtained. Prolonged survival was mainly a function of salvage therapies.

Cerebral correlates of muscle tone fluctuations in restless legs syndrome: A pilot study with combined functional magnetic resonance imaging and anterior tibial muscle electromyography

BACKGROUND: The pathology of restless legs syndrome (RLS) is still not understood. To investigate the pathomechanism of the disorder further we recorded a surface electromyogram (EMG) of the anterior tibial muscle during functional magnetic resonance imaging (fMRI) in patients with idiopathic RLS. METHODS: Seven subjects with moderate to severe RLS were investigated in the present pilot study. Patients were lying supine in the scanner for over 50min and were instructed not to move voluntarily. Sensory leg discomfort (SLD) was evaluated on a 10-point Likert scale. For brain image analysis, an algorithm for the calculation of tonic EMG values was developed. RESULTS: We found a negative correlation of tonic EMG and SLD (p <0.01). This finding provides evidence for the clinical experience that RLS-related subjective leg discomfort increases during muscle relaxation at rest. In the fMRI analysis, the tonic EMG was associated with activation in motor and somatosensory pathways and also in some regions that are not primarily related to motor or somatosensory functions. CONCLUSIONS: By using a newly developed algorithm for the investigation of muscle tone-related changes in cerebral activity, we identified structures that are potentially involved in RLS pathology. Our method, with some modification, may also be suitable for the investigation of phasic muscle activity that occurs during periodic leg movements.

Respiratory syncytial virus infection in 406 hospitalized premature infants: results from a prospective German multicentre database

Premature birth, chronic lung disease of prematurity (CLD), congenital heart disease and immunodeficiency predispose to a higher morbidity and mortality in respiratory syncytial virus (RSV) infection. This study describes the preterms hospitalised with RSV infection from the prospective German DSM RSV Paed database. The DMS RSV Paed database was designed for the prospective multicentre documentation and analysis of clinically relevant aspects of the management of inpatients with RSV infection. This study covers six consecutive RSV seasons (1999-2005); the surveillance took place in 14 paediatric hospitals in Germany. Of the 1,568 prospectively documented RSV infections, 26% (n=406) were observed in preterms [vs. 1,162 children born at term (74%)] and 3% (n=50) had CLD, of which 49 had received treatment in the last 6 months ('CLDplus'). A significantly higher proportion in the preterm group had congenital heart disease, nosocomial infection, and neuromuscular impairment. There were significantly more children older than 24 months in the preterm group. The attributable mortality was 0.2% (n=2) in children born at term vs. 1.2% (n=5) in the preterm group (p=0.015) [preterm plus CLD 8.0% (n=4 of 50); McIntosh grade 1, 8.6% (n=3 of 35) and McIntosh Grade 4, 15% (n=3 of 20)]. Eight patients were categorized as 'palivizumab failures'. In the multivariate analysis, premature birth, CLD(plus), and nosocomial infection were significantly and independently associated with the combined outcome 'complicated course of disease'. In conclusion, this is the first prospective multicentre study from Germany that confirms the increased risk for severe RSV disease in preterms, in particular in those with CLD treated in the last 6 months before the onset of the infection. From the perspective of our results, the statements of the German Society of Paediatric Infectious Diseases considering the use of passive immunisation (2003) seem reasonable.