E-cadherin/beta-catenin/T-cell factor pathway is involved in smooth muscle cell proliferation elicited by oxidized low-density lipoprotein

The E-cadherin/beta-catenin/T-cell factor (Tcf) signaling pathway plays a crucial role in embryogenesis and carcinogenesis and has recently emerged in atherosclerosis. The aim of this work was to investigate whether this signaling pathway is involved in smooth muscle cell proliferation induced by oxidized low-density lipoprotein (LDL). In human aortic smooth muscle cells, mitogenic concentration of mildly oxidized LDL induced the activation of beta-catenin, as assessed by the dissociation of the beta-catenin/cadherin complex, and the concomitant rise of active beta-catenin in the cytosol. The oxidized LDL-induced rise of active beta-catenin required metalloproteinase activation, as well as epidermal growth factor receptor and Src signaling, as assessed by the use of pharmacological inhibitors and cells overexpressing a SrcK-inactive form. The concomitant phosphatidylinositol 3-kinase/Akt activation and glycogen synthase kinase 3-beta phosphorylation induced the inhibition of the proteasomal degradation of beta-catenin. Then active beta-catenin associated with Tcf4 and translocated into the nucleus. This enhanced the expression of the cell cycle activator cyclin D1. This crucial role of beta-catenin in the mitogenic effect of oxidized LDL was confirmed by silencing beta-catenin by specific small interfering RNA that blocked DNA synthesis. Immunohistochemistry staining of stable and disrupted plaques from carotid endarterectomy sections showed a correlation between active beta-catenin and Ki67, a proliferation marker, and a more intense staining in the smooth muscle cell layer surrounding the lipid core of disrupted plaques. In conclusion, the beta-catenin pathway is required for the mitogenic effect of oxidized LDL on human aortic smooth muscle cells. This study highlights the putative important role of the E-cadherin/beta-catenin/Tcf signaling pathway in atherosclerosis.     

HRAS germline mutations impair LKB1/AMPK signaling and mitochondrial homeostasis in Costello syndrome models

Germline mutations that activate genes in the canonical RAS/MAPK signaling pathway are responsible for rare human developmental disorders known as RASopathies. Here, we analyzed the molecular determinants of Costello syndrome (CS) using a mouse model expressing HRAS p.G12S, patient skin fibroblasts, hiPSC-derived human cardiomyocytes, a HRAS p.G12V zebrafish model, and human fibroblasts expressing lentiviral constructs carrying HRAS p.G12S or HRAS p.G12A mutations. The findings revealed alteration of mitochondrial proteostasis and defective oxidative phosphorylation in the heart and skeletal muscle of CS mice that were also found in the cell models of the disease. The underpinning mechanisms involved the inhibition of the AMPK signaling pathway by mutant forms of HRAS, leading to alteration of mitochondrial proteostasis and bioenergetics. Pharmacological activation of mitochondrial bioenergetics and quality control restored organelle function in HRAS p.G12A and p.G12S cell models, reduced left ventricle hypertrophy in CS mice, and diminished the occurrence of developmental defects in the CS zebrafish model. Collectively, these findings highlight the importance of mitochondrial proteostasis and bioenergetics in the pathophysiology of RASopathies and suggest that patients with CS may benefit from treatment with mitochondrial modulators.     

Evaluation of nested and real-time PCR assays in the diagnosis of candidaemia

Polymerase chain reaction (PCR) assays have a very low theoretical detection threshold and are therefore advocated for the diagnosis of fungaemia. However, their effectiveness in this respect remains to be assessed. This study compared real-time PCR ( Can -G) and nested PCR assays with blood culture for the diagnosis of Candida spp. bloodstream infections. A total of 200 clinical blood samples obtained from 110 patients at risk for developing a systemic fungal infection, hospitalized in the University Hospital of Sfax (Tunisia), were submitted to testing by culture, nested PCR and real-time PCR. Blood culture was positive in 36 patients. When compared with culture, the Can -G assay (81% sensitivity, 96% specificity) performed better than the nested PCR assay (86% sensitivity, 54% specificity). The real-time PCR assay, which avoids both the contamination hazard with amplicons that may cause false-positive results and the use of time-consuming post-PCR steps, appears more suitable than the nested PCR assay for the laboratory diagnosis of Candida spp. bloodstream infections. In this study, real-time PCR did not enhance the diagnostic sensitivity for Candida spp. bloodstream infections compared with conventional blood culture; however, it may lead to earlier implementation of an adequately targeted antifungal treatment.     

<Emphasis Type="Italic">Mycobacterium tuberculosis</Emphasis> complex drug resistance pattern and identification of species causing tuberculosis in the West and Centre regions of Cameroon

Background  

Data on the levels of resistance of Mycobacterium tuberculosis complex (MTBC) strains to first line anti-tuberculosis drugs in Cameroon, and on the species of MTBC circulating in the country are obsolete. The picture about 10 years after the last studies, and 6 years after the re-organisation of the National Tuberculosis (TB) Control Programme (NTBCP) is not known.     

Drug-induced skin, nail and hair disorders.

Drug eruptions are among the most common adverse drug reactions, affecting approximately 3% of hospitalised patients. Although the rate of severe cutaneous adverse reactions to medications is low, these reactions can affect anyone who takes medication, and can result in death or disability. Two general patterns can be distinguished, depending on the type of onset of these cutaneous adverse drug reactions: acute or chronic. Acute-onset events are usually rather specific cutaneous 'syndromes' that constitute emergencies and should therefore be promptly recognised and treated, while chronic-onset events often present as dermatological diseases. The challenge is therefore to recognise the drug aetiology in front of a 'classical' dermatosis such as acne, lichen or pemphigus. Therefore, clinicians should carefully evaluate the signs or symptoms of all adverse reactions thought to be drug related, and discontinue the offending agent when feasible. Erythematous drug eruptions are the most frequent and less severe acute immune drug-induced rashes, and are sometimes difficult to differentiate from viral eruptions. On the other hand, acute urticaria and angioedema are sometimes life-threatening eruptions for which a drug aetiology must be investigated. Photosensitivity, vasculitis and skin necrosis belong to the acute onset reactions, which are not always drug-induced, in contrast to fixed drug eruptions. The early recognition of acute generalised exanthematous pustulosis, DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome, Stevens-Johnson syndrome and toxic epidermal necrolysis are of high importance because of the specific mechanisms involved and the different prognosis of each of these diseases. Chronic onset drug-induced disorders include pigmentary changes, drug-induced autoimmune bullous diseases, lupus, pseudo lymphoma and acneiform eruptions; these are discussed, along with specific data on drug-induced hair and nail disorders. As the disorders are numerous, the mechanisms and the drugs involved in the development of these various reactions are multiple. The list of drugs discussed in relation to the different disorders are as accurate as possible at the time of preparation of this review, but will need updating as new drugs emerge onto the market. We emphasize the clinical recognition, pathophysiology and treatment of skin, hair and nail adverse drug reactions, and the role of each doctor involved in the management of these patients in the notification of the adverse drug reaction to health authorities, using the minimal requirement for notification proposed.     

Quand et comment conduire une nutrition entérale au cours de l’anorexie mentale ?

Lifesaving treatment in patients with anorexia nervosa and compromised nutritional status is controversial. Enteral nutrition, via a nasogastric tube can be useful in this situation. The digestive tract can be used better than parenteral nutrition. Enteral nutrition can also be used in a situation with moderate malnutrition and stable body weight despite an adequate psychological treatment. In all cases, this treatment should be discussed and accepted with the patient. Polymeric standard solutions can be used, taking care of the level of protein which should not be too high. The start of enteral nutrition is progressive, in order to avoid the risk of Refeeding Syndrome. Vitamins and phosphorus should be added to the enteral nutrition during the first few days. Complications of treatment is not frequent with these patients and are presented. Enteral nutrition should be not too long and should be decreased in the same time that oral nutrition progressively increases. The results of literature show that, enteral nutrition does not deteriorate the psychological state of the patients and is found to be accepted more positively than forced feeding orally in the initial critical phases, and is less dangerous in terms of metabolic tolerance. For these reasons, enteral nutrition should be included in the armament of treatment of anorexia nervosa.     

Extrinsic allergic alveolitis. Apropos of a severe case

A case of atypical extrinsic allergic alveolitis in a 13-year-old is reported. Onset was sudden with gradually increasing dyspnea on exertion over a four-day period. The chest film evidenced a reticulonodular syndrome with decreased respiratory movements. The patient's clinical status worsened over the next 48 hours with the development of respiratory distress. Under oxygen therapy (3 l/min), PO2 was 49 mmHg and SO2 was 82%. Dramatic improvement occurred after initiation of corticosteroid and antimicrobial therapy. Etiologic investigations were negative except for the immunofluorescence test with pigeon droppings which showed three precipitation arcs. A CT scan of the chest disclosed diffuse micronodular densities without thickening of connective tissue trabeculae, suggesting alveolar disease. Mediastinal lymph nodes were not enlarged. Vital capacity was 26% of the theoric value. Corticosteroids were given for one month. On follow-up chest films, the reticulomicronodular syndrome was seen to abate, globally at first, then from the apices to the bases of the lungs. However, a repeat CT scan at the 4th month showed that diffuse lesions were still present although the chest film was normal; 8 months after onset, there was only a bulla in the left lung base, with no evidence of fibrosis. Lung function tests slowly returned to normal, as did CT scan findings.     

Treatment of tumour-induced hypercalcaemia with the bisphosphonate pamidronate: Dose-response relationship and influence of tumour type

BACKGROUND:: Patients with humoral hypercalcaemia of malignancy appear torespond less well to biphosphonate therapy than hypercalcaemicpatients with osteolytic metastases. On the other hand, pamidronateis currently the most potent of the commercially available biphosphonatesand it is recommended that its dose be increased as a functionof pre-treatment calcium levels. PATIENTS AND METHODS:: We reviewed our experience with pamidronate in 160 patientswith tumour-induced hypercalcemia (TIH) persisting after rehydration,particularly the influence of the dose administered, the tumourtype and the presence of bone metastatic involvement on thecalcaemic and calciuric response to pamidronate therapy. RESULTS:: Serum Ca was normalized in 92% of the cases (87% when Ca wascorrected for protein levels). After therapy, 59% of the patientsdeveloped asymptomatic hypocalcaemia (30% for Corn Ca levels).A multiparameter regression analysis revealed that the responseto pamidronate was significantly (P < 0.01) influenced byinitial Ca levels up to days 5–7 and, thereafter, onlyby the dose received. To confirm the dose effect, we dividedthe patients into three groups according to the median dosereceived, namely 0.5 mg/kg (n = 35), 1.0 mg/kg (n = 52), and1.5 mg/kg (n = 73). The differences among the three groups becamesignificant(P < 0.05) from days 5–7 until the end ofthe evaluation (days 22–26). Similarly, the success rate,considering Corr. Ca levels, was 80% for the 0.5 and 1.0 mg/kggroups combined, compared to 94% for the 1.5 mg/kg group (P< 0.05). The duration of normocalcaemia was similarly moreprolonged in the high-dose group. There was a dose-responserelationship only in patients with Ca levels above 3.0 mmol/Land in patients with an elevated index of tubular calcium reabsorption.By contrast, the decrease in Ca levels and in fasting urinarycalcium excretion, a sensitive index of bone resorption, werenot significantly influenced by the primary tumour site or bythe presence of bone metastatic involvement. CONCLUSIONS:: Our data demonstrate a dose-response relationship for pamidronatein TIH over an efficient hypocalcaemic dose range, at leastin patients with an elevated tubular calcium reabsorption, whichhelps to resolve conflicting data in the literature. We suggestthat a dose of around 1.5 mg of pamidronate/kg is optimal forthe treatment of TIH, except in patients with mild hypercalcaemia,for whom a dose of 1 mg/kg appears to be sufficient. At thesedose levels, the efficacy of pamidronate is not significantlyinfluenced by the tumour type or the degree of metastatic boneinvolvement. bisphosphonate, bone, hypercalcaemia, paraneoplastic, supportive care     

Antibiotics for coughing in general practice: a questionnaire study to quantify and condense the reasons for prescribing

Background  

Antibiotics are being overprescribed in ambulant care, especially for respiratory tract infections (RTIs). Gaining insight into the actual reasons for prescribing remains important for the design of effective strategies to optimise antibiotic prescribing. We aimed to determine items of importance for the antibiotic prescribing decision and to make them operational for an intervention trial.