AopP, a type III effector protein of Aeromonas salmonicida, inhibits the NF-kappaB signalling pathway

Aeromonas salmonicida subsp. salmonicida contains a functional type III secretion system that is responsible for the secretion of the ADP-ribosylating toxin AexT. In this study, the authors identified AopP as a second effector protein secreted by this system. The aopP gene was detected in both typical and atypical A. salmonicida isolates and was found to be encoded on a small plasmid of approximately 6.4 kb. Sequence analysis indicates that AopP is a member of the YopJ family of effector proteins, a group of proteins that interfere with mitogen-activated protein kinase (MAPK) and/or nuclear factor kappa B (NF-kappaB) signalling pathways. AopP inhibits the NF-kappaB pathway downstream of IkappaB kinase (IKK) activation, while a catalytically inactivated mutant, AopPC177A, does not possess this inhibitory effect. Unlike other effectors of the YopJ family, such as YopJ and VopA, AopP does not inhibit the MAPK signalling pathway.

Prevalence of risk factors for cardiovascular disease in HIV-infected patients over time: the Swiss HIV Cohort Study

OBJECTIVE: Metabolic changes caused by antiretroviral therapy (ART) may increase the risk of coronary heart disease (CHD). We evaluated changes in the prevalence of cardiovascular risk factors (CVRFs) and 10-year risk of CHD in a large cohort of HIV-infected individuals. METHODS: All individuals from the Swiss HIV Cohort Study (SHCS) who completed at least one CVRF questionnaire and for whom laboratory data were available for the period February 2000 to February 2006 were included in the analysis. The presence of a risk factor was determined using cut-offs based on the guidelines of the National Cholesterol Education Program (NCEP ATP III), the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7), the American Diabetes Association, and the Swiss Society for Cardiology. RESULTS: Overall, 8,033 individuals completed at least one CVRF questionnaire. The most common CVRFs in the first completed questionnaire were smoking (57.0%), low high-density lipoprotein (HDL) cholesterol (37.2%), high triglycerides (35.7%), and high blood pressure (26.1%). In total, 2.7 and 13.8% of patients were categorized as being at high (>20%) and moderate (10-20%) 10-year risk for CHD, respectively. Over 6 years the percentage of smokers decreased from 61.4 to 47.6% and the percentage of individuals with total cholesterol >6.2 mmol/L decreased from 21.1 to 12.3%. The prevalence of CVRFs and CHD risk was higher in patients currently on ART than in either pretreated or ART-naive patients. CONCLUSION: During the 6-year observation period, the prevalence of CVRFs remains high in the SHCS. Time trends indicate a decrease in the percentage of smokers and individuals with high cholesterol.

Exercise training in normobaric hypoxia in endurance runners. III. Muscular adjustments of selected gene transcripts

We hypothesized that specific muscular transcript level adaptations participate in the improvement of endurance performances following intermittent hypoxia training in endurance-trained subjects. Fifteen male high-level, long-distance runners integrated a modified living low-training high program comprising two weekly controlled training sessions performed at the second ventilatory threshold for 6 wk into their normal training schedule. The athletes were randomly assigned to either a normoxic (Nor) (inspired O2 fraction = 20.9%, n = 6) or a hypoxic group exercising under normobaric hypoxia (Hyp) (inspired O2 fraction = 14.5%, n = 9). Oxygen uptake and speed at second ventilatory threshold, maximal oxygen uptake (VO2 max), and time to exhaustion (Tlim) at constant load at VO2 max velocity in normoxia and muscular levels of selected mRNAs in biopsies were determined before and after training. VO2 max (+5%) and Tlim (+35%) increased specifically in the Hyp group. At the molecular level, mRNA concentrations of the hypoxia-inducible factor 1alpha (+104%), glucose transporter-4 (+32%), phosphofructokinase (+32%), peroxisome proliferator-activated receptor gamma coactivator 1alpha (+60%), citrate synthase (+28%), cytochrome oxidase 1 (+74%) and 4 (+36%), carbonic anhydrase-3 (+74%), and manganese superoxide dismutase (+44%) were significantly augmented in muscle after exercise training in Hyp only. Significant correlations were noted between muscular mRNA levels of monocarboxylate transporter-1, carbonic anhydrase-3, glucose transporter-4, and Tlim only in the group of athletes who trained in hypoxia (P < 0.05). Accordingly, the addition of short hypoxic stress to the regular endurance training protocol induces transcriptional adaptations in skeletal muscle of athletic subjects. Expressional adaptations involving redox regulation and glucose uptake are being recognized as a potential molecular pathway, resulting in improved endurance performance in hypoxia-trained subjects.

Multicycle dose-intensive chemotherapy for women with high-risk primary breast cancer: results of International Breast Cancer Study Group Trial 15-95

PURPOSE: To compare adjuvant dose-intensive epirubicin and cyclophosphamide chemotherapy administered with filgrastim and progenitor cell support (DI-EC) with standard-dose anthracycline-based chemotherapy (SD-CT) for patients with early-stage breast cancer and a high risk of relapse, defined as stage II disease with 10 or more positive axillary nodes; or an estrogen receptor-negative or stage III tumor with five or more positive axillary nodes. PATIENTS AND METHODS: Three hundred forty-four patients were randomized after surgery to receive seven cycles of SD-CT over 22 weeks, or three cycles of DI-EC (epirubicin 200 mg/m2 plus cyclophosphamide 4 gm/m2 with filgrastim and progenitor cell support) over 6 weeks. All patients were assigned tamoxifen at the completion of chemotherapy. The primary end point was disease-free survival (DFS). RESULTS: After a median follow-up of 5.8 years (range, 3 to 8.4 years), 188 DFS events had occurred (DI-EC, 86 events; SD-CT, 102 events). The 5-year DFS was 52% for DI-EC and 43% for SD-CT, with hazard ratio of DI-EC compared with SD-CT of 0.77 (95% CI, 0.58 to 1.02; P = .07). The 5-year overall survival was 70% for DI-EC and 61% for SD-CT, with a hazard ratio of 0.79 (95% CI, 0.56 to 1.11; P = .17). There were eight cases (5%) of anthracycline-induced cardiomyopathy (two fatal) among those who received DI-EC. Women with hormone receptor-positive tumors benefited significantly from DI-EC. CONCLUSION: There was a trend in favor of DI-EC with respect to disease-free survival. A larger trial or meta-analysis will be required to reveal the true effect of dose-intensive therapy.

Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981-NCIC CE3 phase III randomized trial

PURPOSE: The European Organisation for Research and Treatment of Cancer and National Cancer Institute of Canada trial on temozolomide (TMZ) and radiotherapy (RT) in glioblastoma (GBM) has demonstrated that the combination of TMZ and RT conferred a significant and meaningful survival advantage compared with RT alone. We evaluated in this trial whether the recursive partitioning analysis (RPA) retains its overall prognostic value and what the benefit of the combined modality is in each RPA class. PATIENTS AND METHODS: Five hundred seventy-three patients with newly diagnosed GBM were randomly assigned to standard postoperative RT or to the same RT with concomitant TMZ followed by adjuvant TMZ. The primary end point was overall survival. The European Organisation for Research and Treatment of Cancer RPA used accounts for age, WHO performance status, extent of surgery, and the Mini-Mental Status Examination. RESULTS: Overall survival was statistically different among RPA classes III, IV, and V, with median survival times of 17, 15, and 10 months, respectively, and 2-year survival rates of 32%, 19%, and 11%, respectively (P < .0001). Survival with combined TMZ/RT was higher in RPA class III, with 21 months median survival time and a 43% 2-year survival rate, versus 15 months and 20% for RT alone (P = .006). In RPA class IV, the survival advantage remained significant, with median survival times of 16 v 13 months, respectively, and 2-year survival rates of 28% v 11%, respectively (P = .0001). In RPA class V, however, the survival advantage of RT/TMZ was of borderline significance (P = .054). CONCLUSION: RPA retains its prognostic significance overall as well as in patients receiving RT with or without TMZ for newly diagnosed GBM, particularly in classes III and IV.

Infection at titanium implants with or without clinical inflammation

Objectives: The aims of the present study were (1)to assess the microbiota at implants in function diagnosed as having either peri-implantitis, or mucositis, or being clinically without symptoms of inflammation, (2) to identify explanatory factors to implant status. Material and Methods: Clinical and microbiological data were collected from 138 subjects (mean age: 62.3 ± 14.9) with 524 implants in function for an average of 10.8 years (S.D. +1.5). The checkerboard DNA-DNA hybridization method was used to identify 40 bacterial species. Results: Subjects had poor oral hygiene with a mean % plaque score 53.2 ± 24.4. In 36% of cases periodontitis was reported as the cause for implant therapy. Mucositis was diagnosed in 61.6% and per-implantitis in 15.9% of all cases. Edentulous subjects had at implants with peri-implantitis significantly higher bacterial loads for Streptococcus sanguis (p<0.01), Fusobacterium nucleatum sp. nucleatum (p<0.02), and Leptothrichia buccalis (p<0.05) than did dentate implant subjects. Dentate subjects had higher bacterial loads of Porphyromonas gingivalis (p<0.02). The levels of Fusobacterium nucleatum sp.vincentii and Capnocytophaga ochracea were explanatory to mucositis. Only a history of periodontitis as cause of tooth loss and smoking were explanatory to peri-implantitis. The microbiota was not affect by supportive care patterns. Conclusions: Presence or absence of teeth partly explains the implant microbiota. A past history of periodontitis and smoking are associated with peri-implantitis. The microbiota at implants with mucositis, or peri-implantitis is similar to that of teeth. Supportive periodontal and implant therapy fails to have an impact on implant microbiota and does not prevent mucositis and peri-implantitis.

Benefits of cardiac surgery in octogenarians--a postoperative quality of life assessment

OBJECTIVE: Assessment of postoperative quality of life in patients over 80 years after cardiac surgery including coronary artery bypass grafting (CABG), aortic valve replacement (AVR) and combined procedures. METHODS: Quality of life of n=136 patients over 80 years at operation (82.3+/-2.1 years), undergoing isolated CABG in 61 patients (45%), isolated AVR in 34 patients (25%) and a combination of CABG and AVR in 41 patients (30%) between January 1999 and December 2003 was reviewed. Preoperatively 66.2% presented in NYHA-class III/IV or CCS-class III/IV. Mean ejection fraction (EF) was 59.5%+/-14.0 (range 25-90%). Quality of life assessment was performed via a Seattle Angina Questionnaire. Follow-up was 100% complete for a total of 890 days (69-1853 days). RESULTS: Five-year survival was 70% for the CABG group, 75% for the AVR group and 65% for the CABG/AVR group. Quality of life was remarkable in all of the three groups after surgery. Overall 97 patients (81%) were not or little disabled in their daily activity. One hundred and twelve patients (93%) were free or considerably less symptomatic. Seventy-eight patients or 65% reported to be very satisfied with their current quality of life and 112 patients (93%) felt very reassured to have continuous full access to medical treatment despite of their advanced age. CONCLUSIONS: A remarkable quality of life and important improvement in the functional status after cardiac surgery in patients over 80 paired with a satisfactory medium-term survival justify early intervention for heart disease in this age group. Therefore, referral practice for patients over 80 years for heart surgery should be handled liberally.

Expression of nitric oxide synthase III in human thyroid follicular cells: evidence for increased expression in hyperthyroidism

Nitric oxide mediates a wide array of cellular functions in many tissues. It is generated by three known isoforms of nitric oxide synthases (NOS). Recently, the endothelial isoform, NOSIII, was shown to be abundantly expressed in the rat thyroid gland and its expression increased in goitrous glands. In this study, we analyzed whether NOSIII is expressed in human thyroid tissue and whether levels of expression vary in different states of thyroid gland function. Semiquantitative RT-PCR was used to assess variations in NOSIII gene expression in seven patients with Graves' disease, one with a TSH-receptor germline mutation and six hypothyroid patients (Hashimoto's thyroiditis). Protein expression and subcellular localization were determined by immunohistochemistry (two normal thyroids, five multinodular goiters, ten hyperthyroid patients and two hypothyroid patients). NOSIII mRNA was detected in all samples: the levels were significantly higher in tissues from hyperthyroid patients compared with euthyroid and hypothyroid patients. NOSIII immunoreactivity was detected in vascular endothelial cells, but was also found in thyroid follicular cells. In patients with Graves' disease, the immunostaining was diffusely enhanced in all follicular cells. A more intense signal was observed in toxic adenomas and in samples obtained from a patient with severe hyperthyroidism due to an activating mutation in the TSH receptor. In multinodular goiters, large follicles displayed a weak signal whereas small proliferative follicles showed intense immunoreactivity near the apical plasma membrane. In hypothyroid patients, NOSIII immunoreactivity was barely detectable. In summary, NOSIII is expressed both in endothelial cells and thyroid follicular cells. The endothelial localization of NOSIII is consistent with a role for nitric oxide in the vascular control of the thyroid. NOSIII expression in thyroid follicular cells and the variations in its immunoreactivity suggest a possible role for nitric oxide in thyrocyte function and/or growth.

The accuracy of FAST in relation to grade of solid organ injuries: a retrospective analysis of 226 trauma patients with liver or splenic lesion

BACKGROUND: This study investigated the role of a negative FAST in the diagnostic and therapeutic algorithm of multiply injured patients with liver or splenic lesions. METHODS: A retrospective analysis of 226 multiply injured patients with liver or splenic lesions treated at Bern University Hospital, Switzerland. RESULTS: FAST failed to detect free fluid or organ lesions in 45 of 226 patients with spleen or liver injuries (sensitivity 80.1%). Overall specificity was 99.5%. The positive and negative predictive values were 99.4% and 83.3%. The overall likelihood ratios for a positive and negative FAST were 160.2 and 0.2. Grade III-V organ lesions were detected more frequently than grade I and II lesions. Without the additional diagnostic accuracy of a CT scan, the mean ISS of the FAST-false-negative patients would be significantly underestimated and 7 previously unsuspected intra-abdominal injuries would have been missed. CONCLUSION: FAST is an expedient tool for the primary assessment of polytraumatized patients to rule out high grade intra-abdominal injuries. However, the low overall diagnostic sensitivity of FAST may lead to underestimated injury patterns and delayed complications may occur. Hence, in hemodynamically stable patients with abdominal trauma, an early CT scan should be considered and one must be aware of the potential shortcomings of a "negative FAST".

Shell brace for stage II posterior tibial tendon insufficiency

BACKGROUND: The nonoperative treatment of posterior tibial tendon insufficiency (PTTI) can lead to unsatisfactory functional results. Short-term results are available but the impact on the evolution of the deformity is not known. To address these problems, a new brace for the flexible Stage II deformity was developed, and midterm followup was obtained. MATERIALS AND METHOD: In a prospective case series, eighteen patients (mean age 64.2 years; range, 31 to 82; four male, 14 female) with flexible Stage II PTTI were fitted with the new custom-molded foot orthosis. At latest followup of a mean of 61.4 (range, 20 to 87) months, functional results were assessed with the AOFAS ankle hindfoot score and clinical or radiographic progression was recorded. RESULTS: The score improved significantly from a mean of 56 points (range, 20 to 64) to a mean of 82 points (range, 64 to 100, p < 0.001). Three patients (3/18, 16%) had a clinical progression to a fixed deformity (Stage III) and a radiographic increase of their deformity. All the other patients were satisfied with the brace's comfort and noted an improvement in their mobility. Complications were seen in three patients (3/18, 16%), and consisted of the development of calluses. CONCLUSION: The "shell brace" is a valuable option for nonoperative treatment of the flexible Stage II PTTI. Hindfoot flexibility was conserved throughout the observation period in all but three patients. Functional outcome and patient acceptance was above average. Problems were few, and closely associated with a progression to a fixed, Stage III deformity.

Epidemiology of pulmonary hypertension: new data from the Swiss registry

BACKGROUND: since 1999 data from pulmonary hypertension (PH) patients from all PH centres in Switzerland were prospectively collected. We analyse the epidemiological aspects of these data. METHODS: PH was defined as a mean pulmonary artery pressure of >25 mm Hg at rest or >30 mm Hg during exercise. Patients with pulmonary arterial hypertension (PAH), PH associated with lung diseases, PH due to chronic thrombotic and/or embolic disease (CTEPH), or PH due to miscellaneous disorders were registered. Data from adult patients included between January 1999 and December 2004 were analysed. RESULTS: 250 patients were registered (age 58 +/- 16 years, 104 (41%) males). 152 patients (61%) had PAH, 73 (29%) had CTEPH and 18 (7%) had PH associated with lung disease. Patients <50 years (32%) were more likely to have PAH than patients >50 years (76% vs. 53%, p <0.005). Twenty-four patients (10%) were lost to followup, 58 patients (26%) died and 150 (66%) survived without transplantation or thrombendarterectomy. Survivors differed from patients who died in the baseline six-minute walking distance (400 m [300-459] vs. 273 m [174-415]), the functional impairment (NYHA class III/IV 86% vs. 98%), mixed venous saturation (63% [57-68] vs. 56% [50-61]) and right atrial pressure (7 mm Hg [4-11] vs. 11 mm Hg [4-18]). DISCUSSION: PH is a disease affecting adults of all ages. The management of these patients in specialised centres guarantees a high quality of care. Analysis of the registry data could be an instrument for quality control and might help identify weak points in assessment and treatment of these patients.

Disagreements in meta-analyses using outcomes measured on continuous or rating scales: observer agreement study

OBJECTIVE: To study the inter-observer variation related to extraction of continuous and numerical rating scale data from trial reports for use in meta-analyses. DESIGN: Observer agreement study. DATA SOURCES: A random sample of 10 Cochrane reviews that presented a result as a standardised mean difference (SMD), the protocols for the reviews and the trial reports (n=45) were retrieved. DATA EXTRACTION: Five experienced methodologists and five PhD students independently extracted data from the trial reports for calculation of the first SMD result in each review. The observers did not have access to the reviews but to the protocols, where the relevant outcome was highlighted. The agreement was analysed at both trial and meta-analysis level, pairing the observers in all possible ways (45 pairs, yielding 2025 pairs of trials and 450 pairs of meta-analyses). Agreement was defined as SMDs that differed less than 0.1 in their point estimates or confidence intervals. RESULTS: The agreement was 53% at trial level and 31% at meta-analysis level. Including all pairs, the median disagreement was SMD=0.22 (interquartile range 0.07-0.61). The experts agreed somewhat more than the PhD students at trial level (61% v 46%), but not at meta-analysis level. Important reasons for disagreement were differences in selection of time points, scales, control groups, and type of calculations; whether to include a trial in the meta-analysis; and data extraction errors made by the observers. In 14 out of the 100 SMDs calculated at the meta-analysis level, individual observers reached different conclusions than the originally published review. CONCLUSIONS: Disagreements were common and often larger than the effect of commonly used treatments. Meta-analyses using SMDs are prone to observer variation and should be interpreted with caution. The reliability of meta-analyses might be improved by having more detailed review protocols, more than one observer, and statistical expertise.

Range of motion after computed tomography-based simulation of intertrochanteric corrective osteotomy in cases of slipped capital femoral epiphysis: comparison of uniplanar flexion osteotomy and multiplanar flexion, valgisation, and rotational osteotomies

BACKGROUND: Various osteotomy techniques have been developed to correct the deformity caused by slipped capital femoral epiphysis (SCFE) and compared by their clinical outcomes. The aim of the presented study was to compare an intertrochanteric uniplanar flexion osteotomy with a multiplanar osteotomy by their ability to improve postoperative range of motion as measured by simulation of computed tomographic data in patients with SCFE. METHODS: We examined 19 patients with moderate or severe SCFE as classified based on slippage angle. A computer program for the simulation of movement and osteotomy developed in our laboratory was used for study execution. According to a 3-dimensional reconstruction of the computed tomographic data, the physiological range was determined by flexion, abduction, and internal rotation. The multiplanar osteotomy was compared with the uniplanar flexion osteotomy. Both intertrochanteric osteotomy techniques were simulated, and the improvements of the movement range were assessed and compared. RESULTS: The mean slipping and thus correction angles measured were 25 degrees (range, 8-46 degrees) inferior and 54 degrees (range, 32-78 degrees) posterior. After the simulation of multiplanar osteotomy, the virtually measured ranges of motion as determined by bone-to-bone contact were 61 degrees for flexion, 57 degrees for abduction, and 66 degrees for internal rotation. The simulation of the uniplanar flexion osteotomy achieved a flexion of 63 degrees, an abduction of 36 degrees, and an internal rotation of 54 degrees. CONCLUSIONS: Apart from abduction, the improvement in the range of motion by a uniplanar flexion osteotomy is comparable with that of the multiplanar osteotomy. However, the improvement in flexion for the simulation of both techniques is not satisfactory with regard to the requirements of normal everyday life, in contrast to abduction and internal rotation. LEVEL OF EVIDENCE: Level III, Retrospective comparative study.

Blunt traumatic thoracic aortic injuries: early or delayed repair-results of an American Association for the Surgery of Trauma prospective study

BACKGROUND: The traditional approach to stable blunt thoracic aortic injuries (TAI) is immediate repair, with delayed repair reserved for patients with major associated injuries. In recent years, there has been a trend toward delayed repair, even in low-risk patients. This study evaluates the current practices in the surgical community regarding the timing of aortic repair and its effects on outcomes. METHODS: This was a prospective, observational multicenter study sponsored by the American Association for the Surgery of Trauma. The study included patients with blunt TAI scheduled for aortic repair by open or endovascular procedure. Patients in extremis and those managed without aortic repair were excluded. The data collection included demographics, initial clinical presentation, Injury Severity Scores, type and site of aortic injury, type of aortic repair (open or endovascular repair), and time from injury to aortic repair. The study patients were divided into an early repair (< or = 24 hours) and delayed repair groups (> 24 hours). The outcome variables included survival, ventilator days, intensive care unit (ICU) and hospital lengths of stay, blood transfusions, and complications. The outcomes in the two groups were compared with multivariate analysis after adjusting for age, Glasgow Coma Scale, hypotension, major associated injuries, and type of aortic repair. A second multivariate analysis compared outcomes between early and delayed repair, in patients with and patients without major associated injuries. RESULTS: There were 178 patients with TAI eligible for inclusion and analysis, 109 (61.2%) of which underwent early repair and 69 (38.8%) delayed repair. The two groups had similar epidemiologic, injury severity, and type of repair characteristics. The adjusted mortality was significantly higher in the early repair group (adjusted OR [95% CI] 7.78 [1.69-35.70], adjusted p value = 0.008). The adjusted complication rate was similar in the two groups. However, delayed repair was associated with significantly longer ICU and hospital lengths of stay. Analysis of the 108 patients without major associated injuries, adjusting for age, Glasgow Coma Scale, hypotension, and type of aortic repair, showed that in early repair there was a trend toward higher mortality rate (adjusted OR 9.08 [0.88-93.78], adjusted p value = 0.064) but a significantly lower complication rate (adjusted OR 0.4 [0.18-0.96], adjusted p value 0.040) and shorter ICU stay (adjusted p value = 0.021) than the delayed repair group. A similar analysis of the 68 patients with major associated injuries, showed a strong trend toward higher mortality in the early repair group (adjusted OR 9.39 [0.93-95.18], adjusted p value = 0.058). The complication rate was similar in both groups (adjusted p value = 0.239). CONCLUSIONS: Delayed repair of stable blunt TAI is associated with improved survival, irrespective of the presence or not of major associated injuries. However, delayed repair is associated with a longer length of ICU stay and in the group of patients with no major associated injuries a significantly higher complication rate.