Patterns of failure and outcome in patients with carcinoma of the anal margin.

BACKGROUND: To evaluate the outcome of patients with carcinoma of anal margin in terms of recurrence, survival, and radiation toxicity. METHODS: A series of 45 consecutive patients, with anal margin carcinoma treated between 1983 and 2006 with curative intent at two institutions, was retrospectively analyzed. A surgical excision (close or positive surgical margin in 22 out of 29 patients) was realized before radiotherapy (RT). RT consisted of definitive external beam RT (EBRT) in 36 patients, brachytherapy (BT) alone in two patients, and both BT and EBRT in seven patients. The median total radiation dose was 59.4 Gy (range, 30-74 Gy). RESULTS: The 5-year locoregional control (LRC) rate was 78% [95% confidence interval (CI), 64-93%]. The 5-year disease-specific survival (DSS) and overall survival (OS) rates were respectively 86% (95% CI, 72-99%) and 55% (95% CI, 44-66%). The overall anal conservation rate was 80% for the whole series. There was no significant association between local recurrence and patient age, histological grade, tumor size, T stage, overall treatment time, RT dose, or chemotherapy. Long-term side effects were observed in 15 patients (33%). Only three patients developed grade 3-4 late toxicity (CTCAE/NCI v3.0). Significant relationship was found between dose, and complication rate (48% for dose >or=59.4 Gy versus 8% for dose < 59.4 Gy; P = 0.03). CONCLUSIONS: We conclude that definitive RT and/or BT yield a good local control and disease-specific survival comparable with published data. This study suggests that radiation dose over 59.4 Gy seems to increase treatment-related morbidity.

Goodpasture's disease presenting with acute renal failure

A 15-year-old boy was admitted for vomiting, diarrhea, fatigue, crampy abdominal pain and oliguria. A renal failure was diagnosed (creatinine 2523 μmol/, urea 53,1 mmol/l) with severe aregenerative anemia (80 g/l), metabolic acidosis, hyperkalemia, elevated inflammatory markers and normal platelet count. A nephrotic proteinuria was noticed (350 g/mol). Patient's creatinine was normal 4 months before. The diagnosis of rapidly progressive glomerulonephritis was suspected. C3 and C4 were normal, ANA and ANCA were negative; anti-glomerular basement membrane antibody (anti-GBM) was positive (1/320) which lead to the diagnosis of Goodpasture's disease. Chest X-ray showed bilateral hilar infiltration and CT-scan revealed multiple alveolar haemorrhages, confirmed by broncho-alveolar lavage. Renal ultrasound showed swollen and hyperechogenous kidneys with loss of corticomedullary differentiation. Renal biopsy revealed a global extracapillary necrotising glomerulonephritis, with IgG lining the membrane at immunofluorescence. The patient was treated with continuous venovenous hemodia- filtration, plasmapheresis and immunosuppressive therapy (cyclophosphamid and corticoids) which lead to normalisation of anti-GBM level and favourable respiratory evolution with no sequelae. The renal evolution was unfavourable and the patient developed end stage renal disease and was treated with haemodialysis. Goodpasture's disease is an autoimmune process in which anti-GBM are produced against collagen IV present in the kidneys and pulmonary alveolae, resulting in acute or rapidly progressive glomerulonephritis and altering the pulmonary alveolae. It is a rare disease concerning mostly infants and young adults. Clinical presentation consists in an acute renal failure with proteinuria. Pulmonary symptoms (60-70% of the total cases) are dyspnea, cough, and haemoptysis. Diagnosis is made with the dosage of immunological anti-GBM and with renal biopsy. Factors of poor prognosis are initial oliguria, alteration of >50% of the glomerulus, very high creatinine or need of dialysis. Anti-GBM dosage is used for follow up. Patients are treated with immunosuppressive therapy for 6 to 9 months and plasmapheresis. Few recurrences are seen. Goodpasture's disease should be evoqued whenever a young patient is seen with glomerulonephritis, especially if pulmonary abnormalities are present. The disease requires an aggressive treatment in order to prevent respiratory and kidney failure.

Postmortem biochemical investigations in hypothermia fatalities.

Despite the progress made during the past several decades in forensic pathology, the possibilities for the postmortem diagnosis of hypothermia remains relatively limited. Aside from histology and immunohistochemistry, numerous authors have investigated the postmortem biochemistry of hypothermia fatalities. Several biochemical markers (e.g., glucose, electrolytes, hormones, ketone bodies, and neurotransmitters) and various biological samples (e.g., blood, urine, heart, liver, skeletal muscle as well as pericardial and cerebrospinal fluids) have been proposed as potentially useful markers to improve the insufficient diagnostic efficacy of macroscopic and microscopic findings. The aim of this article is to review the medicolegal literature covering the postmortem biochemical investigations that are associated with hypothermia cases as well as report our own research results on this topic where possible.

Feasibility of non-invasive pressure support ventilation in infants with respiratory failure after extubation: a pilot study.

OBJECTIVE: To evaluate the feasibility and effects of non-invasive pressure support ventilation (NIV) on the breathing pattern in infants developing respiratory failure after extubation. DESIGN: Prospective pilot clinical study; each patient served as their own control. SETTING: A nine-bed paediatric intensive care unit of a tertiary university hospital. PATIENTS: Six patients (median age 5 months, range 0.5-7 months; median weight 4.2 kg, range 3.8-5.1 kg) who developed respiratory failure after extubation. INTERVENTIONS: After a period of spontaneous breathing (SB), children who developed respiratory failure were treated with NIV. MEASUREMENTS AND RESULTS: Measurements included clinical dyspnoea score (DS), blood gases and oesophageal pressure recordings, which were analysed for respiratory rate (RR), oesophageal inspiratory pressure swing (dPes) and oesophageal pressure-time product (PTPes). All data were collected during both periods (SB and NIV). When comparing NIV with SB, DS was reduced by 44% (P < 0.001), RR by 32% (P < 0.001), dPes by 45% (P < 0.01) and PTPes by 57% (P < 0.001). A non-significant trend for decrease in PaCO(2) was observed. CONCLUSION: In these infants, non-invasive pressure support ventilation with turbine flow generator induced a reduction of breathing frequency, dPes and PTPes, indicating reduced load of the inspiratory muscles. NIV can be used with some benefits in infants with respiratory failure after extubation.

Multiplex PCR of sonication fluid accurately differentiates between prosthetic joint infection and aseptic failure.

OBJECTIVE: Cultures have limited sensitivity in the diagnosis of prosthetic joint infection (PJI), especially in low-grade infections. We assessed the value of multiplex PCR in differentiating PJI from aseptic failure (AF). METHODS: Included were patients in whom the joint prosthesis was removed and submitted for sonication. The resulting sonication fluid was cultured and investigated by multiplex PCR, and compared with periprosthetic tissue culture. RESULTS: Among 86 explanted prostheses (56 knee, 25 hip, 3 elbow and 2 shoulder prostheses), AF was diagnosed in 62 cases (72%) and PJI in 24 cases (28%). PJI was more common detected by multiplex PCR (n=23, 96%) than by periprosthetic tissue (n=17, 71%, p=0.031) or sonication fluid culture (n=16, 67%, p=0.016). Among 12 patients with PJI who previously received antibiotics, periprosthetic tissue cultures were positive in 8 cases (67%), sonication fluid cultures in 6 cases (50%) and multiplex PCR in 11 cases (92%). In AF cases, periprosthetic tissue grew organisms in 11% and sonication fluid in 10%, whereas multiplex PCR detected no organisms. CONCLUSIONS: Multiplex PCR of sonication fluid demonstrated high sensitivity (96%) and specificity (100%) for diagnosing PJI, providing good discriminative power towards AF, especially in patients previously receiving antibiotics.

Serum-free aggregate cultures of rat CNS glial cells: biochemical, immunocytochemical and morphological characterization.

Aggregate cultures of mixed glial cells, as well as of enriched astrocytes and oligodendrocytes were prepared, and maintained in serum-free medium for up to 25 days. Biochemical measurements of both neuron-specific and glia-specific enzyme activities showed that these three types of aggregate cultures were virtually devoid of neurons. Astrocyte-enriched cultures were greater than 95% pure, with oligodendrocytes as the only apparent contaminant, whereas oligodendrocyte-enriched cultures still contained a considerable proportion of astrocytes. In all these neuron-free aggregate cultures both astrocytes and oligodendrocytes attained a high degree of maturation. These findings were confirmed by morphological examinations, and by immunofluorescence studies. Furthermore, ultrastructural as well as immunocytochemical investigations using antibodies to myelin basic protein revealed that all three types of glial cell aggregate cultures contained myelin membranes, indicating that the presence of axons is not a prerequisite for the formation of myelin.

Possible synergism of physical exercise and ghrelin-agonists in patients with cachexia associated with chronic heart failure.

The occurrence of cachexia of multifactorial etiology in chronic heart failure (CHF) is a common and underestimated condition that usually leads to poor outcome and low survival rates, with high direct and indirect costs for the Health Care System. Recently, a consensus definition on cachexia has been reached, leading to a growing interest by the scientific community in this condition, which characterizes the last phase of many chronic diseases (i.e., cancer, acquired immunodeficiency syndrome). The etiology of cachexia is multifactorial and the underlying pathophysiological mechanisms are essentially the following: anorexia and malnourishment; immune overactivity and systemic inflammation; and endocrine disorders (anabolic/catabolic imbalance and resistance to growth hormone). In this paper, we review the main pathophysiological mechanisms underlying CHF cachexia, focusing also on the broad spectrum of actions of ghrelin and ghrelin agonists, and their possible use in combination with physical exercise to contrast CHF cachexia.

Interleukin-1 receptor antagonist gene (IL-1RN) polymorphism is a predictive factor of clinical pregnancy after IVF.

BACKGROUND: Only 25% of IVF transfer cycles lead to a clinical pregnancy, calling for continued technical progress but also more in depth analysis of patients' individual characteristics. The interleukin-1 (IL-1) system and matrix metalloproteinases (MMPs) are strongly implicated in embryo implantation. The genes coding for IL-1Ra (gene symbol IL-1RN), IL-1beta, MMP2 and MMP9 bear functional polymorphisms. We analysed the maternal genetic profile at these polymorphic sites in IVF patients, to determine possible correlations with IVF outcome. METHODS: One hundred and sixty women undergoing an IVF cycle were enrolled and a buccal smear was obtained. The presence of IL-1RN variable number of tandem repeats and IL-1B + 3953, MMP2-1306 and MMP9-1562 single nucleotide substitutions were determined. Patients were divided into pregnancy failures (119), biochemical pregnancies (8) and clinical pregnancies (33). RESULTS: There was a 40% decrease in IL-1RN*2 allele frequency (P = 0.024) and a 45% decrease in IL-1RN*2 carrier status in the clinical pregnancy group as compared to the pregnancy failure group (P = 0.017). This decrease was still statistically significant after a multivariate logistic regression analysis. The likelihood of a clinical pregnancy was decreased accordingly in IL-1RN*2 carriers: odds ratio = 0.349, 95% confidence interval = 0.2-0.8, P = 0.017. The IL-1B, MMP2 and MMP9 polymorphisms showed no correlation with IVF outcome. CONCLUSIONS: IL-1RN*2 allele carriage is associated with a poor prognosis of achieving a pregnancy after IVF.

Bolus injections of synthetic atrial natriuretic peptide in patients with chronic renal failure or nephrotic syndrome.

The diuretic and natriuretic responses to exogenous synthetic atrial natriuretic peptide (ANP) were evaluated in patients with chronic renal failure (CRF) or nephrotic syndrome (NS). Patients were studied after an oral water load (8 ml/kg in CRF and 20 ml/kg in NS patients). A short intravenous bolus of either a placebo or ANP was administered when urine output was stable. In each group of patients, three doses of ANP were injected at 24 h intervals, i.e., 1.0, 1.5, and 2.0 micrograms/kg in the CRF and 1.0, 1.5, and 3.0 micrograms/kg in the NS group. Blood pressure and heart rate were monitored throughout the study and urinary volume and electrolyte excretion were measured every 20 min up to 3 h after the bolus. An acute and transient fall in blood pressure was observed immediately after the ANP injection. It was more pronounced in CRF than in NS patients. In CRF patients, ANP caused only a slight increase in urinary volume (13.5-44% over baseline) but a significant increase in urinary sodium excretion (45-114% over baseline). In NS patients, significant increases in both urine volume (60-105%) and sodium excretion (149-248%) were also found. In these latter patients, the renal response to ANP appeared to be better preserved. The hemodynamic and renal changes induced by ANP occurred mainly during the first 20 min following the ANP administration, when the peak plasma ANP levels were obtained. However, no clear dose-response effect could be evidenced in either group with the three doses of ANP chosen in this study.

Robust accelerated failure time regression

Robust estimators for accelerated failure time models with asymmetric (or symmetric) error distribution and censored observations are proposed. It is assumed that the error model belongs to a log-location-scale family of distributions and that the mean response is the parameter of interest. Since scale is a main component of mean, scale is not treated as a nuisance parameter. A three steps procedure is proposed. In the first step, an initial high breakdown point S estimate is computed. In the second step, observations that are unlikely under the estimated model are rejected or down weighted. Finally, a weighted maximum likelihood estimate is computed. To define the estimates, functions of censored residuals are replaced by their estimated conditional expectation given that the response is larger than the observed censored value. The rejection rule in the second step is based on an adaptive cut-off that, asymptotically, does not reject any observation when the data are generat ed according to the model. Therefore, the final estimate attains full efficiency at the model, with respect to the maximum likelihood estimate, while maintaining the breakdown point of the initial estimator. Asymptotic results are provided. The new procedure is evaluated with the help of Monte Carlo simulations. Two examples with real data are discussed.

Biochemical characterization of a myelin fraction isolated from rat brain aggregating cell cultures.

Subcellular fractions isolated from rat brain aggregating cell cultures were studied by electron microscopy and showed the presence of typical myelin membranes. The chemical composition of purified culture myelin was similar to the fraction isolated from rat brain in terms of CNP specific activity, protein and lipid composition. The ratio of small to large components of myelin basic protein was comparable in culture and in vivo. These two proteins incorporated radioactive phosphorus. The major myelin glycoprotein was present and during development in culture its apparent molecular weight decreased although it never reached the position observed in myelin isolated from adult rats. In culture, the yield of myelin did not increase substantially between 33 and 50 days and was comparable to that of 15-day-old rat brain. The ratio basic protein to proteolipid protein resembled immature myelin and the cerebroside content was very low. A 'floating fraction' was isolated from the cultures and contained some myelin but mostly single membranes. Although these results indicate that myelin maturation is delayed in vitro this culture system provides substantial amounts of purified myelin to allow a complete biochemical analysis and metabolic studies during development.

Subclinical thyroid dysfunction, cardiac function, and the risk of heart failure. The Cardiovascular Health study.

OBJECTIVES: The goal of this study was to determine whether subclinical thyroid dysfunction was associated with incident heart failure (HF) and echocardiogram abnormalities. BACKGROUND: Subclinical hypothyroidism and hyperthyroidism have been associated with cardiac dysfunction. However, long-term data on the risk of HF are limited. METHODS: We studied 3,044 adults>or=65 years of age who initially were free of HF in the Cardiovascular Health Study. We compared adjudicated HF events over a mean 12-year follow-up and changes in cardiac function over the course of 5 years among euthyroid participants, those with subclinical hypothyroidism (subdivided by thyroid-stimulating hormone [TSH] levels: 4.5 to 9.9, >or=10.0 mU/l), and those with subclinical hyperthyroidism. RESULTS: Over the course of 12 years, 736 participants developed HF events. Participants with TSH>or=10.0 mU/l had a greater incidence of HF compared with euthyroid participants (41.7 vs. 22.9 per 1,000 person years, p=0.01; adjusted hazard ratio: 1.88; 95% confidence interval: 1.05 to 3.34). Baseline peak E velocity, which is an echocardiographic measurement of diastolic function associated with incident HF in the CHS cohort, was greater in those patients with TSH>or=10.0 mU/l compared with euthyroid participants (0.80 m/s vs. 0.72 m/s, p=0.002). Over the course of 5 years, left ventricular mass increased among those with TSH>or=10.0 mU/l, but other echocardiographic measurements were unchanged. Those patients with TSH 4.5 to 9.9 mU/l or with subclinical hyperthyroidism had no increase in risk of HF. CONCLUSIONS: Compared with euthyroid older adults, those adults with TSH>or=10.0 mU/l have a moderately increased risk of HF and alterations in cardiac function but not older adults with TSH<10.0 mU/l. Clinical trials should assess whether the risk of HF might be ameliorated by thyroxine replacement in individuals with TSH>or=10.0 mU/l.

Biochemical properties of RuvBD113N: a mutation in helicase motif II of the RuvB hexamer affects DNA binding and ATPase activities.

Many DNA helicases utilise the energy derived from nucleoside triphosphate hydrolysis to fuel their actions as molecular motors in a variety of biological processes. In association with RuvA, the E. coli RuvB protein (a hexameric ring helicase), promotes the branch migration of Holliday junctions during genetic recombination and DNA repair. To analyse the relationship between ATP-dependent DNA helicase activity and branch migration, a site-directed mutation was introduced into the helicase II motif of RuvB. Over-expression of RuvBD113N in wild-type E. coli resulted in a dominant negative UVs phenotype. The biochemical properties of RuvBD113N were examined and compared with wild-type RuvB in vitro. The single amino acid substitution resulted in major alterations to the biochemical activities of RuvB, such that RuvBD113N was defective in DNA binding and ATP hydrolysis, while retaining the ability to form hexameric rings and interact with RuvA. RuvBD113N formed heterohexamers with wild-type RuvB, and could inhibit RuvB function by affecting its ability to bind DNA. However, heterohexamers exhibited an ability to promote branch migration in vitro indicating that not all subunits of the ring need to be catalytically competent.

Frailty and risk for heart failure in older adults: The health, aging, and body composition study.

OBJECTIVE: The aim of this study was to assess the association between frailty and risk for heart failure (HF) in older adults. BACKGROUND: Frailty is common in the elderly and is associated with adverse health outcomes. Impact of frailty on HF risk is not known. METHODS: We assessed the association between frailty, using the Health ABC Short Physical Performance Battery (HABC Battery) and the Gill index, and incident HF in 2825 participants aged 70 to 79 years. RESULTS: Mean age of participants was 74 ± 3 years; 48% were men and 59% were white. During a median follow up of 11.4 (7.1-11.7) years, 466 participants developed HF. Compared to non-frail participants, moderate (HR 1.36, 95% CI 1.08-1.71) and severe frailty (HR 1.88, 95% CI 1.02-3.47) by Gill index was associated with a higher risk for HF. HABC Battery score was linearly associated with HF risk after adjusting for the Health ABC HF Model (HR 1.24, 95% CI 1.13-1.36 per SD decrease in score) and remained significant when controlled for death as a competing risk (HR 1.30; 95% CI 1.00-1.55). Results were comparable across age, sex, and race, and in sub-groups based on diabetes mellitus or cardiovascular disease at baseline. Addition of HABC Battery scores to the Health ABC HF Risk Model improved discrimination (change in C-index, 0.014; 95% CI 0.018-0.010) and appropriately reclassified 13.4% (net-reclassification-improvement 0.073, 95% CI 0.021-0.125; P = .006) of participants (8.3% who developed HF and 5.1% who did not). CONCLUSIONS: Frailty is independently associated with risk of HF in older adults.