Quality of life improvement in older patients with heart failure initiated on ivabradine: Results from the UK multi-centre LIVE:LIFE prospective cohort study.

AIMS: LIVE:LIFE is a multi-centre, open-label, prospective observational cohort study assessing health-related quality of life (HRQoL) in older patients with chronic heart failure (CHF) following initiation of ivabradine. The primary endpoint is change in Minnesota Living with Heart Failure Questionnaire (MLWHFQ) total score after 6months. METHODS AND RESULTS: Consenting patients aged ≥70years with CHF, in whom ivabradine was initiated within its licensed indication, were enrolled. Demographic, clinical and HRQoL (MLWHFQ, SF-12) data were collected at baseline (V1), 2 (V2) and 6months (V3). Over 14months, 240 patients were recruited from 44 UK centres. Ninety-nine (41%) were female and 28% aged ≥80years. Aetiology was ischaemic in 152 (63%) and 59% had been diagnosed with CHF for ≤2yrs. 52% of patients were New York Heart Association (NYHA) Class III and 57% had left ventricular ejection fraction <35%. 57% received beta-blockers. Patients had multiple comorbidities (144 (60%) hypertension, 105 (44%) asthma/COPD, 80 (33%) diabetes) and were prescribed a mean of 9±3 daily medications. Resting heart rate was 83bpm at baseline and fell 13bpm by V3. In patients completing both visits (n=187), comparing V3 to baseline: MLWHFQ total score improved by 9 points (p<0.0001, 95% CI: 7-12); 30% of patients improved ≥1 NYHA class and global assessment improved from patient (59%) and physician (60%) perspectives. 88% of patients completing V3 were still taking ivabradine. CONCLUSIONS: These contemporary prospective UK data demonstrate improvements in HRQoL and functional status with ivabradine therapy in typical older CHF patients. Despite comorbidities and polypharmacy, ivabradine was well tolerated.

New-onset temporal lobe epilepsy in children: lesion on MRI predicts poor seizure outcome.

OBJECTIVE: To determine factors predictive of long-term seizure outcome in children with new-onset temporal lobe epilepsy (TLE). METHODS: A community-based cohort of 77 children with new-onset TLE, including 14 with possible TLE, were followed prospectively with formal review 7 and 14 years following seizure onset. Diagnoses were re-evaluated at each review, and changed when new clinical, EEG, or imaging data were compelling. RESULTS: Sixty-four patients sustained the diagnosis of TLE over time; two were lost to follow-up. Age at follow-up was 12 to 29 years (median 20 years). Median follow-up was 13.7 years, 95% being followed for greater than 10 years. Nineteen patients were seizure free (SF) and off treatment, having not had seizures for 5 to 15 years. Duration of active TLE in the SF group was 1 to 8 years, the children being treated with 0 to 3 antiepileptic drugs (AEDs). Forty-three patients were not seizure free (NSF) and had ongoing seizures or had undergone epilepsy surgery. These children were treated with 1 to 10 AEDs. Fifteen NSF patients experienced 22 nonterminal seizure remissions of 1 to 7 years duration. Seventeen children had a significant antecedent to TLE. Lesions were identified on neuroimaging in 28 and included hippocampal sclerosis (HS) in 10, tumor in 8, and dysplasia in 7. All children with lesions on MRI were NSF (p < 0.001). Focal slowing on EEG was also associated with persistent seizures (p = 0.05), although this was correlated with a lesion on MRI. Infantile onset of epilepsy, family history of seizures, initial seizure frequency, antecedents, and early seizure remissions were not predictive of seizure outcome. CONCLUSION: Seizures spontaneously remit in approximately one third of children with new-onset TLE. A lesion on MRI predicts intractable seizures in TLE and the potential need for epilepsy surgery.

The C/EBP bZIP domain can mediate lipopolysaccharide induction of the proinflammatory cytokines interleukin-6 and monocyte chemoattractant protein-1.

C/EBPalpha, beta, and delta are all expressed by bone marrow-derived macrophages. Ectopic expression of any of these transcription factors is sufficient to confer lipopolysaccharide (LPS)-inducible expression of interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) to a B lymphoblast cell line, which normally lacks C/EBP factors and does not display LPS induction of proinflammatory cytokines. Thus, the activities of C/EBPalpha, beta, and delta are redundant in regard to expression of IL-6 and MCP-1. Surprisingly, the bZIP region of C/EBPbeta, which lacks any previously described activation domains, can also confer LPS-inducible expression of IL-6 and MCP-1 in stable transfectants. Transient transfections reveal that the bZIP regions of C/EBPbeta, C/EBPdelta, and, to a lesser extent, C/EBPalpha can activate the IL-6 promoter and augment its induction by LPS. Furthermore, the transdominant inhibitor, LIP, can activate expression from the IL-6 promoter. The ability of the C/EBPbeta bZIP region to activate the IL-6 promoter in transient transfections is completely dependent upon an intact NF-kappaB-binding site, supporting a model where the bZIP protein primarily functions to augment the activity of NF-kappaB. Replacement of the leucine zipper of C/EBPbeta with that of GCN4 yields a chimeric protein that can dimerize and specifically bind to a C/EBP consensus sequence, but shows a markedly reduced ability to activate IL-6 and MCP-1 expression. These results implicate the leucine zipper domain in some function other than dimerization with known C/EBP family members, and suggest that C/EBP redundancy in regulating cytokine expression may result from their highly related bZIP regions.

Hemoglobin and iron-evoked oxidative stress in the brain: protection by bile pigments, manganese and S-nitrosoglutathione.

In the present in vitro and in vivo study we investigated the pro-oxidant effects of hemoglobin, as well as the antioxidant effects of its metabolites, in the brain. Incubation of rat brain homogenates with hemoglobin (0-10 microM) but not hemin induced lipid peroxidation up to 24 h (EC50 = 1.2 microM). Hemoglobin's effects were similar to ferrous ion (EC50 = 1.7 microM) and were blocked by the chelating agent deferoxamine (IC50 0.5 microM) and a nitric oxide-releasing compound S-nitrosoglutathione (IC50 = 40 microM). However, metabolites of hemoglobin - biliverdin and bilirubin - inhibited brain lipid peroxidation induced by cell disruption and hemoglobin (biliverdin IC50 = 12-30 and bilirubin IC50 = 75-170 microM). Biliverdin's antioxidative effects in spontaneous and iron-evoked lipid peroxidation were further augmented by manganese (2 microM) since manganese is an antioxidative transition metal and conjugates with bile pigments. Intrastriatal infusion of hemoglobin (0-24 nmol) produced slight, but significant 20-22% decreases in striatal dopamine levels. Whereas, intrastriatal infusion of ferrous citrate (0-24 nmol) dose-dependently induced a greater 66% depletion of striatal dopamine which was preceded by an acute increase of lipid peroxidation. In conclusion, contrary to the in vitro results hemoglobin is far less neurotoxic than ferrous ions in the brain. It is speculated that hemoglobin may be partially detoxified by heme oxygenase and biliverdin reductase to its antioxidative metabolites in the brain. However, in head trauma and stroke, massive bleeding could significantly produce iron-mediated oxidative stress and neurodegeneration which could be minimized by endogenous antioxidants such as biliverdin, bilirubin, manganese and S-nitrosoglutathione.

Stressors associated with coronary bypass surgery.

The purpose of this investigation was to attempt to replicate the findings of a study by Carr and Powers (1986) which examined differences between patient and nurse perceptions of the severity of stressfulness associated with hospital- and illness-related stressors. The samples consisted of 24 patients who experienced coronary bypass surgery and 24 nurses who cared for them during their hospitalization. All participants responded to the Stressor Scale developed by Carr and Powers (1986) specifically for patients undergoing coronary bypass surgery. Findings indicated that the major findings of the original study were replicated. Three one-way analysis of variance statistical procedures indicated that cardiothoracic nurses rated all stressors and hospital-related and illness-related stressors as statistically significantly more stressful for coronary bypass patients than did the patients themselves.

Clinical safety, tolerability, and pharmacokinetics of murine monoclonal antibody to human tumor necrosis factor-alpha.

The safety, tolerability, and pharmacokinetic profile of murine monoclonal antibody to human tumor necrosis factor-alpha (TNF alpha MAb) were evaluated in 20 uninfected patients at risk of sepsis and 16 septic patients. TNF alpha MAb was well tolerated in all patients, with no immediate or delayed signs of allergic reaction. During the 28-day evaluation, side effects included thrombocytosis (11), hepatic enzyme elevations (8), cardiac arrhythmias (3), and deaths (5). Each was attributed to the patient's severe underlying disease and not to TNF alpha MAb; however, a relationship between TNF alpha MAb and these events cannot be ruled out. The half-life was 52 h for a single infusion of TNF alpha MAb. Human antibody against TNF alpha MAb was observed in 13 (76.5%) of 17 phase IA patients and 10 of 10 phase IB patients and anti-idiotype antibodies in 11 (91.7%) of 12 phase IA patients and 2 (33.3%) of 6 phase IB patients. TNF alpha MAb should be evaluated as adjunctive therapy for patients with sepsis.

Sleep patterns and stress in patients having coronary bypass.

This study examined the self-reported sleep patterns of adult patients undergoing coronary artery bypass graft (CABG) surgery and the relationship between their perceived illness-related stress and sleep disturbances. Twenty-four patients completed data at all three collection points: preadmission, and the third and sixth postoperative mornings. Patients responded to the Verran/Snyder-Halpern Sleep Scale and the Carr and Powers Stressor Scale for patients having CABG. By use of a within-subject, one-factor, repeated measures analysis of variance, statistically significant differences were found in each of the three sleep dimensions measured over time (disturbance, effectiveness, and supplementation). With the Pearson correlation, the hypothesis that sleep disturbances in patients having open-heart surgery are related to psychologic stress associated with illness was not supported. Additional analyses indicated that hospital and illness-related stress, duration of cardiopulmonary bypass, anesthesia time, and sleep medication were related to patients' sleep disturbance, effectiveness, or supplementation in different ways and at different times during the study periods.

Changes in reported drug prevalence among New South Wales secondary school students, 1983 to 1989.

Three drug use surveys employing a standardised questionnaire format and sampling procedure were conducted on samples of New South Wales school students in 1983, 1986 and 1989. Alcohol and tobacco were the most frequently used substances across the surveys, with rates of use of illicit substances being considerably lower. Declines in the prevalence of alcohol, tobacco and stimulant use were found between 1983 and 1986 and between 1986 and 1989 for both males and females. Rates of use of inhalants, sedatives, hallucinogens and narcotics declined between 1983 and 1986, but remained unchanged between the 1986 and 1989 samples. Cannabis use declined significantly among females between 1983 and 1989, but not among males. Possible reasons for the general decline in drug use over the six-year period are discussed.

Prevalences and perceptions of licit and illicit drugs among New South Wales secondary school students, 1989.

This paper presents findings on drug prevalences for licit and illicit drugs among New South Wales secondary school students (n = 3753) in late 1989. It also considers the accuracy of students' perceptions of the drug causing the most and fewest drug-related deaths. Data were analysed by age and gender, using logistic regression for the prevalence data. Findings indicate that licit drugs (tobacco, alcohol and analgesics) were the most frequently and widely used. Rates for illicit drugs were low, although there was some degree of experimental use of cannabis which increased amongst older males. Perceptions were found to be inaccurate in emphasising the dangers of the illicit drug heroin over those of the licit drugs tobacco and alcohol. Reasons for these findings are discussed, and more in-depth research recommended into the relationship between drug prevalences and perceptions for different age groups, and its relevance for planning drug prevention initiatives.

The role of tumor necrosis factor in sepsis.

There is an increasing incidence of sepsis among hospitalized patients. Also, high mortality associated with sepsis and septic shock persists despite appropriate antibiotic therapy. Recent investigations have demonstrated that bacterial antigens stimulate a cascade of cellular mediators or cytokine release. In sepsis and septic shock the response of these cytokines often exceeds natural downregulation and leads to multisystem organ failure and even death in an unacceptably high number of patients. Many investigative studies have shown that tumor necrosis factor (TNF) is the prime mediator of the inflammatory response seen in sepsis and septic shock. Sepsis management in the future will include immune modulating therapy directed against the deleterious effects of cytokines, specifically TNF. This article reviews the current problem of sepsis and the evidence to support the role of TNF in sepsis. also, recent studies employing monoclonal antibodies against TNF as well as considerations for future studies are discussed.

Cellular and viral ligands that interact with the EGF receptor.

The growth regulatory functions of a family of structurally related polypeptides are mediated through the membrane-bound epidermal growth factor receptor molecule. This ligand family includes epidermal growth factor, transforming growth factor-alpha, amphiregulin, and polypeptides encoded by several poxviruses. The structural and functional properties that are characteristic of the ligand family provide a basis for possible evolutionary relationships among the various ligands.

Antibodies to common leukocyte antigen p220 influence human T cell proliferation by modifying IL 2 receptor expression.

The p220 antigen is found on the high m.w. form of the T200 common leukocyte antigen family. Although T200 monoclonal antibodies (MAb) react with all hematopoietic cells, p220 MAb react only with B cells, NK cells, about 50% of CD4+ T helper cells, and about 90% of CD8+ T suppressor cells. The p220 antigen appears to play an important role in T cell activation, because anti-p220 MAb at doses as low as 5 ng/ml accelerate the proliferation kinetics of PHA-stimulated T cells and augment anti-CD3-driven proliferation when IL 2 is in excess. Fab fragments have no effect on PHA-stimulated cells but partially block proliferation in response to anti-CD3. Our data suggest that p220 is functionally related to expression of the IL 2 receptor. Anti-p220 MAb cause an increase in the number of T cells that express the IL 2 receptor early after activation. In addition, T cells begin to turn off expression of p220 after activation, and two-color immunofluorescence shows that by day 3 after activation the cells expressing the most IL 2 receptor have the least p220. The loss of p220 on T cells may reflect a post-thymic differentiation process related to cell activation. Our data are consistent with a model where the p220- T cells in peripheral blood are a more activated population of T cells that have lost p220 and its ability to regulate their IL 2 receptor expression.

Influence of crystallization habit of minerals on in vitro cytotoxicity.

Four samples of cummingtonite-grunerite series in various crystallization habits were tested in vitro. The cytotoxicity to Chinese hamster ovary cells and hemolysis to sheep erythrocytes were inversely proportional to the structural faults and surface defects of the minerals. At a comparable surface area, asbestiform grunerite (UICC amosite), semi-asbestiform cummingtonite, acicular cummingtonite, and acicular grunerite were found to be cytotoxic and hemolytic in a decreasing order. The influence of particle size on hemolysis and cytotoxicity was observed with acicular grunerite. Although samples of relatively large particle size were found to be inert, samples of smaller particle size were cytotoxic as well as hemolytic. No apparent relationship between surface charge and hemolysis as well as cytotoxicity was observed.