Early data on long-term efficacy and safety of inotersen in patients with hereditary transthyretin amyloidosis: a 2-year update from the open-label extension of the NEURO-TTR trial.

BACKGROUND AND PURPOSE: Hereditary transthyretin (hATTR) amyloidosis causes progressive polyneuropathy resulting from transthyretin (TTR) amyloid deposition throughout the body, including the peripheral nerves. The efficacy and safety of inotersen, an antisense oligonucleotide inhibitor of TTR protein production, were demonstrated in the pivotal NEURO-TTR study in patients with hATTR polyneuropathy. Here, the long-term efficacy and safety of inotersen are assessed in an ongoing open-label extension (OLE) study. METHODS: Patients who completed NEURO-TTR were eligible to enroll in the OLE (NCT02175004). Efficacy assessments included the modified Neuropathy Impairment Score plus seven neurophysiological tests composite score (mNIS + 7), the Norfolk Quality of Life - Diabetic Neuropathy (Norfolk QOL-DN) questionnaire total score and the Short-Form 36 Health Survey (SF-36) Physical Component Summary (PCS) score. Safety and tolerability were also assessed. RESULTS: Overall, 97% (135/139) of patients who completed NEURO-TTR enrolled in the OLE. Patients who received inotersen for 39 cumulative months in NEURO-TTR and the OLE continued to show benefit; patients who switched from placebo to inotersen in the OLE demonstrated improvement or stabilization of neurological disease progression by mNIS + 7, Norfolk QOL-DN and SF-36 PCS. No new safety concerns were identified. There was no evidence of increased risk for grade 4 thrombocytopenia or severe renal events with increased duration of inotersen exposure. CONCLUSION: Inotersen slowed disease progression and reduced deterioration of quality of life in patients with hATTR polyneuropathy. Early treatment with inotersen resulted in greater long-term disease stabilization than delayed initiation. Routine platelet and renal safety monitoring were effective; no new safety signals were observed.

Do fathead minnows, Pimephales promelas Rafinesque, alter their club cell investment in responses to variable risk of infection from Saprolegnia?

Fish in the Superorder Ostariophysi possess large epidermal club cells that release chemical cues warning nearby conspecifics of danger. Despite the long-held assumption that such club cells evolved under the selective force of predation, recent studies demonstrated that predation has no effect on club cell investment. Rather, club cells have an immune function and cell production may be stimulated by skin-penetrating pathogens and parasites. The current work investigates whether fathead minnows, Pimephales promelas, alter their club cell characteristics based on variation in infection risk. In a 2 × 3 design, we exposed minnows to infective cysts of two oomycete species (Saprolegnia ferax and S. parasitica) at three different concentrations (2, 20 or 200 cysts L(-1)). Club cell characteristics (number and size) were quantified 12 days after exposure. Saprolegnia parasitica is thought to be more pathogenic than S. ferax, hence we predicted greater club cell investment and a larger turnover rate of cells by minnows exposed to S. parasitica than S. ferax. We also predicted that minnows exposed to higher numbers of cysts should invest more in club cells and have a higher turnover rate of cells. We found no difference in club cell density or size between fish exposed to the two Saprolegnia species; however, fish exposed to high concentrations of pathogens had smaller club cells than those exposed to low concentrations, indicating a higher rate of turnover of cells in the epidermis.

Detection of herpes viruses in respiratory secretions of patients undergoing artificial ventilation.

The significance of detection of herpes viruses in respiratory secretions of critically ill patients is controversial. The study aim was to determine the prevalence of herpes virus DNA in respiratory secretions in patients on artificial ventilation. Respiratory secretions taken thrice weekly from 174 patients in a tertiary center intensive therapy unit (ITU) were tested for herpes simplex virus (HSV) by nested PCR. Samples from 61 patients in ITU for 4 days or more were also tested for Epstein Barr Virus (EBV) and cytomegalovirus (CMV) using real-time PCR. HSV positivity increased with ITU stay with 18.6% admission samples positive, 32.5% day 2-5 samples, and 65.9% day 6-39 samples. Being HSV positive on admission did not influence mortality (9/27, 33.3% vs. 38/118, 32.2%) however, subsequently, mortality of those negative but becoming positive was higher than in those remaining negative (10/35, 29% vs. 5/24 21%). At least one sample was EBV positive in 61% and CMV positive in 19% of patients tested. Of 63 patients tested for all three viruses, 4 were positive for three viruses, 23 patients for two viruses, 24 for one virus and 12 were negative for all the above viruses. Detection of HSV, EBV and CMV is common in ITU patients. Becoming HSV positive while in ITU may increase mortality.

Comparison of total, complexed and free prostate-specific antigens and their ratios in the detection of prostate cancer in a non-screened population.

BACKGROUND: The role of prostate-specific antigen (PSA) isoforms in the detection of prostate cancer in a non-screened population in the UK remains to be determined. METHODS: Consecutive patients undergoing diagnostic transrectal ultrasound-guided biopsy of the prostate were studied. Prior to biopsy, a blood sample was obtained and total, complexed and free PSA concentrations measured. RESULTS: Of the 171 patients included in the study, 103 were found to have prostate cancer. There were significant differences in total and complexed PSA concentrations and in the ratio of free-to-total PSA (all P <0.001) between patients with prostate cancer and those with benign disease. Receiver operating characteristics (ROC) curve analysis showed that the corresponding areas under the curves were similar. Restricting the analysis to the 77 patients who had total PSA concentrations between 2 and 10 micro g/L, ROC curve analysis showed that total and complexed PSA concentrations failed to discriminate between benign and malignant disease. In contrast, the areas under the ROC curve were greater for the free-to-total ratio (P = 0.033). CONCLUSION: These results show that in patients with total PSA concentrations between 2 and 10 micro g/L, the free-to-total PSA ratio was superior to total PSA concentration in discriminating between patients with benign and malignant disease.

Mast cells differentially express and release active high molecular weight neurotrophins.

Nerve growth factor (NGF), a target-derived factor for survival and maintenance of peripheral and central neurons, has been implicated in inflammatory processes. Mast cells are the principal effector cells in IgE-dependent hypersensitivity reactions, and also play a role in diseases characterised by inflammation, including those of the nervous system like multiple sclerosis. Mast cells are capable of synthesising and responding to NGF, although the occurrence of other members of the NGF family of neurotrophins and their protein forms have not been described. Immunoblot analysis with highly selective neurotrophin antibodies has now been used to show that rat peritoneal mast cells express a higher molecular weight form (73 kDa) of NGF, but not the monomeric (13 kDa) NGF polypeptide. Mast cells also expressed 73 kDa forms of neurotrophin-4 and neurotrophin-3; brain-derived neurotrophic factor was not detected. Medium conditioned by degranulating peritoneal mast cells contained similar high molecular weight forms of NGF and neurotrophin-4 on Western blots, but no neurotrophin-3. Mast cell-derived neurotrophin immunoreactivities were inhibited by the respective peptide antigen, further demonstrating the specificity of the mast cell-derived neurotrophic protein. Mast cell-released proteins supported the survival of cultured chicken embryonic neural crest- and placode-derived sensory neurons; neurotrophic activities were inhibited by neutralising antibodies for NGF and neurotrophin-4, respectively. High molecular isoforms of neurotrophins have been reported to occur in experimental colitis and in the inflamed gut of patients with Crohn's disease and ulcerative colitis, tissue sites rich in mast cells. The data suggest an important role for neurotrophins in the pathophysiology of inflammatory disease.

Early transvaginal ultrasonography versus early cerclage in women with an unclear history of incompetent cervix.

OBJECTIVE: Our aim was to compare outcomes in women with a questionable history of incompetent cervix, followed up with early transvaginal ultrasonography, with outcomes in women who had early cerclage. STUDY DESIGN: Charts were reviewed and patients identified for incompetent cervix from our obstetric database from 1995 through 1997. We included women who had an unclear history of incompetent cervix as follows: second-trimester loss or termination, > or =3 first-trimester terminations, cone biopsy or loop electrosurgical excision, or exposure to diethylstilbestrol. The primary outcome variable was gestational age at delivery. RESULTS: A total of 106 women were included, 45 in the early cerclage group and 61 in the early transvaginal ultrasonography group. The mean gestational age at delivery was 35.1 weeks for the early cerclage group versus 36.1 weeks for the early transvaginal ultrasonography group. CONCLUSION: In women with an unclear history of incompetent cervix, early cerclage does not appear to offer significant benefit over early transvaginal ultrasonography.

Timing of cerclage removal after preterm premature rupture of membranes: maternal and neonatal outcomes.

OBJECTIVE: Our aim was to evaluate immediate versus delayed removal of cerclage for women with preterm premature rupture of membranes with respect to maternal and neonatal outcomes. STUDY DESIGN: We retrospectively analyzed women with preterm premature rupture of membranes at <34 weeks' gestation with prior cerclage placement. Exclusion criteria included presentation with chorioamnionitis, active labor, or nonreassuring fetal status. Timing of cerclage removal, immediate (<24 hours) or delayed (>24 hours), was compared. RESULTS: There were 25 women in the delayed-removal group and 37 in the immediate-removal group. Average times to removal were 206.8 +/- 7.4 and 5.4 +/- 0.2 hours, respectively. Use of betamethasone was similar for both groups; however, antenatal antibiotic use (100% vs 80%; P =.03) and short-term tocolytic use (20% vs 3%; P =.04) were higher in the delayed-removal group. Duration of latency was significantly longer with delayed removal (10.1 vs 5.0 days; P <. 001). Delivery occurred >48 hours from preterm premature rupture of membranes in 96% (24/25) versus 54% (20/37; P <.001) and >7 days from rupture in 56% (14/25) versus 24% (9/37; P =.02), respectively. Rates of neonatal sepsis (at <10 days) and maternal infection were not statistically different. Neonatal outcomes did not significantly differ regarding mortality, respiratory distress syndrome, birth weight, or duration of stay in the intensive care nursery. CONCLUSION: With the current management scheme for preterm premature rupture of membranes, cerclage retention significantly increases duration of latency without significantly altering maternal or neonatal outcomes.

Anticoagulation of children undergoing cardiopulmonary bypass is overestimated by current monitoring techniques.

HYPOTHESIS: Children who undergo cardiopulmonary bypass (CPB) are proportionally more hemodiluted than adults who undergo CPB. Current methods of monitoring high-dose heparin sulfate anticoagulation are dependent on fibrinogen level. Because of the decreased fibrinogen levels in children, current methods of monitoring heparin anticoagulation overestimate their level of anticoagulation. DESIGN: Prospective controlled trial. MAIN OUTCOME MEASURE: Production of thrombin (adequacy of anticoagulation). METHODS: Children and adults undergoing cardiac surgery who received CPB were anticoagulated in the standard fashion as directed by activated clotting time (ACT) results. Each subject had blood sampled at baseline; heparinization; start of the CPB; CPB at 30, 60, and 90 minutes; and at termination of CPB. Samples were used to assess anticoagulation with the Heparin Management Test (less dependent on fibrinogen level than ACT). We also assessed 2 subclinical markers of thrombosis, thrombin-antithrombin complexes and prothrombin fragment F1.2; a marker of procoagulant reserve, fibrinogen; the natural antithrombotic, antithrombin; and heparin concentration. RESULTS: Ten children and 10 adults completed the study. Children had lower fibrinogen levels than adults throughout CPB (P<.05). All adults had both therapeutic ACT and Heparin Management Test levels measured throughout CPB. Although children had therapeutic ACT levels, their Heparin Management Test levels were subtherapeutic while undergoing CPB. The children had significantly higher thrombin-antithrombin complexes and prothrombin fragment F1.2 than adults, indicating ongoing thrombin production (P<.01). The increases in thrombin-antithrombin complexes and prothrombin fragment F1.2 in children were inversely proportional to their weight. CONCLUSIONS: Children undergoing CPB with heparin dosing adjusted to optimize the ACT manifest inadequate anticoagulation (ongoing thrombin formation). High-dose heparin anticoagulation therapy in children undergoing CPB should be directed by tests (like the Heparin Management Test) that are less dependent on fibrinogen level than ACT.

Use of an implantable cardioverter defibrillator in an eight-month-old infant with ventricular fibrillation arising from a myocardial fibroma.

We report our experience with use of a ICD in a 7-month-old infant who presented with VF. We utilized an epicardial patch and active generator in the abdomen. Development of mediastinitis required explantation and eventual replacement with a subcutaneous patch and active generator in the abdomen.

Nonmalignant hyperthermia on induction of anesthesia in a pediatric patient undergoing bidirectional Glenn procedure.

We report a case of severe hyperthermia in a 6-month-old boy with a single ventricle, dextrocardia, asplenia, and transposition of the great arteries, during induction of anesthesia on three separate occasions. To our knowledge, this is the first case reported of repeated intraoperative hyperthermia not related to malignant hyperthermia, infection, neuroendocrine tumor, or iatrogenic causes (e.g., anticholinergic blockade or warming devices). The severe hyperthermia may be secondary to the medications given before and during induction and/or the stress of the induction. Among the induction medications given during the three episodes, fentanyl is the most likely contributing drug. Human data indicate that opioids increase the sweating threshold and decrease the vasoconstriction and shivering thresholds. The medications could cause a widening in the thermoregulation interthreshold and the stress could induce nonshivering thermogenesis.

Use of transvenous DDD pacing in a one-year-old with symptomatic hypertrophic cardiomyopathy.

Symptomatic hypertrophic cardiomyopathy (HCM) is rare in infants. Therapeutic options are limited and include beta-blocker or calcium-channel blocker therapy or surgical myotomy/myectomy. Atrioventricular sequential pacing has been utilized as an alternative to surgery in symptomatic adults with HCM. We report our results with transvenous dual chamber pacing in an infant with symptomatic HCM.

Effects of age, physical training, and physical fitness on coronary heart disease risk factors in older track athletes at twenty-year follow-up.

OBJECTIVE: To compare current coronary heart disease (CHD) risk factor values in older athletes with mid-life measures and to examine the associations between changes in CHD risk factors with aging, physical training, and physical fitness. DESIGN: Prospective study with three longitudinal evaluation points: initial (T1), 10-year (T2), and 20-year (T3). Subjects were selected because of their elite status in Masters track competition. SETTING: University and medical center laboratories. PARTICIPANTS: Participants were 60 to 92 years of age and included 21 of the initial 27 subjects. At T3, subjects were divided into three groups, based on physical activity levels: high intensity (H), remained elite in national and international competition (n = 9); moderate intensity (M) continued frequent rigorous endurance training but rarely competed (n = 10); and low intensity (L) greatly reduced their training volume and intensity (n = 2). MEASUREMENTS: Smoking history; family history of coronary or cerebrovascular disease; resting blood pressure; resting electrocardiogram (ECG); serum total cholesterol, plasma glucose; body weight, % body fat, body mass index, waist:hip ratio; training pace and mileage; maximal oxygen consumption VO2 max). MAIN RESULTS: Several risk factors (smoking, diabetes, obesity) were never present, and the prevalence of other risk factors (family history of cardiovascular disease, abnormal resting ECG) remained low through T3 (< or = 14% of subjects). Mean systolic and diastolic blood pressure remained low without medication, but diastolic blood pressure measurements had the greatest redistribution between evaluation periods of any risk factor (r = .16, P = .479, T1 to T2). Mean total cholesterol was lower at T2 (-13%, P = .005) and T3 (-14%, P = .019) compared with T1. Change in VO2 max was correlated with changes in body weight (r = -.44, P = .048) and % fat (r = -.52, P = .015) from T1 to T2, whereas age was correlated to changes in systolic blood pressure (r = -.61, P = .003) and total cholesterol (r = -.49, P = .023) from T2 to T3. CONCLUSIONS: The prevalence of CHD risk factors remained low, and mean risk factor values remained low and generally stable in older athletes who had maintained habitual exercise training.

Essential role of a kinesin-like protein in Arabidopsis trichome morphogenesis.

Little is known about how cell shape is controlled. We are using the morphogenesis of trichomes (plant hairs) on the plant Arabidopsis thaliana as a model to study how cell shape is controlled. Wild-type Arabidopsis trichomes are large, single epidermal cells with a stalk and three or four branches, whereas in zwichel (zwi) mutants the trichomes have a shortened stalk and only two branches. To further understand the role of the ZWI gene in trichome morphogenesis we have cloned the wild-type ZWICHEL (ZWI) gene by T-DNA tagging, and report here that it encodes a member of the kinesin superfamily of microtubule motor proteins. Kinesin proteins transport diverse cellular materials in a directional manner along microtubules. Kinesin-like proteins are characterized by a highly conserved "head" region that comprises the motor domain, and a nonconserved "tail" region that is thought to participate in recognition and binding of the appropriate cargo.

Tamponade in patients undergoing cardiac surgery: a clinical-echocardiographic diagnosis.

The purpose of this study was to evaluate the sensitivity of current echocardiographic criteria in detecting cardiac tamponade in the patient who has undergone cardiovascular surgery. Because the current echocardiographic criteria for tamponade were initially developed and studied predominantly in patients with medical problems, relatively less information is available in patients who have undergone cardiac surgery. Of 848 consecutive patients who underwent cardiovascular surgery, patients were selected for the study if they had clinical or hemodynamic deterioration and had undergone an echocardiogram just before a successful pericardiocentesis or a surgical evacuation of pericardial blood or clot. The echocardiograms were evaluated for evidence of chamber collapse, cardiac motion, Doppler flow variations, and the location and width of pericardial separation. Fourteen patients were identified who met the inclusion criteria (clinical or hemodynamic deterioration, recent echocardiogram, and successful intervention) for cardiac tamponade. The clinical and hemodynamic findings were hypotension (13 patients), low cardiac output (7), low urine output (3), cardiopulmonary arrest (1), elevated central venous pressure (1), and shortness of breath (1). In these patients current echocardiographic criteria were seen infrequently: chamber collapse in the right atrium (6 of 14 patients) and right ventricle (4 of 14); Doppler flow variation (2 of 5); and swinging heart (0 of 15), whereas increased pericardial separation (> or = 10 mm) was seen in all (14 of 14) the patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Advantages of continuous noncardioplegic warm blood retrograde perfusion over antegrade perfusion during proximal coronary anastomoses.

Retrograde perfusion via the coronary sinus supplies vascular beds distal to coronary stenoses and has been used for administration of cardioplegia. An additional application is to supply noncardioplegic retrograde perfusion while performing proximal anastomoses (a time when cardiac arrest is not critical). The aim of this study was to determine the safety of this technique and to study the metabolic changes with antegrade versus retrograde warm blood perfusion. Sixty-six patients, with good left ventricular function, underwent distal coronary bypass in a similar fashion. Proximal anastomoses were done with 1) partial occlusion clamp (n = 29) or 2) cross-clamp on and continuous, warm, noncardioplegic retrograde blood perfusion (n = 37). In an additional 10 patients, metabolism was assessed with antegrade and retrograde perfusion during proximal anastomoses. Despite longer cross-clamp times (96.4 +/- 6.2 vs 80.8 +/- 3.1 min, p < 0.05) with retrograde perfusion, the total duration of cardiopulmonary bypass was significantly less (119.6 +/- 6.2 vs 136.6 +/- 4.6 min, p < 0.05). There was superior postbypass, intraoperative hemodynamics (cardiac index) with retrograde perfusion (4.0 +/- 0.2 vs 3.6 +/- 0.1 L/min/m2). The incidence of postoperative dysrhythmia was not significantly different between groups. Oxygen and glucose utilization was more efficient with retrograde perfusion. Retrograde perfusion during proximal anastomoses is a safe technique. There is diminished risk of aortic dissection, atheroembolism, delayed aneurysm formation, or rupture due to avoidance of application of partial occlusion clamps. There is evidence of superior substrate utilization.

Use of Carmeda-coated femoral-femoral bypass during repair of traumatic aortic pseudoaneurysms.

OBJECTIVE: To compare the results and outcomes of three different approaches to posttraumatic pseudoaneurysm repair: clamp and sew, left heart bypass, and the most recent approach, cardiopulmonary support using femoral-femoral bypass. DESIGN: Retrospective series. SETTING: A university-based, level 1 trauma center. PATIENTS: Forty-two consecutive patients treated for posttraumatic aortic pseudoaneurysm whose mean (+/- SEM) Injury Severity Score was 37 +/- 1.7. INTERVENTION: Methods of repair included clamp and sew in nine patients, left heart bypass in 24 patients, and cardiopulmonary support in nine patients. METHODS: Student's t test was used to compare interoperative blood loss, need for blood transfusion, and aortic cross-clamp time. Complications and mortality were also reviewed. RESULTS: Mean (+/- SEM) aortic cross-clamp time for clamp and sew was 28.1 +/- 3.3 minutes vs 52.5 +/- 3.7 for left heart bypass and 49.3 +/- 5.6 for cardiopulmonary support. Blood loss and the need for transfusion were comparable between groups. Complications were also comparable. CONCLUSION: Femoral-femoral cardiopulmonary support is safe to use, has a very low risk of complications, and should provide protection for the spinal cord during aortic repair. We encourage a randomized prospective trial to determine if cardiopulmonary support has a significantly lower rate of paraplegia than the clamp- and -sew technique.

Inclusion body myositis presenting solely as dysphagia.

Two patients presenting with dysphagia due to cricopharyngeal muscle dysfunction developed limb weakness 2 to 3 years later. Cricopharyngeal and limb muscle biopsies demonstrated changes typical of inclusion body myositis (IBM). Both patients improved following cricopharyngeal myotomy. IBM should be considered in patients presenting with dysphagia.

Blood gas dynamics at the onset of exercise in heart transplant recipients.

One hypothesis to explain the rapid neural component of exercise hyperpnea contends that afferent stimuli originating in the ventricles of the heart act reflexly on the respiratory center at the onset of exercise, ie, "cardiodynamic hyperpnea." Orthotopic cardiac transplantation (Tx) results in the loss of afferent information from the ventricles. Thus, Tx possibly results in transient hypercapnia and hypoxemia in deafferented heart transplant recipients (HTR) at the onset of exercise due to hypoventilation. To examine the cardiodynamic hypothesis, we collected serial arterial blood gas (ABG) samples during both the transient and the steady-state responses to moderate cycle exercise in 5 HTRs (55 +/- 7 years) 14 +/- 7 months post-Tx and 5 control subjects matched with respect to gender, age, and body composition. Forced vital capacity, forced expiratory volume in 1 s, total lung capacity, and diffusion capacity did not differ (p > or = 0.05) between groups. Resting arterial PO2, PCO2, and pH did not differ between groups (p > or = 0.05). The ABGs were drawn every 30 s during the first 5 min and at 6, 8, and 10 min of constant load square wave cycle exercise at 40 percent of the peak power output (watts). Absolute and relative changes in arterial PO2, PCO2, and pH were similar (p > or = 0.05) between HTR and the control group at all measurement periods during exercise. Heart rate (%HRmax reserve), rating of perceived exertion, and reductions in plasma volume (% delta from baseline) did not differ between HTR and control during exercise at 40 percent of peak power output (p > or = 0.05). Our results demonstrate that there is no discernible abnormality in ABG dynamics during the transient response to exercise at 40 percent of peak power output in patients with known cardiac denervation. These data do not support the cardiodynamic hyperpnea hypothesis of ventilatory control in humans. The absence of hypercapnia in HTRs is further evidence for the existence of redundant mechanisms capable of stimulating exercise hyperpnea.

Transtracheal delivery of gas decreases the oxygen cost of breathing.

Transtracheally administered gases decrease inspired minute ventilation in both dogs and humans. To test if this is associated with a decrease in the oxygen cost of breathing and to evaluate subsequent changes in the breathing pattern, we studied five patients with chronic respiratory diseases while they spontaneously breathed air and different flows of tracheally administered gases. In a blinded crossover design, the gas consisted of either oxygen or air at 2, 4, and 6 L/min. Oxygen cost of breathing was estimated by the calculation of pleural pressure-time index (PPTI). The pattern of breathing was evaluated utilizing the tension time index for the diaphragm (TTdi). There were significant decreases in PPTI when the patients received 2, 4, and 6 L/min of transtracheal oxygen or air. TTdi also decreased as gas flow increased. This drop was significant at 6 L/min flow for both gases. We conclude that transtracheally administered gas reduces the oxygen cost of breathing. It also changes the respiratory pattern of the diaphragm to a less demanding pattern. This may offer an alternative form of treatment to rest overworked respiratory muscles.

Pericardial patch repair of left ventricular aneurysm.

Infectious complications associated with the use of Teflon felt buttresses in left ventricular aneurysm repair may result in serious morbidity. Use of an autologous pericardial patch is an alternative approach that should be considered. The technique, which we have used in 4 patients, is described.