Randomized, double-blind, controlled trial of human anti-LIGHT monoclonal antibody in COVID-19 acute respiratory distress syndrome.

BACKGROUNDSevere coronavirus disease 2019 (COVID-19) is associated with a dysregulated immune response, which can result in cytokine-release syndrome and acute respiratory distress syndrome (ARDS). Patients with COVID-19-associated ARDS have elevated free serum levels of the cytokine lymphotoxin-like inducible protein that competes with glycoprotein D for herpesvirus entry on T cells (LIGHT; also known as TNFSF14). Such patients may benefit from LIGHT-neutralization therapy.METHODSThis randomized, double-blind, multicenter, proof-of-concept trial enrolled adults hospitalized with COVID-19-associated pneumonia and mild to moderate ARDS. Patients received standard of care plus a single dose of a human LIGHT-neutralizing antibody (CERC-002) or placebo. The primary endpoint was the proportion of patients receiving CERC-002 who remained alive and free of respiratory failure through day 28. Safety was assessed via adverse event monitoring.RESULTSFor most of the 83 enrolled patients, standard of care included systemic corticosteroids (88.0%) or remdesivir (57.8%). A higher proportion of patients remained alive and free of respiratory failure through day 28 after receiving CERC-002 (83.9%) versus placebo (64.5%; P = 0.044), including in patients 60 years of age or older (76.5% vs. 47.1%, respectively; P = 0.042). Mortality rates were 7.7% (CERC-002) and 14.3% (placebo) on day 28 and 10.8% and 22.5%, respectively, on day 60. Treatment-emergent adverse events were less frequent with CERC-002 than placebo.CONCLUSIONFor patients with COVID-19-associated ARDS, adding CERC-002 to standard-of-care treatment reduces LIGHT levels and might reduce the risk of respiratory failure and death.TRIAL REGISTRATIONClinicalTrials.gov NCT04412057.FUNDINGAvalo Therapeutics.

Fully automated endoscopic disease activity assessment in ulcerative colitis.

BACKGROUND AND AIMS: Endoscopy is essential for disease assessment in ulcerative colitis (UC), but subjectivity threatens accuracy and precision. We aimed to pilot a fully automated video analysis system for grading endoscopic disease in UC. METHODS: A developmental set of high-resolution UC endoscopic videos were assigned Mayo endoscopic scores (MESs) provided by 2 experienced reviewers. Video still-image stacks were annotated for image quality (informativeness) and MES. Models to predict still-image informativeness and disease severity were trained using convolutional neural networks. A template-matching grid search was used to estimate whole-video MESs provided by human reviewers using predicted still-image MES proportions. The automated whole-video MES workflow was tested using unaltered endoscopic videos from a multicenter UC clinical trial. RESULTS: The developmental high-resolution and testing multicenter clinical trial sets contained 51 and 264 videos, respectively. The still-image informative classifier had excellent performance with a sensitivity of 0.902 and specificity of 0.870. In high-resolution videos, fully automated methods correctly predicted MESs in 78% (41 of 50, κ = 0.84) of videos. In external clinical trial videos, reviewers agreed on MESs in 82.8% (140 of 169) of videos (κ = 0.78). Automated and central reviewer scoring agreement occurred in 57.1% of videos (κ = 0.59), but improved to 69.5% (107 of 169) when accounting for reviewer disagreement. Automated MES grading of clinical trial videos (often low resolution) correctly distinguished remission (MES 0,1) versus active disease (MES 2,3) in 83.7% (221 of 264) of videos. CONCLUSIONS: These early results support the potential for artificial intelligence to provide endoscopic disease grading in UC that approximates the scoring of experienced reviewers.

Phase 1 Open-Label, Multicenter Study of First-in-Class RORγ Agonist LYC-55716 (Cintirorgon): Safety, Tolerability, and Preliminary Evidence of Antitumor Activity.

PURPOSE: Transcription factor retinoic acid receptor-related orphan receptor γ (RORγ) regulates type 17 effector T-cell differentiation and function and is key to immune cell regulation. Synthetic RORγ agonists modulate immune cell gene expression to increase effector T-cell activity and decrease immune suppression. A phase 1 study evaluated the safety and tolerability of LYC-55716 (cintirorgon), a first-in-class, oral, small-molecule RORγ agonist in adults with relapsed/refractory metastatic cancer. PATIENTS AND METHODS: Patients received 28-day treatment cycles of oral LYC-55716; dose and dosing regimen were determined according to pharmacokinetic profile and safety. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective tumor response rate. RESULTS: No dose-limiting toxicities occurred among the 32 enrolled patients who received LYC-55716 150 mg BID to 450 mg BID. Treatment-related adverse events (AE) were primarily grade 1-2 and included diarrhea (n = 11), fatigue (n = 7), anemia (n = 4), decreased appetite (n = 4), and nausea (n = 4). Grade 3 AEs were anemia (n = 2), elevated gamma-glutamyl transferase (n = 1), and hypophosphatemia (n = 1). Pharmacokinetic concentrations achieved levels expected for target gene regulation. Pharmacodynamic results indicated RORγ pathway engagement. Two patients (NSCLC and sarcomatoid breast cancer) had confirmed partial responses; 11 had disease stabilization for 2 to 12 months (6 received >4 months of treatment). CONCLUSIONS: These data support the safety and tolerability of LYC-55716 and selection of 450 mg BID dose for a phase 2a study assessing LYC-55716 clinical activity, safety, and biomarkers in patients with NSCLC, head and neck, gastroesophageal, renal cell, urothelial, and ovarian cancers.

Human-specific phages infecting Enterococcus host strain MW47: are they reliable microbial source tracking markers?

AIM: The aim of this study was to determine the morphological diversity and environmental survival of human-specific phages infecting Enterococcus faecium host strain MW47, to support their use as microbial source tracking (MST) markers. METHODS AND RESULTS: Twenty phages capable of infecting strain MW47 were propagated and their morphologies were determined using transmission electron microscopy (TEM), which revealed that a heterogeneous group of phages was able to infect strain MW47. Three distinct morphologies from two different families (Myoviridae and Siphoviridae) were observed. In situ inactivation experiments were subsequently conducted to determine their environmental persistence. CONCLUSION: The findings revealed a statistically significant link between morphology and the rate of inactivation, with phages belonging to the Myoviridae family demonstrating more rapid inactivation in comparison to those belonging to the Siphoviridae family. SIGNIFICANCE AND IMPACT OF STUDY: The results suggest that while Enterococcus MW47 phages appear to be a potentially valuable MST tools, significant variations in the persistence of the different phages mean that the approach should be used with caution, as this may adversely affect the reliability of the approach, especially when comparing MW47 phage levels or the presence across different matrices (e.g. levels in sediments or shellfish). This highlights the importance of elucidating the ecological characteristics of newly proposed MST markers before they are used in full-scale MST investigations.

Mitochondria, Cybrids, Aging, and Alzheimer's Disease.

Mitochondrial and bioenergetic function change with advancing age and may drive aging phenotypes. Mitochondrial and bioenergetic changes are also documented in various age-related neurodegenerative diseases, including Alzheimer's disease (AD). In some instances AD mitochondrial and bioenergetic changes are reminiscent of those observed with advancing age but are greater in magnitude. Mitochondrial and bioenergetic dysfunction could, therefore, link neurodegeneration to brain aging. Interestingly, mitochondrial defects in AD patients are not brain-limited, and mitochondrial function can be linked to classic AD histologic changes including amyloid precursor protein processing to beta amyloid. Also, transferring mitochondria from AD subjects to cell lines depleted of endogenous mitochondrial DNA (mtDNA) creates cytoplasmic hybrid (cybrid) cell lines that recapitulate specific biochemical, molecular, and histologic AD features. Such findings have led to the formulation of a "mitochondrial cascade hypothesis" that places mitochondrial dysfunction at the apex of the AD pathology pyramid. Data pertinent to this premise are reviewed.

Nicotine treatment of mild cognitive impairment: a 6-month double-blind pilot clinical trial.

OBJECTIVE: To preliminarily assess the safety and efficacy of transdermal nicotine therapy on cognitive performance and clinical status in subjects with mild cognitive impairment (MCI). METHODS: Nonsmoking subjects with amnestic MCI were randomized to transdermal nicotine (15 mg per day or placebo) for 6 months. Primary outcome variables were attentional improvement assessed with Connors Continuous Performance Test (CPT), clinical improvement as measured by clinical global impression, and safety measures. Secondary measures included computerized cognitive testing and patient and observer ratings. RESULTS: Of 74 subjects enrolled, 39 were randomized to nicotine and 35 to placebo. 67 subjects completed (34 nicotine, 33 placebo). The primary cognitive outcome measure (CPT) showed a significant nicotine-induced improvement. There was no statistically significant effect on clinician-rated global improvement. The secondary outcome measures showed significant nicotine-associated improvements in attention, memory, and psychomotor speed, and improvements were seen in patient/informant ratings of cognitive impairment. Safety and tolerability for transdermal nicotine were excellent. CONCLUSION: This study demonstrated that transdermal nicotine can be safely administered to nonsmoking subjects with MCI over 6 months with improvement in primary and secondary cognitive measures of attention, memory, and mental processing, but not in ratings of clinician-rated global impression. We conclude that this initial study provides evidence for nicotine-induced cognitive improvement in subjects with MCI; however, whether these effects are clinically important will require larger studies. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that 6 months of transdermal nicotine (15 mg/day) improves cognitive test performance, but not clinical global impression of change, in nonsmoking subjects with amnestic MCI.

Reslizumab in children and adolescents with eosinophilic esophagitis: results of a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Eosinophilic esophagitis is a chronic allergic disease with insufficient treatment options. Results from animal studies suggest that IL-5 induces eosinophil trafficking in the esophagus. OBJECTIVE: We sought to evaluate the effect of reslizumab, a neutralizing antibody against IL-5, in children and adolescents with eosinophilic esophagitis. METHODS: Patients with symptom severity scores of moderate or worse and an esophageal biopsy specimen with 24 or more intraepithelial eosinophils per high-power field were randomly assigned to receive infusions of 1, 2, or 3 mg/kg reslizumab or placebo at weeks 0, 4, 8, and 12. The coprimary efficacy measures were changes in peak esophageal eosinophil count and the physician's global assessment score at week 15 (end of therapy). RESULTS: Two-hundred twenty-six patients received study medication. Median reductions from baseline to the end of therapy in peak esophageal eosinophil counts were 59%, 67%, 64%, and 24% in the 1, 2, and 3 mg/kg reslizumab (all P < .001) and placebo groups, respectively. All treatment groups, including the placebo group, showed improvements in physician's global assessment scores; the differences between the reslizumab and placebo groups were not statistically significant. The most common adverse events in the reslizumab groups were headache, cough, nasal congestion, and upper respiratory tract infection. One patient in each reslizumab group and 2 in the placebo group had serious adverse events; none were considered related to the study medication. CONCLUSION: Reslizumab significantly reduced intraepithelial esophageal eosinophil counts in children and adolescents with eosinophilic esophagitis. However, improvements in symptoms were observed in all treatment groups and were not associated with changes in esophageal eosinophil counts.

Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study.

RATIONALE: Eosinophilic asthma is a phenotype of asthma characterized by the persistence of eosinophils in the airways. IL-5 is involved in the activation and survival of eosinophils. OBJECTIVES: To evaluate the effect of the antibody to IL-5, reslizumab, in patients with eosinophilic asthma that is poorly controlled with high-dose inhaled corticosteroid. METHODS: Patients were randomly assigned to receive infusions of reslizumab at 3.0 mg/kg (n = 53) or placebo (n = 53) at baseline and at Weeks 4, 8, and 12, with stratification by baseline Asthma Control Questionnaire (ACQ) score less than or equal to 2 or greater than 2. The primary efficacy measure was the difference between the reslizumab and placebo groups in the change in ACQ score from baseline to end of therapy (Week 15 or early withdrawal). MEASUREMENTS AND MAIN RESULTS: Mean changes from baseline to end of therapy in ACQ score were -0.7 in the reslizumab group and -0.3 in the placebo group (P = 0.054) and in FEV(1) were 0.18 and -0.08 L, respectively (P = 0.002). In those patients with nasal polyps, the changes in ACQ score were -1.0 and -0.1, respectively (P = 0.012). Median percentage reductions from baseline in sputum eosinophils were 95.4 and 38.7%, respectively (P = 0.007). Eight percent of patients in the reslizumab group and 19% of patients in the placebo group had an asthma exacerbation (P = 0.083). The most common adverse events with reslizumab were nasopharyngitis, fatigue, and pharyngolaryngeal pain. CONCLUSIONS: Patients receiving reslizumab showed significantly greater reductions in sputum eosinophils, improvements in airway function, and a trend toward greater asthma control than those receiving placebo. Reslizumab was generally well tolerated.

Cell-specific effects of insulin receptor substrate-1 deficiency on normal and IGF-I-mediated colon growth.

Insulin-like growth factor I (IGF-I) potently stimulates intestinal growth. Insulin receptor substrate-1 (IRS-1) mediates proliferative and antiapoptotic actions of IGF-I in cell lines, but its in vivo relevance in intestine is not defined. This study tested the hypothesis that there is cell type-specific dependence on IRS-1 as a mediator of IGF-I action. Length, mass, crypt cell proliferation, and apoptosis were measured in small intestine and colon of IRS-1-null mice and wild-type (WT) littermates and in colon of IRS-1-null or WT mice expressing IGF-I transgenes. Expression of IGF-I receptor and signaling intermediates was examined in intestine of WT and IRS-1-null mice, cultured intestinal epithelial cells, and myofibroblasts. Absolute IRS-1 deficiency reduced mucosal mass in jejunum and colon, but effects were more pronounced in colon. Muscularis mass was decreased in both segments. In IGF-I transgenics, IRS-1 deficiency significantly attenuated IGF-I-stimulated growth of colonic mucosa and abolished antiapoptotic but not mitogenic effects of IGF-I transgene on crypt cells. IGF-I-induced muscularis growth was unaffected by IRS-1 deficiency. In intestinal epithelial cells, IRS-1 was expressed at higher levels than IRS-2 and was preferentially activated by IGF-I. In contrast, IGF-I activated both IRS-1 and IRS-2 in intestinal myofibroblasts and IRS-2 activation was upregulated in IRS-1-null myofibroblasts. We conclude that the intestinal epithelium but not the muscularis requires IRS-1 for normal trophic actions of IGF-I and that IRS-1 is required for antiapoptotic but not mitogenic effects of IGF-I in the intestinal crypts in vivo.

Extended duration of efficacy of vardenafil when taken 8 hours before intercourse: a randomized, double-blind, placebo-controlled study.

OBJECTIVES: This study explored the efficacy of vardenafil in men with erectile dysfunction (ED) when taken 8 hours before sexual intercourse. METHODS: A 10-week, randomized, double-blind, placebo-controlled, parallel-group, flexible-dose study of vardenafil (5, 10 or 20mg) was conducted in men with ED for >6 months who failed >or=50% of intercourse attempts during a 4-week treatment-free run-in period. Sexual Encounter Profile Question 3 (SEP3) was the primary efficacy measure; secondary measures included SEP2, International Index of Erectile Function-Erectile Function (IIEF-EF) domain score, Global Assessment Question (GAQ), Global Confidence Question (GCQ) and Erection Quality Scale (EQS). Adverse-event and safety monitoring were conducted throughout. RESULTS: 383 patients were randomized to vardenafil (n=194) or placebo (n=189). Patients treated with vardenafil 8 hours before sexual activity achieved clinically meaningful (>or=18%) and statistically significantly greater least-squares mean per-patient SEP3 and SEP2 success rates over weeks 2-10, compared with patients receiving placebo (SEP3 69% vs 34%; SEP2 81% vs 51%; both p<0.001). SEP3 and SEP2 measures demonstrated the significant superiority of vardenafil over placebo from week 2 onwards (p<0.001). Measurements of IIEF-EF domain score, GAQ, GCQ and EQS showed that vardenafil led to significantly greater improvements in erectile function, compared with placebo (all p<0.001). Vardenafil was generally well tolerated. CONCLUSIONS: The extended duration of efficacy of vardenafil up to 8 hours postdose may provide couples with more flexibility in their sexual life than anticipated.

Efficacy and safety of vardenafil in men with erectile dysfunction caused by spinal cord injury.

OBJECTIVE: To assess the efficacy and tolerability of vardenafil in men with erectile dysfunction (ED) due to traumatic spinal cord injury (SCI). METHODS: In this multicenter, double-blind, placebo-controlled, parallel-group 12-week study, 418 men aged 18 years and older with ED for more than 6 months consequent to SCI were randomized to vardenafil (n = 207) or placebo (n = 211) (10 mg for 4 weeks, then maintained or titrated to 5 or 20 mg at weeks 4 and 8). Efficacy assessments included the erectile function (EF) domain score of the International Index of Erectile Function questionnaire and diary questions regarding penetration, maintenance of erection to completion of intercourse, and ejaculation. RESULTS: Baseline patient characteristics were similar in the vardenafil (mean age 40 years) and placebo (mean age 39 years) groups. Mean baseline EF domain scores were 11.6 in the vardenafil group and 12.1 (moderate ED) in the placebo group. EF domain score in the vardenafil group improved to 22.0 (mild ED) at last observation carried forward vs 13.5 in the placebo group (p < 0.001). Over 12 weeks of treatment, mean per-patient penetration (76% vs 41%), maintenance (59% vs 22%), and ejaculation (19% vs 10%) success rates were significantly greater vs placebo (all p < 0.001). The most frequently reported drug-related adverse events were headache (vardenafil 15%, placebo 4%), flushing (vardenafil 6%, placebo 0%), nasal congestion (vardenafil 5%, placebo 0%), and dyspepsia (vardenafil 4%, placebo 0%). CONCLUSION: Vardenafil significantly improved erectile and ejaculatory function and was generally well tolerated in men with erectile dysfunction due to spinal cord injury.

Erectile response to vardenafil in men with a history of nonresponse to sildenafil: a time-from-dosing descriptive analysis.

BACKGROUND: The efficacy and tolerability of vardenafil hydrochloride in men with erectile dysfunction (ED) and a history of nonresponse to sildenafil citrate have previously been reported. OBJECTIVE: The aim of this descriptive analysis was to assess the efficacy and tolerability of vardenafil at various times after dosing in men with ED and a history of nonresponse to sildenafil and who chose to attempt sexual intercourse between 0.25 and 6 hours after dosing with vardenafil. METHODS: This analysis used data from a previously published 12-week, prospective, randomized, double-blind, flexible-dose, placebo-controlled study conducted at 41 hospitals and outpatient clinics across Australia, Europe, Asia, and North America. In that study, men with ED and sildenafil nonresponse, defined using 6 rigorous criteria (including nonresponse to the highest recommended dose, 100 mg/d) were assigned to receive vardenafil 10 mg or placebo QD. At study weeks 4 and 8, patients in both groups were given the option to maintain the 10-mg/d dose, or have the dose titrated to 5 or 20 mg/d. The present analysis used data from patient diaries completed daily, which included information concerning attempts at sexual intercourse, time from dosing to attempt, penetration, and maintenance of erection sufficient for successful intercourse. At week 12, diary data were categorized into time intervals (in hours) after dosing. For each interval, the per-patient success rate was based on the total number of attempts made in that interval. Comparative statistics were not performed on the time-interval analysis. Tolerability was monitored throughout the study. Data concerning the primary end point were reported previously. RESULTS: A total of 463 men were enrolled, of whom 457 were included in the safety analysis (vardenafil, n = 231; placebo, n = 226) and 454 in the intent-to-treat analysis (vardenafil, n = 229; placebo, n = 225; mean age, 60.1 vs 59.0 years; mean body mass index, 28.7 vs 28.0 kg/m2). Six patients were excluded from the safety analysis (2 patients did not use study medication [placebo group], postbaseline safety data unavailable in 4 patients [2 in each study group]). Men receiving vardenafil had numerically greater penetration and completion success rates compared with those receiving placebo at all time intervals. Penetration success rates were numerically higher with vardenafil compared with placebo as early as within 0.25 hour after dosing (62% vs 30%); efficacy continued beyond 6 hours after dosing in 77% and 50% of patients, respectively. Similarly, vardenafil-treated patients had numerically greater completion success rates compared with those receiving placebo at 0.25 hour (53% vs 12%) and beyond 6 hours after dosing (70% vs 24%). The most common drug-related adverse events in the vardenafil and placebo groups were flushing (7% vs 1%), headache (6% vs 2%), and nasal congestion (5% vs <1%). CONCLUSIONS: This descriptive analysis suggests that erection sufficient for penetration and intercourse completion was achieved within 0.25 hour and lasted for >6 hours after dosing with vardenafil 10 mg in these men with mostly moderate to severe ED and a history of nonresponse to sildenafil and who chose to make attempts during those intervals. The drug was generally well tolerated.

Hypereosinophilic syndrome: an update.

Hypereosinophilic syndrome (HES) is a rare disorder that is characterized by persistent and marked eosinophilia combined with organ system dysfunction. HES has substantial clinical heterogeneity but can be fatal without treatment, especially in patients who present with a myelodysplastic variant of the disorder. Although the pathophysiology of HES is poorly defined, dysregulation of cytokines (interleukin 5 [IL-5], IL-3, granulocyte-macrophage colony-stimulating factor [GM-CSF]) responsible for the maturation of eosinophils is a primary feature. Of these cytokines, IL-5 appears to have the greatest role in the regulation of eosinophil maturation. There is no Food and Drug Administration-approved treatment for HES as yet; current strategies are designed to lower blood eosinophils and attempt to limit end-organ damage. Historically, corticosteroids and cytotoxic agents have been the mainstays of therapy, with biological response modifiers such as interferon-alpha also effective in some patients. However, despite improvements in survival, available agents have significant limitations in terms of efficacy, tolerability, and long-term toxicity. More recently, new agents directed at specific targets in the pathogenesis of HES have been developed. These include imatinib mesylate, a tyrosine kinase inhibitor, and more recently, mepolizumab, an anti-IL-5 monoclonal antibody. In a small case series of patients, these agents have been shown to produce hematological and clinical responses in patients with HES, although they may be effective in different subsets of patients. These targeted therapies have the potential to improve clinical outcomes and to further the understanding the pathophysiology of this difficult-to-treat condition.

Erectile response with vardenafil in sildenafil nonresponders: a multicentre, double-blind, 12-week, flexible-dose, placebo-controlled erectile dysfunction clinical trial.

OBJECTIVE: To evaluate the efficacy of vardenafil in patients previously unresponsive to sildenafil. PATIENTS AND METHODS: A multicentre, double-blind, 12-week, flexible-dose, placebo-controlled trial was conducted, involving 463 men aged > or = 18 years with moderate-to-severe erectile dysfunction (ED) and who were unresponsive to sildenafil (by history). After a 4-week treatment-free run-in, patients received placebo or vardenafil 10 mg with the option to maintain current dose or to titrate by one dose level (5, 10 or 20 mg) based on efficacy and tolerability at 4 and 8 weeks. Outcome measures were the erectile function (EF) domain score of the International Index of Erectile Function, two Sexual Encounter Profile diary questions (vaginal penetration and maintenance of erection until successful completion of intercourse), and the Global Assessment Question (GAQ). RESULTS: There was significantly better EF with vardenafil than with placebo throughout the study. The least-square mean EF domain scores increased from 9.3 at baseline to 17.6 at the 'last' observation carried forward (LOCF) analysis with vardenafil (P < 0.001). Overall least-square mean per-patient success rates more than doubled for penetration (30.3% to 62.3%) and quadrupled for successful intercourse (10.5% to 46.1%) with vardenafil. Improved erections (positive response to the GAQ) were reported by 61.8% of patients receiving vardenafil and 14.7% of those receiving placebo at LOCF (P < 0.001). Normal EF (domain score > or = 26) was achieved by 30% of patients receiving vardenafil and 6% receiving placebo at LOCF (P < 0.001). Adverse events were infrequent and representative of the phosphodiesterase-5 inhibitor profile. CONCLUSION: Vardenafil is an effective and generally safe treatment for ED, even in men unresponsive to sildenafil (by history).

Emerging therapeutic targets in psoriasis.

Biopharmaceuticals that target specific disease-mediating molecules have advanced our understanding of the pathogenesis of psoriasis. The traditional paradigm that psoriasis is primarily a disease of epidermal cells has been replaced with a model that now includes keratinocyte-derived factors, inflammatory mediators and angiogenic mechanisms. Recent studies have highlighted some of the key molecules involved in all of these pathogenic processes. Several have already been evaluated as putative targets in in vitro and in vivo studies, whereas other molecules are significantly upregulated in psoriasis and require further study to elucidate their role and contribution to disease. Although not all these molecules will eventually qualify as drug targets, data from similar experimental strategies are predicted to underpin the next generation of candidate targets and novel therapeutic approaches.

Mystery of the toxic flea dip: an interactive approach to teaching aerobic cellular respiration.

We designed an interrupted case study to teach aerobic cellular respiration to major and nonmajor biology students. The case is based loosely on a real-life incident of rotenone poisoning. It places students in the role of a coroner who must determine the cause of death of the victim. The case is presented to the students in four parts. Each part is followed by discussion questions that the students answer in small groups prior to a classwide discussion. Successive parts of the case provide additional clues to the mystery and help the students focus on the physiological processes involved in aerobic respiration. Students learn the information required to solve the mystery by reading the course textbook prior to class, listening to short lectures interspersed throughout the case, and discussing the case in small groups. The case ends with small group discussions in which the students are given the names and specific molecular targets of other poisons of aerobic respiration and asked to determine which process (i.e., glycolysis, citric acid cycle, or the electron transport chain) the toxin disrupts.

Hair cell death in a hearing-deficient canary.

Cell death has been documented in bird auditory inner ear epithelia after induced damage. This cell death is quickly followed by an increase in supporting cell division and regeneration of the epithelium, thereby suggesting a possible relationship between these two processes. However, aspects of this relationship still need to be better understood. The Belgian Waterslager (BWS) canary is an ideal system in which to study cell death and subsequent cell division. In contrast to mixed breed (MB) canaries, cell division normally occurs in the auditory end organ of the BWS without any external manipulation. In addition, some of the cells in the auditory epithelium may be dying through an apoptotic-like process. In the present study two methods were used to quantify dying cells in the BWS and MB canary auditory epithelia: morphological criteria and TUNEL. Results confirm that some of the abnormal hair cells in the BWS auditory epithelium are apoptotic-like. The presence of both cell death and cell division indicates that these processes act concurrently in the adult end organ. Future studies are needed to determine if cell death is a stimulus for the observed cell division.

Percutaneous dilatational tracheostomy in a community hospital setting.

BACKGROUND: Over the past 15 years, many large university hospitals have reported their experience with percutaneous dilatational tracheostomy (PDT). The purposes of this study are to evaluate the safety of PDT in a non-university hospital setting and to compare our results with those published in the literature. METHODS: The study was done by retrospective chart review. RESULTS: Over a 6-year period, 300 PDTs were done in two community hospitals in Tyler, Texas. There was one death and 12 complications. Comparison of our results and those reported in five recently published articles in the literature showed no significant difference in mortality rate, pneumothorax, bleeding, paratracheal placement, dislodgement, or cellulitis. There was a trend toward a significantly lower incidence of paratracheal placement using bronchoscopic guidance. CONCLUSION: Bedside PDT with bronchoscopic guidance can be safely done in a community hospital setting.

The safety of prolonging the use of central venous catheters: a prospective analysis of the effects of using antiseptic-bonded catheters with daily site care.

OBJECTIVE: To determine rates of catheter colonization and catheter-related bloodstream infection (CRBSI) when antiseptic-bonded central venous catheters (CVCs) and standardized daily site care are used with no predetermined interval for removal. DESIGN: Prospective observational study. SETTING: Two major trauma centers. PATIENTS: All trauma patients admitted to two major trauma centers that received a CVC from May 1996 through May 1998. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Catheters were semiquantitatively cultured to identify bacterial colonization and CRBSI. Monitored variables included total catheter days, anatomical site of catheter insertion, and area in hospital of catheter insertion. CVC tips and intracutaneous segments were semiquantitatively cultured. A total of 460 (92%) of 501 catheters placed in 324 trauma patients were evaluable, representing 95.5% of all catheter days during the study period. Rates of catheter colonization and CRBSI were 5% (5/1000 catheter days) and 1.5% (1.511000 catheter days), respectively. Subclavian catheters were in place longer than femoral or internal jugular catheters (p < .0001), but the colonization rate was significantly lower (p = .03; relative risk, 0.34; 95% confidence interval, 0.15-0.77). No differences in CRBSI rates among anatomical sites or between catheters used < or =14 days and those used >14 days were identified. CONCLUSION: Femoral and internal jugular antiseptic-bonded CVCs develop bacterial colonization earlier than subclavian CVCs. Subclavian antiseptic-bonded CVCs combined with standardized daily site care may be safely used >14 days in trauma patients.