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Introduction.Endothelial dysfunction is an early manifestation of the atheromatous process and is evident without overt clinical signs or symptoms of the disease. Cigarette smoking has been shown to be associated with endothelial dysfunction in otherwise healthy adults. Although cessation of smoking is the ideal objective, it is not always attainable, and therefore any strategy to prevent early endothelial dysfunction is desirable. Folic acid is currently under review as a rational therapeutic agent in hyperhomocysteinemia. However, folic acid may modify endothelial function independent of its effect on homocysteine. We therefore investigated the effect of folic acid on endothelial function in young otherwise healthy cigarette smokers.Methods. Volunteer cigarette smokers (n = 10) and control lifelong nonsmokers were enrolled in the study. Baseline folate, vitamin B12, homocysteine, and cholesterol levels were analyzed. Flow-mediated dilatation, an endothelial-dependent phenomenon, was assessed using ultrasonography. This scan was performed at baseline and following 4 weeks of folic acid supplementation (5 mg/day).Results. There were no significant differences in the baseline hematological investigations between the groups. Homocysteine levels were within normal limits in both groups and did not change following folic acid supplementation. Cigarette smokers demonstrated significant endothelial dysfunction compared to controls (P < 0.005). This difference was significantly attenuated by folic acid supplementation (P < 0.005).Conclusion. Folic acid significantly improves endothelial function in otherwise healthy cigarette smokers. This provides a potential therapeutic tool in attenuating the atheromatous process in this group. [Copyright &y& Elsevier]

Background: Intensive care unit (ICU) survivors face functional limitations due to ICU-acquired weakness. Arm cycle ergometry (ACE) introduced in the ICU may improve physical function. To our knowledge, there is limited evidence on the effectiveness of ACE and physical function outcomes in critically ill patients., Objective: The objective of this systematic review was to examine the impact of ICU-based ACE on physical function, safety, and other clinical outcomes., Review Method Used: Systematic Review., Data Sources: A search of seven databases was conducted from the inception to January 1, 2023: Medline Ahead of Print, Ovid MEDLINE(R), Allied and Complementary Medicine Database (AMED), Embase, Cochrane Central, Physiotherapy Evidence Database, and Cumulative Index to Nursing and Allied Health Literature (CINAHL)., Review Methods: We included two arm studies of critically ill adults admitted to the ICU who received ACE and any comparator for our primary outcome, physical function. Our secondary outcomes included severe events. We included safety studies with or without a comparator group. Screening, data abstraction, and risk-of-bias assessments were completed independently, in duplicate. We used the Grading of Recommendations, Assessment, Development, and Evaluation approach to assess the overall certainty of evidence., Results: We screened 651 citations and included eight studies that enrolled 183 patients. Due to heterogeneity, meta-analysis was not performed. For our primary outcome, one randomised controlled trial found significant improvements in physical function, measured by the Barthel Index with ACE, whereas a nonrandomised study showed no difference. Out of the six studies reporting safety, none reported any severe safety events. The overall certainty of evidence was very low., Conclusion: ACE initiated in the ICU is a likely safe intervention. Based on the limited ACE studies and heterogeneity between studies, further research with more rigorous studies evaluating important outcomes for patients is needed., (Copyright © 2024 Australian College of Critical Care Nurses Ltd. Published by Elsevier Ltd. All rights reserved.)

Introduction: In-bed leg cycling with critically ill patients is a promising intervention aimed at minimising immobility, thus improving physical function following intensive care unit (ICU) discharge. We previously completed a pilot randomised controlled trial (RCT) which supported the feasibility of a large RCT. In this report, we describe the protocol for an international, multicentre RCT to determine the effectiveness of early in-bed cycling versus routine physiotherapy (PT) in critically ill, mechanically ventilated adults., Methods and Analysis: We report a parallel group RCT of 360 patients in 17 medical-surgical ICUs and three countries. We include adults (≥18 years old), who could ambulate independently before their critical illness (with or without a gait aid), ≤4 days of invasive mechanical ventilation and ≤7 days ICU length of stay, and an expected additional 2-day ICU stay, and who do not fulfil any of the exclusion criteria. After obtaining informed consent, patients are randomised using a web-based, centralised system to either 30 min of in-bed cycling in addition to routine PT, 5 days per week, up to 28 days maximum, or routine PT alone. The primary outcome is the Physical Function ICU Test-scored (PFIT-s) at 3 days post-ICU discharge measured by assessors blinded to treatment allocation. Participants, ICU clinicians and research coordinators are not blinded to group assignment. Our sample size estimate was based on the identification of a 1-point mean difference in PFIT-s between groups., Ethics and Dissemination: C ritical Care C yc ling to improve L ower E xtremity (CYCLE) is approved by the Research Ethics Boards of all participating centres and Clinical Trials Ontario (Project 1345). We will disseminate trial results through publications and conference presentations., Trial Registration Number: NCT03471247 (Full RCT); NCT02377830 (CYCLE Vanguard 46 patient internal pilot)., Competing Interests: Competing interests: MEK received an equipment loan of 4 RT300 supine cycles from Restorative Therapies, Baltimore, Maryland, USA for this study. On behalf of the remaining authors, the corresponding author states there is no conflict of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The arrival of the Delta variant of SARS-CoV-2 was associated with increased transmissibility and illness of greater severity. Reports of nosocomial outbreaks of Delta variant COVID-19 in acute care hospitals have been described but control measures varied widely., Aim: Epidemiological investigation of a linked two-ward COVID-19 Delta variant outbreak was conducted to elucidate its source, risk factors, and control measures., Methods: Investigations included epidemiologic analysis, detailed case review serial SARS-CoV-2 reverse transcriptase-polymerase chain reaction (RT-PCR) testing of patients and healthcare workers (HCWs), viral culture, environmental swabbing, HCW-unaware personal protective equipment (PPE) audits, ventilation assessments, and the use of whole genome sequencing (WGS)., Findings: This linked two-ward outbreak resulted in 17 patient and 12 HCW cases, despite an 83% vaccination rate. In this setting, suboptimal adherence and compliance to PPE protocols, suboptimal hand hygiene, multi-bedded rooms, and a contaminated vital signs cart with potential fomite or spread via the hands of HCWs were identified as significant risk factors for nosocomial COVID-19 infection. Sudden onset of symptoms, within 72 h, was observed in 79% of all Ward 2 patients, and 93% of all cases (patients and HCWs) on Ward 2 occurred within one incubation period, consistent with a point-source outbreak. RT-PCR assays showed low cycle threshold (C T ) values, indicating high viral load from environmental swabs including the vital signs cart. WGS results with ≤3 SNP differences between specimens were observed., Conclusion: Outbreaks on both wards settled rapidly, within 3 weeks, using a `back-to-basics' approach without extraordinary measures or changes to standard PPE requirements. Strict adherence to recommended PPE, hand hygiene, education, co-operation from HCWs, including testing and interviews, and additional measures such as limiting movement of patients and staff temporarily were all deemed to have contributed to prompt resolution of the outbreak., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background/objective: In recent years, treatment of heart failure patients has proved to benefit from implantation of pressure sensors in the pulmonary artery (PA). While longitudinal measurement of PA pressure profoundly improves a clinician's ability to manage HF, the full potential of central venous pressure as a clinical tool has yet to be unlocked. Central venous pressure serves as a surrogate for the right atrial pressure, and thus could potentially predict a wider range of heart failure conditions. However, it is unclear if current sensor anchoring methods, designed for the PA, are suitable to hold pressure sensors safely in the inferior vena cava. The purpose of this study was to design an anchoring system for accurate apposition in inferior vena cava and evaluate whether it is a potential site for central venous pressure measurement., Materials and Methods: A location inferior to the renal veins was selected as an optimal site based on a CT scan analysis. Three anchor designs, a 10-strut anchor, and 5-struts with and without loops, were tested on a custom-made silicone bench model of Vena Cava targeting the infra-renal vena cava. The model was connected to a pulsatile pump system and a heated water bath that constituted an in-vitro simulation unit. Delivery of the inferior vena cava implant was accomplished using a preloaded introducer and a dilator as a push rod to deploy the device at the target area. The anchors were subjected to manual compression tests to evaluate their stability against dislodgement. Computational Fluid Dynamics (CFD) analysis was completed to characterize blood flow in the anchor's environment using pressure-based transient solver. Any potential recirculation zones or disturbances in the blood flow caused by the struts were identified., Results: We demonstrated successful anchorage and deployment of the 10-strut anchor in the Vena Cava bench model. The 10-strut anchor remained stable during several compression attempts as compared with the other two 5-strut anchor designs. The 10-strut design provided the maximum number of contact points with the vessel in a circular layout and was less susceptible to movement or dislodgement during compression tests. Furthermore, the CFD simulation provided haemodynamic analysis of the optimum 10-strut anchor design., Conclusions: This study successfully demonstrated the design and deployment of an inferior vena cava anchoring system in a bench test model. The 10-strut anchor is an optimal design as compared with the two other 5-strut designs; however, substantial in-vivo experiments are required to validate the safety and accuracy of such implants. The CFD simulation enabled better understanding of the haemodynamic parameters and any disturbances in the blood flow due to the presence of the anchor. The ability to place a sensor technology in the vena cava could provide a simple and minimally invasive approach for heart failure patients.

Rationale: The COVID-19 pandemic disrupted non-COVID critical care trials globally as intensive care units (ICUs) prioritized patient care and COVID-specific research. The international randomized controlled trial CYCLE (Critical Care Cycling to Improve Lower Extremity Strength) was forced to halt recruitment at all sites in March 2020, creating immediate challenges. We applied the CONSERVE (CONSORT and SPIRIT Extension for RCTs Revised in Extenuating Circumstance) statement as a framework to report the impact of the pandemic on CYCLE and describe our mitigation approaches., Methods: On March 23, 2020, the CYCLE Methods Centre distributed a standardized email to determine the number of patients still in-hospital and those requiring imminent 90-day endpoint assessments. We assessed protocol fidelity by documenting attempts to provide the in-hospital randomized intervention (cycling or routine physiotherapy) and collect the primary outcome (physical function 3-days post-ICU discharge) and 90-day outcomes. We advised sites to prioritize data for the study's primary outcome. We sought feedback on pandemic barriers related to trial procedures., Results: Our main Methods Centre mitigation strategies included identifying patients at risk for protocol deviations, communicating early and frequently with sites, developing standardized internal tools focused on high-risk points in the protocol for monitoring patient progress, data entry, and validation, and providing guidance to conduct some research activities remotely. For study sites, our strategies included determining how institutional pandemic research policies applied to CYCLE, communicating with the Methods Centre about capacity to continue any part of the research, and developing contingency plans to ensure the protocol was delivered as intended. From 15 active sites (12 Canada, 2 US, 1 Australia), 5 patients were still receiving the study intervention in ICUs, 6 required primary outcomes, and 17 required 90-day assessments. With these mitigation strategies, we attempted 100% of ICU interventions, 83% of primary outcomes, and 100% of 90-day assessments per our protocol., Conclusions: We retained all enrolled patients with minimal missing data using several time-sensitive strategies. Although CONSERVE recommends reporting only major modifications incurred by extenuating circumstances, we suggest that it also provides a helpful framework for reporting mitigation strategies with the goal of improving research transparency and trial management., Trial Registration: NCT03471247. Registered on March 20, 2018., (© 2022. The Author(s).)

The Canadian population is aging. With aging, biological and social changes occur increasing the risk of developing chronic conditions and functional loss leading to frailty. Older adults living with frailty are more vulnerable to minor stressors, take longer to recover from illness, and have difficulty participating in daily activities. The Canadian Frailty Network's (CFN) mission is to improve the lives of older adults living with frailty. In September 2019, CFN launched the Activity & Exercise, Vaccination, Optimization of medications, Interaction & Socialization, and Diet & Nutrition (AVOID) Frailty public health campaign to promote assessing and reducing risk factors leading to the development of frailty. As part of the campaign, CFN held an Enabling Healthy Aging Symposium with 36 stakeholders from across Canada. Stakeholders identified individual and community-level opportunities and challenges for the enablement of healthy aging and frailty mitigation, as part of a focused consultative process. Stakeholders ranked the three most important challenges and opportunities at the individual and community levels for implementing AVOID Frailty recommendations. Concrete actions, further research areas, policy changes, and existing resources/programs to enhance the AVOID Frailty campaign were identified. The results will help inform future priorities and behaviour change strategies for healthy aging in Canada., Competing Interests: CONFLICT OF INTEREST DISCLOSURES Dr. Megan Racey was supported by a Post-Doctoral Fellowship through the Canadian Frailty Network at the time of the Enabling Healthy Aging Symposium. Dr. Emily McDonald is co-owner of MedSafer, a medication deprescribing software. All remaining authors declare no conflicts of interest exist., (© 2022 Author(s). Published by the Canadian Geriatrics Society.)

Background: Clinical data on patients admitted to hospital with coronavirus disease 2019 (COVID-19) provide clinicians and public health officials with information to guide practice and policy. The aims of this study were to describe patients with COVID-19 admitted to hospital and intensive care, and to investigate predictors of outcome to characterize severe acute respiratory infection., Methods: This observational cohort study used Canadian data from 32 selected hospitals included in a global multisite cohort between Jan. 24 and July 7, 2020. Adult and pediatric patients with a confirmed diagnosis of COVID-19 who received care in an intensive care unit (ICU) and a sampling of up to the first 60 patients receiving care on hospital wards were included. We performed descriptive analyses of characteristics, interventions and outcomes. The primary analyses examined in-hospital mortality, with secondary analyses of the length of hospital and ICU stay., Results: Between January and July 2020, among 811 patients admitted to hospital with a diagnosis of COVID-19, the median age was 64 (interquartile range [IQR] 53-75) years, 495 (61.0%) were men, 46 (5.7%) were health care workers, 9 (1.1%) were pregnant, 26 (3.2%) were younger than 18 years and 9 (1.1%) were younger than 5 years. The median time from symptom onset to hospital admission was 7 (IQR 3-10) days. The most common symptoms on admission were fever, shortness of breath, cough and malaise. Diabetes, hypertension and cardiac, kidney and respiratory disease were the most common comorbidities. Among all patients, 328 received care in an ICU, admitted a median of 0 (IQR 0-1) days after hospital admission. Critically ill patients received treatment with invasive mechanical ventilation (88.8%), renal replacement therapy (14.9%) and extracorporeal membrane oxygenation (4.0%); 26.2% died. Among those receiving mechanical ventilation, 31.2% died. Age was an influential predictor of mortality (odds ratio per additional year of life 1.06, 95% confidence interval 1.03-1.09)., Interpretation: Patients admitted to hospital with COVID-19 commonly had fever, respiratory symptoms and comorbid conditions. Increasing age was associated with the development of critical illness and death; however, most critically ill patients in Canada, including those requiring mechanical ventilation, survived and were discharged from hospital., Competing Interests: Competing interests: See the end of the article. Competing interests: Todd Lee reports salary support from Fonds de recherche du Québec – Santé. Deepali Kumar reports grants and personal fees from Roche. Michelle Kho reports grants from Canada Research Chairs. Matthew Cheng reports grants from the McGill Interdisciplinary Initiative in Infection and Immunity and personal fees from GEn1E Lifesciences (as a member of the scientific advisory board) and personal fees from nplex biosciences (as a member of the scientific advisory board). Philippe Jouvet reports consulting for Mallinckrodt Pharmaceuticals and grants to his institution from VitalTracer and Evolucare. Patrick Archambault is a co-investigator in the Canadian Institutes of Health Research (CIHR)–funded Canadian COVID-19 Emergency Department Rapid Response Network (https://canadiancovid19ednetwork.org). No other competing interests were declared., (© 2021 Joule Inc. or its licensors.)

Background/objective: Central venous pressure (CVP) serves as a surrogate for right atrial pressure, and thus could potentially predict a wider range of heart failure conditions. The purpose of this work is to assess CVP, through an implantable sensor incorporated with a novel anchor design, in the inferior and superior vena cava of an animal model., Methods: Two animals (Dorset sheep) were implanted with sensors at 3 different locations: inferior vena cava (IVC), superior vena cava (SVC), and pulmonary artery (PA). Two sensors with distinct anchor designs considering anatomical requirements were used. A standard PA sensor (trade name Cordella) was deployed in the PA and SVC, whereas a sensor with a modified cylindrical anchor with various struts was designed to reside in the IVC. Each implant was calibrated against a Millar catheter reference sensor. The ability of the central venous sensors to detect changes in pressure was evaluated by modifying the fluid volume of the animal., Results: The sensors implanted in both sheep were successful, which provided an opportunity to understand the relationship between PA and CVP via simultaneous readings. The mapping and implantation in the IVC took less than 15 minutes. Multiple readings were taken at each implant location using a hand-held reader device under various conditions. CVP recorded in the IVC (6.49 mm Hg) and SVC (6.14 mm Hg) were nearly the same. PA pressure (13-14 mm Hg) measured was higher than CVP, as expected. The SVC waveforms showed clear beats and respiration. Respiration could be seen in the IVC waveforms, but not all beats were easily distinguishable. Both SVC and IVC readings showed increases in pressure (3.7 and 2.7 mm Hg for SVC and IVC, respectively) after fluid overload was induced via extra saline administration., Conclusion: In this work, the feasibility of measuring CVP noninvasively was demonstrated. The established ability of wireless PA pressure sensors to enable prevention of decompensation events weeks ahead can now be explored using central venous versions of such sensors., (© 2020 Heart Rhythm Society.)

In an effort to identify novel antithrombotics, we have investigated protease-activated receptor 4 (PAR4) antagonism by developing and evaluating a tool compound, UDM-001651 , in a monkey thrombosis model. Beginning with a high-throughput screening hit, we identified an imidazothiadiazole-based PAR4 antagonist chemotype. Detailed structure-activity relationship studies enabled optimization to a potent, selective, and orally bioavailable PAR4 antagonist, UDM-001651 . UDM-001651 was evaluated in a monkey thrombosis model and shown to have robust antithrombotic efficacy and no prolongation of kidney bleeding time. This combination of excellent efficacy and safety margin strongly validates PAR4 antagonism as a promising antithrombotic mechanism.

Purpose: The presence and progression of heart failure (HF) are associated with cardiac remodelling, defined as cellular, molecular and interstitial changes which occur after injury and manifest as changes in left ventricular (LV) size, mass, geometry and function. This research study was designed to investigate the changes to LV morphology and shape which occur in the presence of heart failure using three-dimensional (3D) modelling and analysis of cardiac-gated CT scans from both healthy individuals and patients classified with HF., Methods: A number of quantitative and qualitative strategies were applied to cardiac CT scans of HF patients and healthy controls (n = 7) in order to analyse changes to LV size, shape and structure and to examine LV remodelling in the different classes of HF. Three-dimensional wireframe representations of endocardial and epicardial borders were created, three-dimensional computer stereolithography models of the inner LV cavity and myocardial wall segments were generated and three-dimensionally printed and a number of clinical LV dimension and shape indices were measured. All data were analysed using one-way ANOVA with post hoc Tukey method for multiple comparisons for significant variables., Results: Results of most significance included abnormalities in LV mass and end-systolic dimensions and significantly increased septal wall thickness among mid-range ejection fraction cases. Also of importance were significant increases in both dimension-based and volumetric sphericity index measures in all HF cases. Three-dimensional printed models provided qualitative information as to changes in inner LV cavity and myocardial wall morphology across the cardiac cycle for healthy and HF cases and validated quantitative findings., Conclusion: Findings from this study can successfully be applied to motivate the research and development of new HF treatment strategies and devices as well as for the development of a realistic cardiac simulator system.

Background: Transanal mesorectal resection has been developed to facilitate minimally invasive proctectomy for rectal cancer., Objective: The purpose of this study was to evaluate the evidence regarding technical parameters, oncological outcomes, morbidity, and mortality after transanal mesorectal resection., Data Sources: The Cochrane Library, PubMed, and MEDLINE databases were reviewed., Study Selection: Systematic review of the literature from January 2005 to September 2015 was used for study selection., Intervention: Intervention included transanal mesorectal resection for rectal cancer., Main Outcome Measures: Technical parameters, histological outcomes, morbidity, and mortality were the outcomes measured., Results: Fifteen predominately retrospective studies involving 449 patients were included (mean age, 64.3 years; 64.1% men). Different platforms were used. The operative mortality rate was 0.4% and the cumulative morbidity rate 35.5%. Circumferential resection margins were clear in 98%, and the resected mesorectum was grade III in 87% of patients. Median follow-up was 14.7 months. There were 4 local recurrences (1.5%) and 12 patients (5.6%) with metastatic disease. No study followed patients long enough to report on 5-year overall and disease-free survival rates. Functional outcome was only reported in 3 studies., Limitations: A low number of procedures were performed by expert early adopters. There are no comparative or randomized data included in this study and inconsistent reporting of outcome variables., Conclusions: Transanal mesorectal resection for rectal cancer may enhance negative circumferential margin rates with a reasonable safety profile. Contemporary randomized, controlled studies are required before there can be universal recommendation.

A 57-year-old man with no medical history and comorbidities presented to the outpatient clinic with a 2-week history of increasing cough and shortness of breath following a recent viral upper respiratory tract infection. Chest X-ray showed increased mediastinal opacity. A CT scan of the thorax was performed which revealed a large right-sided diaphragmatic hernia extending across the mediastinum to the left side of the chest. Repair was performed via combined transthoracic and transabdominal approaches.

The introduction of an aryl ring onto the 4-position of the C-6 benzyl amino group of the Cdk inhibitor roscovitine (2), maintained the potent Cdk inhibition demonstrated by roscovitine (2) as well as greatly improving the antiproliferative activity. A series of C-6 biarylmethylamino derivatives was prepared addressing modifications on the C-6 biaryl rings, N-9 and C-2 positions to provide compounds that displayed potent cytotoxic activity against tumor cell lines. In particular, derivative 21h demonstrated a >750-fold improvement in the growth inhibition of HeLa cells compared to roscovitine (2).

We report the long-term follow-up of successful treatment of mucopolysaccharidosis type I H (MPS IH, Hurler syndrome) with combined enzyme replacement therapy and haematopoietic progenitor stem cell transplant.

Mycotic femoral pseudoaneurysms, particularly in the drug-abusing population, pose a difficult problem to the vascular surgeon. Management ranges from ligation with debridement to extra-anatomical bypass. This study reviewed the management of mycotic femoral pseudoaneurysms presenting in intravenous drug abusers to an inner city tertiary referral center. Between 2001 and 2006, 11 cases presenting in nine patients were treated. The mean age was 30.7 years with a male-to-female ratio of 1:2. Eight patients had a positive viral status for the human immunodeficiency virus and/or hepatitis C. Two patients re-presented with a contralateral pseudoaneurysm. A combination of groin pain and swelling was the most common presentation. Two patients presented with significant hemorrhage. The diagnosis was confirmed by ultrasound in the majority of cases. Nine cases were managed with arterial ligation and debridement of the necrotic tissue. The two remaining cases were managed with ultrasound-guided thrombin injection and arterial puncture closure. On follow-up, one patient required a below-knee amputation following reinjection into the postoperative wound site. One further patient underwent a fifth metatarsal amputation due to ischemia. Ligation and debridement are well tolerated in the majority of drug-abusing patients diagnosed with mycotic femoral pseudoaneurysms.

Pancreatic neuroendocrine tumours (PET) are rare neoplasms of the pancreas accounting for less than 5% of all primary pancreatic malignancies. Included in this group are insulinomas, gastrinomas, glucagonoma and somatostatinomas. Collectively these neoplasms are classified as functional PETs. Where a PET is not associated with a clinical syndrome due to hormone oversecretion, it is referred to as a non-functioning PET. Non-functioning PETs are pancreatic tumours with endocrine differentiation but lack a clinical syndrome of hormone hypersecretion. The incidence of these tumours varied between 15 and 53%. Presentation is related to the mass effect of the tumour with symptoms often non-specific. Treatment is surgical excision with chemotherapy and hormonal therapy is controversial. For functioning PETs, surgery remains the optimal therapy, however, long-term survival can be expected even in the presence of metastases. With advances in medical management, radiolabelled somatostatin therapy, hepatic arterial chemoembolisation and radiofrequency ablation, symptoms may be controlled to optimize quality of life.

Recent studies have shown that a subgroup of phenylketonuric patients respond to high doses of BH4 (20 mg/kg) by a decrease of plasma phenylalanine. A clinically significant response has been defined as a decrease in phenylalanine by more than 30% within 24 h, after a BH4 challenge. We report our experience with 37 patients diagnosed with hyperphenylalaninemia, mild, moderate, or classical Phenylketonuria (PKU) using a seven day combined BH4 and phenylalanine load. Nine of the 37 patients responded with a 30% decrease in their phenylalanine levels in the first 8 h of treatment. A total of 17 patients (46%) had a decrease of at least 30% during the study period. This study confirms that a significant number of patients with mild to moderate PKU will respond to a BH4 load. Furthermore, it confirms that the seven-day phenylalanine test is more sensitive in detecting BH4 responsive patients.

Eighty percent of bladder cancers present as superficial disease. Many are multifocal, and apparently successful treatment is frequently followed by recurrence. The use of monoclonal antibodies (MAbs) to target radiotherapy to these tumors offers great potential, especially since they can be administered directly into the bladder (intravesically) bypassing many of the side effects encountered to date with systemic MAb-based therapy. Implantation of human bladder cancer cell lines in the bladder wall of nude rats results in tumor formation, providing an excellent model to test this. Tumor size can be monitored by X-ray analysis after administration of urograffin. Comparative studies of two murine MAbs, BLCA-8, IgG3, and C1-137, IgG1, against malignant human bladder cancer cells have been performed. Radioimmunoconjugates produced with 125Iodine (125I) have been used for biodistribution studies following administration directly into rat bladder. Radioiodinated intact MAbs or Fabs administered intravesically into nontumor bearing rats did not leak into the systemic circulation and were stable in urine for up to 100 h. Biodistribution studies carried out following intravesical administration of radioimmunoconjugates to tumor-bearing nude rats indicate better tumor uptake of C1-137 than BLCA-8. Further studies to test two-step intravesical administration of biotinylated MAb followed by radioiodinated streptavidin are in progress. Our studies indicate that the C1-137 MAb may have considerable potential for intravesical radioimmunotherapy of patients with superficial bladder tumors.

Background: Whether the plasma triglyceride level is a risk factor for coronary heart disease has been controversial, and evaluation of the triglyceride level as a risk factor is fraught with methodologic difficulties., Methods: We studied the association between plasma triglyceride levels and the 12-year incidence of death from coronary heart disease in 10 North American populations participating in the Lipid Research Clinics Follow-up Study, while adjusting for the potential confounding effects of other risk factors for cardiovascular disease, including the level of high-density lipoprotein (HDL) cholesterol. All analyses were sex-specific, and separate analyses were performed in high and low strata of HDL cholesterol, low-density lipoprotein (LDL) cholesterol, fasting plasma glucose, and age., Results: The rates of coronary death in both men and women increased with the triglyceride level. In Cox proportional-hazards models adjusted for age, in which the natural log of the triglyceride levels was used to give a normal distribution, the relative risk per natural-log unit of triglyceride (e.g., a triglyceride level of 150 mg per deciliter vs. a level of 55 mg per deciliter) was 1.54 (95 percent confidence interval, 1.19 to 1.98; P < 0.001) in men and 1.88 (95 percent confidence interval, 1.19 to 2.98; P < 0.007) in women. After an adjustment for potential covariates, however, these relative risks were not statistically significant. Analyses based on lipoprotein cholesterol levels revealed a positive association between the triglyceride level and coronary mortality in the lower stratum of both HDL and LDL cholesterol, but not in the higher stratum. Conversely, the HDL cholesterol level was unrelated to coronary mortality in the lower stratum of LDL cholesterol, but was strongly inversely associated with coronary death in the higher stratum of LDL cholesterol. The relative risk of coronary death associated with triglyceride level was higher at younger ages. The associations between the triglyceride level and coronary mortality in the lower HDL cholesterol, LDL cholesterol, and age strata were small and were further reduced by an adjustment for the fasting plasma glucose level., Conclusions: Overall, the plasma triglyceride level showed no independent association with coronary mortality. However, in subgroups of subjects with lower HDL and LDL cholesterol levels and in younger subjects, defined a priori, an association between the triglyceride level and coronary mortality was observed, although this association was small and was not statistically significant after an adjustment for the plasma glucose level.