Arterial stiffness for the early prediction of pre-eclampsia compared with blood pressure, uterine artery Doppler and angiogenic biomarkers: a prospective cohort study.

OBJECTIVE: Our aim was to evaluate the ability of arterial stiffness parameters to predict pre-eclampsia early compared with peripheral blood pressure, uterine artery Doppler and established angiogenic biomarkers. DESIGN: Prospective cohort study. SETTING: Tertiary care antenatal clinics in Montreal, Canada. POPULATION: Women with singleton high-risk pregnancies. METHODS: In the first trimester, arterial stiffness was measured by applanation tonometry, along with peripheral blood pressure and serum/plasma angiogenic biomarkers; uterine artery Doppler was measured in the second trimester. The predictive ability of different metrics was assessed through multivariate logistic regression. MAIN OUTCOME MEASURES: Arterial stiffness (carotid-femoral pulse wave velocity, carotid-radial pulse wave velocity) and wave reflection (augmentation index, reflected wave start time), peripheral blood pressure, ultrasound indices of velocimetry and circulating angiogenic biomarker concentrations. RESULTS: In this prospective study, among 191 high-risk pregnant women, 14 (7.3%) developed pre-eclampsia. A first-trimester 1 m/s increase in carotid-femoral pulse wave velocity was associated with 64% increased odds (P < 0.05), and a 1-millisecond increase in time to wave reflection with 11% decreased odds for pre-eclampsia (P < 0.01). The area under the curve of arterial stiffness, blood pressure, ultrasound indices and angiogenic biomarkers was 0.83 (95% confidence interval [CI] 0.74-0.92), 0.71 (95% CI 0.57-0.86), 0.58 (95% CI 0.39-0.77), and 0.64 (95% CI 0.44-0.83), respectively. With a 5% false-positive rate, blood pressure had a sensitivity of 14% for pre-eclampsia and arterial stiffness a sensitivity of 36%. CONCLUSIONS: Arterial stiffness predicted pre-eclampsia earlier and with greater ability than blood pressure, ultrasound indices or angiogenic biomarkers.

First Results from the DEAP-3600 Dark Matter Search with Argon at SNOLAB.

This Letter reports the first results of a direct dark matter search with the DEAP-3600 single-phase liquid argon (LAr) detector. The experiment was performed 2 km underground at SNOLAB (Sudbury, Canada) utilizing a large target mass, with the LAr target contained in a spherical acrylic vessel of 3600 kg capacity. The LAr is viewed by an array of PMTs, which would register scintillation light produced by rare nuclear recoil signals induced by dark matter particle scattering. An analysis of 4.44 live days (fiducial exposure of 9.87 ton day) of data taken during the initial filling phase demonstrates the best electronic recoil rejection using pulse-shape discrimination in argon, with leakage <1.2×10^{-7} (90% C.L.) between 15 and 31 keV_{ee}. No candidate signal events are observed, which results in the leading limit on weakly interacting massive particle (WIMP)-nucleon spin-independent cross section on argon, <1.2×10^{-44} cm^{2} for a 100 GeV/c^{2} WIMP mass (90% C.L.).

Integrating cytokines and angiogenic factors and tumour bulk with selected clinical criteria improves determination of prognosis in advanced renal cell carcinoma.

BACKGROUND: In two clinical trials of the vascular endothelial growth factor (VEGF) receptor inhibitor pazopanib in advanced renal cell carcinoma (mRCC), we found interleukin-6 as predictive of pazopanib benefit. We evaluated the prognostic significance of candidate cytokines and angiogenic factors (CAFs) identified in that work relative to accepted clinical parameters. METHODS: Seven preselected plasma CAFs (interleukin-6, interleukin-8, osteopontin, VEGF, hepatocyte growth factor, tissue inhibitor of metalloproteinases (TIMP-1), and E-selectin) were measured using multiplex ELISA in plasma collected pretreatment from 343 mRCC patients participating in the phase 3 registration trial of pazopanib vs placebo (NCT00334282). Tumour burden (per sum of longest diameters (SLD)) and 10 other clinical factors were also analysed for association with overall survival (OS; based on initial treatment assignment). RESULTS: Osteopontin, interleukin-6, and TIMP-1 were independently associated with OS in multivariable analysis. A model combining the three CAFs and five clinical variables (including SLD) had higher prognostic accuracy than the International Metastatic Renal Cell Carcinoma Database Consortium criteria (concordance-index 0.75 vs 0.67, respectively), and distinguished two groups of patients within the original intermediate risk category. CONCLUSIONS: A prognostic model incorporating osteopontin, interleukin-6, TIMP-1, tumour burden, and selected clinical criteria increased prognostic accuracy for OS determination in mRCC patients.

Script concordance testing in continuing professional development: local or international reference panels?

Context The PRACTICUM Institute has developed large-scale international programs of on-line continuing professional development (CPD) based on self-testing and feedback using the Practicum Script Concordance Test© (PSCT). Aims To examine the psychometric consequences of pooling the responses of panelists from different countries (composite panels) and the effect of increasing composite panel size. Method 97 cardiologists in Mexico answered a set of 62 PSCT cases/305 questions. A local panel was recruited in Mexico (n = 7). Other panelists were recruited in Argentina (n = 10) and Brazil (n = 11). Together they constituted a composite panel of 28 experts. Random panels of reference of increasing sizes (5, 10, 15, 20, and 25) were generated. Participants' scores were computed for each panel sample. Units of analysis were means of participants' scores per case. Discrimination, ranking and reliability of the scores obtained with each panel were estimated. Descriptive statistics, Pearson correlation coefficient, generalizability analysis, computation of Cronbach's alpha were used in the analyses. Results Correlation coefficients between the local and the composite panels ranged from 0.951 to 0.981. Cronbach alpha coefficient values were above 0.85 for all panels. The value of the relative G coefficient from the generalizability analyses varied from 0.91 to 0.93, indicating very high and stable ranking of participants, though absolute value of scores increased with increasing composite panel size. Conclusions In CPD environments, and with panel members selected with the highest standards, composite panels can be used. Panels of all sizes yielded high psychometric qualities. Absolute scores should be interpreted with caution.

Advanced practice physiotherapy care in emergency departments for patients with musculoskeletal disorders: a pragmatic cluster randomized controlled trial and cost analysis.

BACKGROUND: Advanced practice physiotherapy (APP) models of care where physiotherapists are primary contact emergency department (ED) providers are promising models of care to improve access, alleviate physicians' burden, and offer efficient centered patient care for patients with minor musculoskeletal disorders (MSKD). OBJECTIVES: To compare the effectiveness of an advanced practice physiotherapist (APPT)-led model of care with usual ED physician care for persons presenting with a minor MSKD, in terms of patient-related outcomes, health care resources utilization, and health care costs. METHODS: This trial is a multicenter stepped-wedge cluster randomized controlled trial (RCT) with a cost analysis. Six Canadian EDs (clusters) will be randomized to a treatment sequence where patients will either be managed by an ED APPT or receive usual ED physician care. Seven hundred forty-four adults with a minor MSKD will be recruited. The main outcome measure will be the Brief Pain Inventory Questionnaire. Secondary measures will include validated self-reported disability questionnaires, the EQ-5D-5L, and other health care utilization outcomes such as prescription of imaging tests and medication. Adverse events and re-visits to the ED for the same complaint will also be monitored. Health care costs will be measured from the perspective of the public health care system using time-driven activity-based costing. Outcomes will be collected at inclusion, at ED discharge, and at 4, 12, and 26 weeks following the initial ED visit. Per-protocol and intention-to-treat analyses will be performed using linear mixed models with a random effect for cluster and fixed effect for time. DISCUSSION: MSKD have a significant impact on health care systems. By providing innovative efficient pathways to access care, APP models of care could help relieve pressure in EDs while providing efficient care for adults with MSKD. TRIAL REGISTRATION: ClinicalTrials.gov NCT05545917 . Registered on September 19, 2022.

Feasibility of vesicoamniotic shunt insertion in an inanimate model: comparison of fetoscopic and ultrasound-guided techniques.

OBJECTIVES: To determine the feasibility of fetoscopic vesicoamniotic shunt insertion (F-VASI) in an inanimate model and to compare F-VASI to ultrasound (US)-guided VASI (US-VASI) with respect to accuracy of shunt placement and overall success rate. METHODS: An inanimate second-trimester fetus with a replaceable bladder balloon was suspended in a pressurized water tank and localized with US. Fetal position was randomized, the operator was blinded and a 5-Fr Harrison Shunt® decompressed the bladder in both groups. Thirty shunt insertions were performed per group. RESULTS: Procedure time was longer for F-VASI (15.0 vs. 2.8 min, p < 0.05), although it decreased with practice. F-VASI and US-VASI were similar for adequate depth of insertion (27/30 vs. 27/30, p = 1.0), placement within 1 cm of midline (27/30 vs. 25/30, p = 0.42), bladder puncture (28/30 vs. 28/30, p = 1.0), and overall success rate (27/30 vs. 23/30, p = 0.3). CONCLUSIONS: F-VASI is feasible in an inanimate model. Overall success rate was similar between the groups, although procedure time was longer for F-VASI. Further study is required to determine whether shunt migration is decreased with F-VASI.

Pulse-shape discrimination against low-energy Ar-39 beta decays in liquid argon with 4.5 tonne-years of DEAP-3600 data.

The DEAP-3600 detector searches for the scintillation signal from dark matter particles scattering on a 3.3 tonne liquid argon target. The largest background comes from 39 Ar beta decays and is suppressed using pulse-shape discrimination (PSD). We use two types of PSD estimator: the prompt-fraction, which considers the fraction of the scintillation signal in a narrow and a wide time window around the event peak, and the log-likelihood-ratio, which compares the observed photon arrival times to a signal and a background model. We furthermore use two algorithms to determine the number of photons detected at a given time: (1) simply dividing the charge of each PMT pulse by the mean single-photoelectron charge, and (2) a likelihood analysis that considers the probability to detect a certain number of photons at a given time, based on a model for the scintillation pulse shape and for afterpulsing in the light detectors. The prompt-fraction performs approximately as well as the log-likelihood-ratio PSD algorithm if the photon detection times are not biased by detector effects. We explain this result using a model for the information carried by scintillation photons as a function of the time when they are detected.

Lapatinib monotherapy in patients with relapsed, advanced, or metastatic breast cancer: efficacy, safety, and biomarker results from Japanese patients phase II studies.

BACKGROUND: HER2-positive metastatic breast cancer (MBC) relapsing after trastuzumab-based therapy may require continued HER2 receptor inhibition to control the disease and preserve the patients' quality-of-life. Efficacy and safety of lapatinib monotherapy was evaluated in Japanese breast cancer patients after trastuzumab-based therapies. METHODS: In studies, EGF100642 and EGF104911 evaluated the efficacy and safety of oral lapatinib given 1500 mg once daily in patients with advanced or MBC. All patients progressed on anthracyclines and taxanes; HER2-positive patients had also progressed on trastuzumab. RESULTS: For HER2-positive tumours (n=100), objective response rate was 19.0% (95% confidence interval (CI): 11.8-28.1) and clinical benefit rate (CBR) was 25.0% (95% CI: 16.9-34.7). One out of 22 HER2-negative tumour was documented as complete response (n=22). The median time-to-progression (TTP) in the HER2-positive and HER2-negative groups was 13.0 and 8.0 weeks (P=0.007); median overall survival was 58.3 and 40.0 weeks, respectively. The most frequent adverse event was diarrhoea. TTP and CBR were significantly associated with HER2 expression. Patients with tumours harbouring an H1047R PIK3CA mutation or low expression of PTEN derived clinical benefit from lapatinib. CONCLUSION: Lapatinib monotherapy had shown anti-tumour activity in Japanese patients with HER2-positive MBC that relapsed after trastuzumab-based therapy, including those with brain metastases. Patients benefiting from lapatinib may have biomarker profiles differing from that reported for trastuzumab.

Province-wide population survey of acute appendicitis in Canada. New twists to an old disease.

BACKGROUND: This study, sponsored and conducted by Le Collège des Médecins du Québec, audited the management of acute appendicitis in the Province of Québec (Population 7.6 million), Canada, over a period of 1 year (April 2002-March 2003). METHODS: A questionnaire was sent to the Health Records Department of all hospitals surgically treating appendicitis in the province. Data from 85 (100%) hospitals were received and reviewed. RESULTS: During the study period, 7,599 appendectomies were performed, and 5,707 (75%) were selected for study (55% men). The rate of normal and perforated appendix was 5.4% and 15.9% respectively. Median hospital stay for simple and perforated appendicitis was 2.6 and 5.8 days, respectively. At least one imaging procedure was done in 86% of cases (23% computed tomography [CT], 55% ultrasound). Antibiotics were not given in 7% of cases and in 8% of patients with a perforation. Seventeen percent of patients did not receive preoperative or intraoperative doses, and postoperatively, 69% of patients received unnecessary doses. Laparoscopy was used in 35% of cases and was associated with a reduction in postoperative stay for simple (2.6 versus 2.9 days, p < 0.001) and perforated appendicitis (4.6 versus 5.9 days, p = 0.004). A low rate of laparoscopy (<25%) was found in 53% of teaching (University and Affiliated) and 45% of nonteaching institutions. Conversion to open surgery was necessary in 9.7% of simple appendicitis and 29.3% of perforated ones (p < 0.001). CONCLUSIONS: Although results of this survey are comparable to those of similar published series, a few concerns emerge. Many have to do with patient noncompliance with recommended antibiotic usage for acute appendicitis. Further, although laparoscopy seems to be slowly making its way into the surgical armamentarium, the low rate of laparoscopic appendectomies in teaching hospitals raises the issue of appropriate resident training.

Diabetes screening of children in a remote First Nations community on the west coast of Canada: challenges and solutions.

Type 2 diabetes (T2D) and its precursor, impaired glucose tolerance (IGT), are now reaching epidemic proportions among Aboriginal Canadians. Of particular concern is the appearance and increasing prevalence of T2D and IGT among Aboriginal youth. At the request of three communities in the Tsimshian nation on the northern coast of British Columbia (with which the Department of Pediatrics, University of British Columbia, had a pre-existing partnership) a screening program was undertaken to determine the prevalence of T2D and IGT among the children. The long-term goal was the collaborative development of intervention programs for each community. The challenges of meeting this request included the sociological and ethical issues associated with research in First Nations communities, as well as the pragmatic issues of conducting complex research in remote communities. Three separate visits were undertaken to respect the cultural dynamics and capacity of the community to accommodate a project of this magnitude. The process began with dialogue, listening and presentations to the community. Only then began the planning of logistics and application for funding. Next, the team visited the communities to ensure understanding of exactly what was involved for the community, each child and family, and to be certain that consent was fully informed. For the diabetes screening visit, special arrangements including chartering a Beaver float plane were needed for the transport of the five-member team with all the necessary equipment, including a -20(o)C freezer to safeguard the integrity of blood samples. The 100% consent rate, successful conduct of study, and retention of community support achieved by the process, indicate that population-based clinical research is possible in remote First Nations communities. This is best achieved with appropriate dialogue, care, respect and planning to overcome the sociological, ethical and practical challenges.

Low urine pH is associated with reduced indinavir crystalluria in indinavir-treated HIV-infected individuals.

Indinavir is a potent HIV-1 protease inhibitor included in current antiretroviral therapeutic regimens. It is associated with renal and urological complications ascribed to indinavir crystalluria. We have previously reported that indinavir crystalluria is frequently observed soon after initiation of therapy. In a cohort of 54 asymptomatic indinavir-naive HIV-1-infected individuals during their first year of treatment with indinavir, approximately 25% of urinalyses (U/A) contained indinavir crystals. Because the determinants of the crystalluria are unknown, we examined the relationship between urine specific gravity (SG) and pH, singly and in combination, and indinavir crystalluria in these subjects. A total of 579 U/A were obtained from the study subjects at their scheduled monthly outpatient medical assessments. The frequency of indinavir crystalluria was lower in U/A with lower pH, irrespective of the SG. Conversely, U/A with high pH (> or = 6.0) had a higher frequency of indinavir crystalluria, which was further influenced by the urine SG. As a result, nearly half of the U/A (46.7%) with high pH (> or = 6.0) and intermediate-high SG (> or = 1.015) contained indinavir crystals. In conclusion, the frequency of indinavir crystalluria in asymptomatic HIV-1 infected individuals during their first year of treatment with indinavir was markedly influenced by the urine pH and SG. Our findings suggest that low urine pH may have a protective effect against indinavir crystalluria across the entire range of urine SG.

Northern innovation in rabies prevention and control: The Weeneebayko Area Health Authorities (WAHA) dog population management pilot project.

BACKGROUND: Remote northern communities in Ontario face unique challenges in rabies prevention and control. With large, free-roaming dog populations at high risk of exposure to rabies from wildlife, and a lack of regular access to veterinary services and vaccinations, these communities run a higher risk of human exposure to rabies than southern regions of the province. OBJECTIVE: To provide the baseline data on a novel approach to controlling the dog population in the Weeneebayko Area Health Authority (WAHA) in northern Ontario, implemented as part of a sustainable, humane and cost-effective pilot project to manage dog population numbers and improve public safety. INTERVENTION: In 2015, WAHA launched a large-scale two-year regional project that involved microchipping all dogs in the region to quantify and monitor population levels, vaccinating them with canine core vaccinations (including rabies) and piloting the use of an injectable ganodotropin-releasing hormone (GnRH) agonist contraceptive implant in female dogs. The Project's objectives included control of dog population numbers, reducing aggressive behaviours in community dogs, reducing the risk of rabies in communities, improving the health of community dogs and educating community members about the importance of dog population control. OUTCOMES: In 2015, 513 dogs were microchipped and vaccinated as part of the WAHA Project: 211 females and 301 males. Seventy-six intact, free-roaming females were given the contraceptive implant, 113 females were identified as previously spayed and only 22 females were either too young or too small (toy breeds) to receive an implant. CONCLUSION: While the final outcomes of the WAHA Project are still pending, preliminary findings, including dog population demographics and observed dynamics, support the feasibility of contraceptive implants in female dogs as a primary intervention to quickly and cost-effectively reduce dog population numbers in remote northern regions and reduce the risk of rabies transmission.

The national ambulatory medical care survey: 1973 summary United States, may 1973-april 1974.

There were an estimated 644.9 million "encounters", or "visits", in the offices of "office-based" physicians in the United States during the period May 1973-April 1974. By definition, these were visits for the purpose of seeking or receiving care that involved a direct personal exchange between the patient and the physician or a member of his staff, Females accounted for three of every five visits. White persons accounted for nearly 9 of every 10 visits. The average person made 3.1 visits during the 1-year period. General and family practitioners accounted for 40.4 percent of all visits; medical specialties, 26.3 percent; and surgical specialties, 28.5 percent. More than 60 percent of all visits were by patients seen previously for the same problem; and about 20 percent were for problems considered serious or very serious by the physician. During 63 percent of all visits, the patient expressed a "symptomatic" problem or complaint as the major reason for the visit. "Nonsymptomatic" problems accounted for 18 percent of all visits. Either a disease of the respiratory system or a disease of the circulatory system was the diagnosis in about one of every four visits. Drug therapy was part of the treatment prescribed at half of all visits. Laboratory tests were ordered nearly 20 percent of the time as was an injection or immunization. No treatment was considered necessary at 5 percent of all visits. For 61.2 percent of the visits, the patient was instructed to return at a specified time. No followup was planned at 12.7 percent of the visits.

Obstructive lung disease and low lung function in adults in the United States: data from the National Health and Nutrition Examination Survey, 1988-1994.

BACKGROUND: Obstructive lung disease (OLD) is an important cause of morbidity and mortality in the US adult population. Potentially treatable mild cases of OLD often go undetected. This analysis determines the national estimates of reported OLD and low lung function in the US adult population. METHODS: We examined data from the Third National Health and Nutrition Examination Survey (NHANES III), a multistage probability representative sample of the US population. A total of 20,050 US adults participated in NHANES III from 1988 to 1994. Our main outcome measures were low lung function (a condition determined to be present if the forced expiratory volume in 1 second-forced vital capacity ratio was less than 0.7 and the forced expiratory volume in 1 second was less than 80% of the predicted value), a physician diagnosis of OLD (chronic bronchitis, asthma, or emphysema), and respiratory symptoms. RESULTS: Overall a mean (SE) of 6.8% (0.3%) of the population had low lung function, and 8.5% (0.3%) of the population reported OLD. Obstructive lung disease (age-adjusted to study population) was currently reported among 12.5% (0.7%) of current smokers, 9.4% (0.6%) of former smokers, 3.1% (1.1%) of pipe or cigar smokers, and 5.8% (0.4%) of never smokers. Surprisingly, 63.3% (0.2%) of the subjects with documented low lung function had no prior or current reported diagnosis of any OLD. CONCLUSIONS: This study demonstrates that OLD is present in a substantive number of US adults. In addition, many US adults have low lung function but no reported OLD diagnosis, which may indicate the presence of undiagnosed lung disease.

Effect of chronic renal failure on the expression of erythropoietin message in a murine model.

The anemia of chronic renal failure (CRF) is largely due to decreased production of erythropoietin (EPO) by the kidney. A small amount of EPO also originates from extra-renal sources, and this would be expected to assume a more important role in maintaining erythropoiesis when renal production is impaired. In this study, we examined the production of EPO mRNA by RT-PCR in kidney, liver, and bone marrow tissues isolated from normal mice, mice rendered acutely anemic by phlebotomy, and from mice with surgically induced CRF. The induction of acute anemia results in an expected increase in the expression of EPO mRNA in renal and hepatic tissue. In contrast, while the expression of EPO mRNA was expectedly reduced in the kidney from CRF mice, it was completely absent in the liver of these same animals. EPO mRNA expression was also absent in the bone marrow in both states of acute anemia and CRF. These results show that CRF can directly or indirectly can suppress the extrarenal production of EPO by the liver and that this effect may further aggravate the anemia of CRF.

Application of in vivo and ex vivo magnetic resonance imaging for evaluation of tranilast on neointima formation following balloon angioplasty of the rat carotid artery.

OBJECTIVE: Recent studies suggest that tranilast inhibits a variety of agents implicated in neointimal growth and restenosis in experimental animal models and humans. We report here a study evaluating the efficacy of tranilast in the rat carotid artery balloon angioplasty model, a model that mimics many aspects of the percutaneous transluminal angioplasty procedure in humans. Efficacy was determined based on in vivo and ex vivo magnetic resonance imaging (MRI) as well as by histomorphometry. The utility of this study, using a reverse paradigm, is to investigate if agents successful in the clinic can demonstrate efficacy in this animal model primary screen as measured by MRI and histomorphometry. METHODS: Tranilast (300 mg/kg/day, p.o.) was administered to Sprague-Dawley rats 3 days prior to balloon injury and continued for 14 days after injury. Three methods of measuring the vascular injury that occurs in this model were employed: (1) in vivo MRI, used to measure in vivo lumen volumes for the carotid artery once at baseline (pre-surgery) and again at 14 days post angioplasty; (2) ex vivo MRI (and histomorphometry), used to evaluate the total arterial wall thickness and the intima-to-media ratio; and (3) analysis of collagen density, used to evaluate the efficacy of tranilast to abrogate collagen synthesis and deposition following vascular injury. RESULTS: Tranilast provided 33% protection (P<0.05) from angioplasty-induced lumen narrowing as measured by MRI in vivo. The results of the ex vivo MR analysis of total wall thickness showed a 14% protection of angioplasty-induced narrowing (P<0.05), and the mean intima-to-media ratio showed a 39% (P<0.006) protection for the tranilast-treated rats. Histological analysis of the mean intima-to-media ratio demonstrated that tranilast provided 36% (P<0. 01) protection in the intima-to-media ratio. Further, treatment with tranilast showed a 52% reduction in collagen density of the intimal layer and a 70% reduction in collagen density of the medial layer of the injured arteries. CONCLUSION: The data obtained by in vivo MRI, ex vivo MRI, histology and collagen analysis demonstrate that tranilast provided significant beneficial effects in inhibiting neointimal formation in the rat carotid artery model. Also this study, to the best of our knowledge, is the first to harness complimentary information from various technologies, including lumen patency by in vivo MRI, neointimal formation by ex vivo MRI and conventional histomorphometry, and histological analysis for collagen density, to provide a comprehensive understanding of the pathology in this disease model.

Antibody-dependent cell-mediated cytotoxicity (ADCC) assay for specific IgG antibody produced in vitro.

IgG antibody production by immune spleen cells in vitro was assayed by antibody-dependent cell-mediated cytolysis (ADCC). The use of this technique as a sensitive and reproducible alternative to indirect haemolytic plaque assays is examined.

Erythrocytosis after renal transplantation represents an abnormality of insulin-like growth factor-I and its binding proteins.

BACKGROUND: Secondary erythrocytosis is classically defined by an increase in erythropoietin (EPO) production. Despite increased levels of EPO often seen in secondary erythrocytosis, some of these forms such as that seen after renal transplantation remain undefined. Our group has recently investigated the in vivo function of insulin-like growth factor-I (IGF-I) in erythropoiesis both in humans and in a murine model of chronic renal failure. These data, and the recently recognized role of IGF-I in polycythemia vera, suggested that IGF-I might be involved in secondary erythrocytosis. METHODS: Renal transplant recipients who developed erythrocytosis after transplantation were compared to normal individuals and to renal transplant recipients without erythrocytosis. We measured fasting serum EPO and IGF-I in all three groups. Because binding proteins may modify IGF-I function, IGF-I-binding proteins (IGFBP) 1 and 3, major binding proteins of IGF-I, were also measured. RESULTS: Renal transplant recipients have significantly elevated serum of IGF-I and IGFBP3 compared to normal individuals. When transplant recipients with and without posttransplant erythrocytosis were compared, similar levels of IGF-I were found; however, the group with erythrocytosis had significantly elevated IGFBP1 and IGFBP3. No other significant differences including EPO levels were found between the groups. CONCLUSIONS: Erythrocytosis after renal transplantation represents an anomaly of both IGF-I and its major binding proteins. Further studies are under way to better define this dysregulation and determine whether IGF-I can play a more generalized role in secondary forms of erythropoiesis.

Hemodynamic and coronary effects of intravenous labetalol in coronary artery disease.

Labetalol, an alpha and beta receptor blocking agent, was evaluated in 11 patients with documented coronary artery disease and stable angina. The mean dose of labetalol was 1.5 (range 1 to 2) mg/kg. Cardiovascular effects began within 1 minute after injection and were maximal within 10 minutes. Mean arterial pressure decreased from 105 +/- 13 to 81 +/- 10 mm Hg (p less than 0.0001), heart rate from 70 +/- 10 to 66 +/- 7 beats/min (p less than 0.05) and the pressure-rate product from 10,322 +/- 2,344 to 7,171 +/- 1,650 (p less than 0.001). Cardiac output and pulmonary wedge pressure did not change significantly. Mean pulmonary arterial pressure decreased from 20 +/- 3 to 16 +/- 2 mm Hg (p less than 0.005). Systemic and pulmonary resistances also decreased significantly (p less than 0.0001 and p less than 0.01, respectively). Coronary sinus flow increased from 107 +/- 26 to 118 +/- 25 ml/min (p less than 0.01) and coronary vascular resistance decreased from 1.0 +/- 0.2 to 0.77 +/- 0.1 mm Hg/ml per min (p less than 0.001). Labetalol may be a useful adjunct in the treatment of angina not only because it diminishes myocardial oxygen requirements but also because it improves coronary hemodynamics. Thus, labetalol appears to have some advantage compared with the usual beta blocking agents with their potentially detrimental effects on coronary hemodynamics.

Prospective study of urinalysis abnormalities in HIV-positive individuals treated with indinavir.

Indinavir is a potent protease inhibitor widely used in combination with reverse-transcriptase inhibitors to treat human immunodeficiency virus (HIV) disease. Individuals treated with indinavir are prone to develop urinary complications, including renal colic, renal calculi, lower urinary tract symptoms, and indinavir crystalluria. Although renal stones secondary to indinavir have been described and characterized, little is known about the onset, frequency, and significance of the crystalluria. To document the longitudinal characteristics of indinavir crystalluria and associated urine abnormalities, 54 asymptomatic indinavir-naive HIV-positive individuals had urinalysis testing initially weekly and then monthly during the first year of indinavir treatment. Six hundred eight urinalyses were performed (11 +/- 2 urinalysis/subject), including 579 microscopy examinations performed by a nephrologist (10 +/- 2 examinations/subject). Baseline urinalysis results were essentially normal. After the start of treatment, indinavir crystalluria was frequently observed (67% of subjects). After the first 2 weeks, indinavir crystalluria remained constant at a frequency of approximately 25% of urine sediments examined at each test point. Other urine abnormalities, principally leukocytes (>/=10/high-power field) and casts, were observed in 39% of subjects. These abnormalities were more severe in five subjects, with concomitant increasing serum creatinine levels in three of them. Additional urine findings include the predominance of low pH (/=1.025 in 66% of urinalyses). In conclusion, abnormal urinalysis results were noted frequently during the first year of treatment with indinavir. The main findings were the high proportion of subjects with crystalluria and the relatively high frequency of crystalluria observed consistently throughout. These findings may occasionally be associated with other urine abnormalities, presumably secondary to indinavir crystalluria.