Bone Marrow Transplantation Does Not Ameliorate the Neurologic Symptoms in Mice Deficient in Hypoxanthine Guanine Phosphoribosyl Transferase (HPRT)

The use of bone marrow transplantation (BMT) for the treatment of genetic diseases with neurologic involvement has yielded mixed results. We have employed a mouse model of Lesch-Nyhan disease (LND) to assess the efficacy of BMT in ameliorating the neurologic manifestations of the disease. Adult HPRT-deficient mice exhibit a measurable decrease in striatal dopamine levels and a hypersensitivity to amphetamine. Marrow-ablated adult HPRT-deficient mice were transplanted with marrow from congenic HPRT-expressing mice. BMT altered neither the neurochemical nor the behavioral phenotypes in either HPRT-positive or HPRT-deficient mice. Barring any important species differences, these results suggest that BMT in its present form may not be an effective therapy for Lesch-Nyhan syndrome.     

Residential exposure to overhead high-voltage lines and the risk of testicular cancer: results of a population-based case–control study in Hamburg (Germany)

Background: In a population-based case–control study we examined the association between residential exposure to overhead high-voltage lines and testicular cancer. Methods: We recorded the residential biography of cases with testicular cancer identified by the Hamburg Cancer Registry and of controls that were randomly selected from the mandatory registry of residents in Hamburg. The study included 145 incident cases between 15 and 69 years of age, diagnosed between 1995 and 1997, and 313 controls, matched for age in 5-year strata. In model A, exposure was defined by distance (ever vs never). Model B took into account residence time and the inverse distance from the nearest high-voltage line. It distinguished between low and high exposure, the never exposed persons serving as a reference group. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated by unconditional logistic regression. For men below the age of 40 years and men aged 40 years and over separate analyses were carried out. Results: Within a corridor of 100 m the prevalence of exposure to high-voltage lines in Hamburg was 6.9% in cases and 5.8% in controls (OR=1.3; 95% CI=0.56–2.80). In the more complex model B we found an OR of 1.2 (95% CI=0.60–2.47) for low exposure and 1.7 (95% CI=0.91–3.32) for high exposure. Younger men show slightly increased risks in both models. Conclusions: In all, residential exposure to high-voltage lines did not seem to be a major risk factor for testicular cancer in our study. Yet, the fact that risks for men below the age of 40 years were slightly increased in both exposure models deserves further attention.     

The von Willebrand factor A-1 domain binding aptamer BT200 elevates plasma levels of von Willebrand factor and factor VIII: a first-in-human trial

von Willebrand factor (VWF) and factor VIII (FVIII) circulate in a noncovalent complex in blood and promote primary hemostasis and clotting, respectively. A new VWF A1-domain binding aptamer, BT200, demonstrated good subcutaneous bioavailability and a long half-life in non-human primates. This first-in-human, randomized, placebo-controlled, double-blind trial tested the hypothesis that BT200 is well tolerated and has favorable pharmacokinetic and pharmacodynamic effects in 112 volunteers. Participants received one of the following: a single ascending dose of BT200 (0.18-48 mg) subcutaneously, an intravenous dose, BT200 with concomitant desmopressin or multiple doses. Pharmacokinetics were characterized, and the pharmacodynamic effects were measured by VWF levels, FVIII clotting activity, ristocetin-induced aggregation, platelet function under high shear rates, and thrombin generation. The mean half-lives ranged from 7-12 days and subcutaneous bioavailability increased dose-dependently exceeding 55% for doses of 6-48 mg. By blocking free A1 domains, BT200 dose-dependently decreased ristocetin-induced aggregation, and prolonged collagen-adenosine diphosphate and shear-induced platelet plug formation times. However, BT200 also increased VWF antigen and FVIII levels 4-fold (P<0.001), without increasing VWF propeptide levels, indicating decreased VWF/FVIII clearance. This, in turn, increased thrombin generation and accelerated clotting. Desmopressin-induced VWF/FVIII release had additive effects on a background of BT200. Tolerability and safety were generally good, but exaggerated pharmacology was seen at saturating doses. This trial identified a novel mechanism of action for BT200: BT200 dose-dependently increases VWF/FVIII by prolonging half-life at doses well below those which inhibit VWF-mediated platelet function. This novel property can be exploited therapeutically to enhance hemostasis in congenital bleeding disorders.     

Elevated Plasma D-Dimer Concentrations in Adults after an Outpatient-Treated COVID-19 Infection

Elevated D-dimer plasma concentrations are common in hospitalized COVID-19 patients and are often associated with a worse prognosis, but it is not yet clear whether this also applies to outpatient cases. The present cross-sectional study evaluated D-dimer levels and their association with clinical parameters and inflammation biomarkers after a COVID-19 disease in individuals treated as outpatients. The study included 411 individuals (43.3% men) with an average age of 46.8 years (SD 15.2). Study participants who had acute COVID-19 disease at a median of 235 days (120; 323) ago were examined at the University Hospital Augsburg, Southern Germany, between 11/2020 and 05/2021. Plasma D-dimers were measured by a particle-enhanced immunoturbidimetric assay. Sixty-one subjects (15%) showed increased D-dimer concentrations (≥500 µg/L). Study participants with elevated D-dimer levels in comparison to subjects with levels in the reference range were significantly older, and more frequently reported a history of cardiovascular disease, hypertension, venous thromboembolism, and chronic venous insufficiency. In multivariable logistic regression analysis, CRP levels (OR 5.58 per mg/dL, 95% CI 1.77–17.60) and white blood cell count (OR 1.48 per nL, 95% CI 1.19–1.83) were significantly related to elevated D-dimers even after adjustment for multiple testing. However, acute or persistent symptoms were not significantly associated with increased D-dimers. Elevated D-dimer levels months after an acute COVID-19 disease seems to be associated with markers of inflammation. Further studies are needed to investigate the underlying pathophysiological mechanisms and consequences of prolonged D-dimer elevation in these patients.     

Incorrect use of peak flow meters: are you observing your patients?

Background: Monitoring peak expiratory flow (PEF) values is one option as part of asthma action plans per national guidelines. PEF assessment is also recommended in emergency department and hospitalized patients. Incorrect use of peak flow meters (PFM) has obvious implications for appropriate decisions by patients and clinicians. Methods: We searched the English literature via PubMed and SCOPUS using the following search terms: PEF maneuver; incorrect use of PFM. When pertinent articles were found, we assessed publications cited in those papers. All studies related to incorrect use of PFM in patients with asthma were included. Results: Nine studies have reported errors in performing the PEF maneuver, including three pediatric and six adult studies. Errors were found at most steps of the maneuver, and inability to perform all steps correctly was common in these investigations. Examples of errors included failure to inhale fully or give maximum effort on exhalation, accelerating air with the tongue and buccal musculature, and performing only one attempt versus three. Gender differences in correct use of PFM are suggested by three adult studies. One study described falsifying PEF values by manipulating the PFM indicator, and another investigation assessed the PEF maneuver in two positions in bed versus the correct posture of standing. Conclusion: Many pediatric and adult patients do not use PFM correctly. Clinicians should regularly observe patients use PFM to detect errors and help ensure correct use and accurate PEF measurements.