Transplantation of Haploidentical TcRaß‐Depleted Hematopoietic Cells Allows for Optimal Timing and Sustained Correction of the Metabolic Defect in Children With Infantile Osteopetrosis

In osteopetrosis, osteoclast dysfunction can lead to deafness, blindness, bone marrow failure, and death. Hematopoietic cell transplantation (HCT) is currently the only curative treatment, but outcome remains disappointing. Although a rapid progression toward HCT is detrimental to prevent further progress of disease manifestations, 70% of cases lack an HLA‐matched sibling and require alternative stem cell sources. We present two cases of osteopetrosis that successfully received an HCT with haploidentical TcRαβ‐depleted cells from one of the parents. These cases showed no further disease progression, had restoration of functional osteoclasts, and illustrate this approach to enable prompt HCT with ready available parental donors and rapid and sustained hematological, including osteoclast, recovery. © 2016 American Society for Bone and Mineral Research.     

Lipid Levels: A Link Between Cardiovascular Disease and Osteoporosis?

Epidemiological observations support a positive relationship between cardiovascular diseases (CVD) and osteoporosis, where cholesterol has been indicated to be a possible link. Only a few studies have investigated the relation between lipids and BMD, but the association remains unclear. We studied the relationship between serum lipids and BMD of the calcaneus. A cross‐sectional population‐based study was performed, based on data from the Longitudinal Aging Study Amsterdam, including 620 men and 635 women, 65–88 yr of age. BMD was measured by quantitative ultrasound (QUS), velocity of sound (VOS; m/s), and broadband ultrasound attenuation (BUA; dB/MHz). Models were adjusted for age, body mass index, physical activity, smoking, alcohol, diabetes mellitus, hypertension, testosterone, and 25‐hydroxyvitamin D. No association was found between total cholesterol (TC) and QUS. Men and women in the highest quartile of high‐density lipoprotein cholesterol (HDL‐c) had a significantly lower QUS (men—VOS: β = ?20.8, p = 0.00; BUA: β = ?5.2, p = 0.02; women—VOS: β = ?18.6, p = 0.00) compared with men and women in the lowest quartile. An even stronger positive association was seen between TC/HDL‐c ratio and QUS (men—VOS: β = 21.8, p = 0.00; BUA: β = 5.5, p = 0.01; women—VOS: β = 19.2, p = 0.00; BUA: β = 3.6, p = 0.05). Our analysis shows that the lipid profile that is favorable in the prevention of CVD (i.e., high levels of HDL‐c and low TC/HDL‐c ratio) is unfavorable for QUS. These results indicate that HDL‐c levels do not explain the association between osteoporosis and CVD.     

Arterial and Venous Pharmacokinetics of Ropivacaine with and without Epinephrine after Thoracic Paravertebral Block

Background: Animal and volunteer studies indicate that ropivacaine is associated with less neurologic and cardiac toxicity than bupivacaine. Ropivacaine may offer advantages when used for thoracic paravertebral block. This study was designed to describe the pharmacokinetics of ropivacaine after thoracic paravertebral block.

Methods: Twenty female patients undergoing elective unilateral breast surgery were randomly assigned to receive a single bolus thoracic paravertebral injection of 2 mg/kg ropivacaine, with or without 5 [mu]g/ml epinephrine. Simultaneous arterial and venous blood samples were obtained for plasma ropivacaine assay. Data were analyzed with NONMEM, using two possible absorption models: conventional first-order absorption and absorption following the inverse gaussian density function.

Results: Epinephrine reduced the peak plasma concentrations and delayed the time of peak concentration of ropivacaine in both the arterial and venous blood. The time course of drug input into the systemic circulation was best described by two inverse gaussian density functions. The median bioavailability of the rapid component was approximately 20% higher when epinephrine was not used. The mean absorption times were 7.8 min for the rapid absorption phase and 697 min for the slow absorption phase, with wide dispersion of the absorption function for the acute phase. The half-time of arterial-venous equilibration was 1.5 min.     

An ethics core curriculum for Australasian medical Schools

Teaching ethics incorporates teaching of knowledge as well as skills and attitudes. Each of these requires different teaching and assessment methods. A core curriculum of ethics knowledge must address both the foundations of ethics and specific ethical topics. Ethical skills teaching focuses on the development of ethical awareness, moral reasoning, communication and collaborative action skills. Attitudes that are important for medical students to develop include honesty, integrity and trustworthiness, empathy and compassion, respect, and responsibility, as well as critical self-appraisal and commitment to lifelong education.     

Project for Universal Management of Airways – part 1: concept and methods

Multiple professional groups and societies worldwide have produced airway management guidelines. These are typically targeted at the process of tracheal intubation by a particular provider group in a restricted category of patients and reflect practice preferences in a particular geographical region. The existence of multiple distinct guidelines for some (but not other) closely related circumstances, increases complexity and may obscure the underlying principles that are common to all of them. This has the potential to increase cognitive load; promote the grouping of ideas in silos; impair teamwork; and ultimately compromise patient care. Development of a single set of airway management guidelines that can be applied across and beyond these domains may improve implementation; promote standardisation; and facilitate collaboration between airway practitioners from diverse backgrounds. A global multidisciplinary group of both airway operators and assistants was assembled. Over a 3-year period, a review of the existing airway guidelines and multiple reviews of the primary literature were combined with a structured process for determining expert consensus. Any discrepancies between these were analysed and reconciled. Where evidence in the literature was lacking, recommendations were made by expert consensus. Using the above process, a set of evidence-based airway management guidelines was developed in consultation with airway practitioners from a broad spectrum of disciplines and geographical locations. While consistent with the recommendations of the existing English language guidelines, these universal guidelines also incorporate the most recent concepts in airway management as well as statements on areas not widely addressed by the existing guidelines. The recommendations will be published in four parts that respectively address: airway evaluation; airway strategy; airway rescue and communication of airway outcomes. Together, these universal guidelines will provide a single, comprehensive approach to airway management that can be consistently applied by airway practitioners globally, independent of their clinical background or the circumstances in which airway management occurs.     

Immunohistochemical localization of membrane and alpha-granule proteins in human megakaryocytes: application to plastic-embedded bone marrow biopsy specimens

Using a new technique for antigen localization, we have demonstrated platelet proteins in megakaryocytes in plastic-embedded biopsy specimens of normal human bone marrow. In a series of 25 specimens, megakaryocytes showed labeling with antibodies to the integral membrane glycoproteins IIIa, IIb, and the IIb-IIIa complex; granule membrane protein 140; and five alpha-granule matrix proteins: thrombospondin, factor VIII-related antigen, beta-thromboglobulin, platelet factor 4, and fibrinogen. The antibodies to the membrane glycoproteins IIIa, IIb, and IIb-IIIa produced diffuse cytoplasmic staining and heavier staining on the plasma membrane, whereas the antibodies to the alpha-granule matrix proteins produced a distinct granular staining within the cytoplasm. Staining for granule membrane protein 140 was also granular in distribution. Rare mononuclear cells consistent with megakaryocyte precursors were labeled with these markers. Other enzyme histochemical and lectin-binding studies showed that the enzyme alpha-naphthyl acetate esterase, the lectin Ulex europaeus I, and the periodic-acid Schiff reaction were consistent, but not specific, markers of megakaryocytes. This immunohistochemical technique should facilitate the examination of qualitative and quantitative changes in megakaryocytes in a variety of physiologic and pathologic processes.     

Combined therapy trial with interferon alpha-2a and ablative therapy in the treatment of anogenital warts.

OBJECTIVE: To determine whether the combination of systemically administered interferon alpha-2a and ablative surgery for the treatment of genital and/or perianal warts produces a 30% or greater improvement in lasting response rate compared with a control group receiving a combination of placebo and ablative therapy. DESIGN: Randomised, triple-blind, placebo-controlled trial using 1 or 3 MIU of interferon alpha-2a or placebo administered subcutaneously three times weekly for 10 weeks in combination with ablative surgery. SETTING: International, multicentre study in 10 genitourinary medicine clinics. PATIENTS: Two hundred and fifty patients with anogenital warts. MAIN OUTCOME MEASURES: Lasting response at week 38. RESULTS: Standard efficacy analysis at week 38 showed a lasting response in 51% (35/68) of 3 MIU interferon-treated patients, 48% (30/63) of 1 MIU interferon-treated patients and 43% (29/67) of placebo-treated patients. CONCLUSIONS: With the doses and regime described, treatment with interferon alpha-2a in combination with ablative therapy is not significantly superior in the treatment of anogenital warts than placebo and ablative therapy.