A potent analog of 1alpha,25-dihydroxyvitamin D3 selectively induces bone formation

1,25-Dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] is a principal regulator of calcium and phosphorus homeostasis through actions on intestine, kidney, and bone. 1,25(OH)(2)D(3) is not considered to play a significant role in bone formation, except for its role in supporting mineralization. We report here on the properties of 2-methylene-19-nor-(20S)-1alpha,25(OH)(2)D(3) (2MD), a highly potent analog of 1,25(OH)(2)D(3) that induces bone formation both in vitro and in vivo. Selectivity for bone was first demonstrated through the observation that 2MD is at least 30-fold more effective than 1,25(OH)(2)D(3) in stimulating osteoblast-mediated bone calcium mobilization while being only slightly more potent in supporting intestinal calcium transport. 2MD is also highly potent in promoting osteoblast-mediated osteoclast formation in vitro, a process essential to both bone resorption and formation. Most significantly, 2MD at concentrations as low as 10(-12) M causes primary cultures of osteoblasts to produce bone in vitro. This effect is not found with 1,25(OH)(2)D(3) even at 10(-8) M, suggesting that 2MD might be osteogenic in vivo. Indeed, 2MD (7 pmol/day) causes a substantial increase (9%) in total body bone mass in ovariectomized rats over a 23-week period. 1,25(OH)(2)D(3) (500 pmol three times a week) only prevented the bone loss associated with ovariectomy and did not increase bone mass. These results indicate that 2MD is a potent bone-selective analog of 1,25(OH)(2)D(3) potentially effective in treating bone loss diseases.     

Prevalence and correlates of carotid atherosclerosis among elderly Japanese men

We determined intima-media thickness (IMT) and diameter of carotid artery and estimated their correlations with cardiovascular risk factors in 1129 men aged 60-74 years, who participated in a cardiovascular risk survey in three Japanese communities. The multivariate odds ratios (95% confidence interval) for the maximum IMT > or = 1.1 mm in the common carotid artery (CCA) were 1.3 (1.1-1.5) per 4 years of age, 1.8 (1.4-2.5) for hypertension, 1.4 (1.2-1.7) for a 34.4 mg/dl increase in serum total cholesterol, 0.7 (0.6-0.8) for a 14.7 mg/dl increase in serum HDL-cholesterol, and 2.4 (1.1-5.0) for history of stroke, while the maximum IMT > or = 1.5mm in the internal carotid artery (ICA) were 1.6 (1.4-1.8) per 4 years of age, 1.9 (1.5-2.4) for hypertension, 1.6 (1.2-2.1) for current smoking, and 3.5 (1.6-7.6) for history of stroke. Age, height, hypertension, current smoking, ethanol intake and history of coronary heart disease were independent determinants of both the outer and inner CCA diameter. Maximum IMT correlated positively with the outer diameter and inversely with the inner diameter in the CCA. Carotid atherosclerosis suggests to be a risk factor for stroke among Japanese elderly men, although future prospective studies are required to confirm this finding.     

Expression of GPIV and Naka antigen on monocytes in Naka-negative subjects whose platelets lack GPIV

Summary. The platelet antigen Nak^a was once considered to be a platelet-specific alloantigen and is carried on platelet membrane glycoprotein (GP) IV. Recent studies suggest that Nak^a-negative subjects lack platelet GPIV. GPIV is an important adhesive receptor and expressed on the surface of monocytes as well as of platelets. In the present study, flow cytometry was used to detect GPIV and Nak^a antigen on the surface of monocytes. Nak^a antigen was expressed on monocytes as well as on platelets in Nak^a-positive subjects ( n = 6) (P-GPIV-positive subjects). To our surprise, monocytes of Nak^a-negative subjects ( n = 7) (P-GPIV-negative subjects) having no anti-Nak^a antibody in their serum expressed GPIV and Nak^a antigen to almost the same degree as did the monocytes of P-GPIV-positive subjects. Competitive experiments using OKM5 (a monoclonal antibody against GPIV) and anti-Nak^a antibody showed that the epitope of anti-Nak^a antibody on monocytes was very close to that of OKM5. In two P-GPIV-negative subjects having anti-Nak^a antibody in their serum, GPIV and Nak^a antigen were not expressed on the surface of either monocytes or platelets. These results indicate that the GPIV molecules and Nak^a antigen are expressed on the surface of monocytes in the majority of P-GPIV-negative subjects, but that in a very few P-GPIV-negative subjects neither GPIV nor Nak^a antigen is expressed on the surface of their monocytes. We hypothesize that P-GPIV-negative subjects who carry neither GPIV nor Nak^a antigen on their monocytes produce anti-Nak^a antibody as a result of transfusion or pregnancy.     

Genotypes at chromosome 22q12-13 are associated with HIV-1-exposed but uninfected status in Italians

OBJECTIVE: Despite multiple and repeated exposures to HIV-1, some individuals possess no detectable HIV genome and show T-cell memory responses to the viral antigens. HIV-1-reactive mucosal IgA detected in such uninfected individuals suggests their possible immune resistance against HIV. We tested if the above HIV-1-exposed but uninfected status was associated with genetic markers other than a homozygous deletion of the CCR5 gene. METHODS: Based on our mapping in chromosome 15 of a gene controlling the production of neutralizing antibodies in a mouse retrovirus infection, we genotyped 42 HIV-1-exposed but uninfected Italians at polymorphic loci in the syntenic segment of human chromosome 22, and compared them with 49 HIV-1-infected and 47 uninfected healthy control individuals by a closed testing procedure. RESULTS: A significant association was found between chromosome 22q12-13 genotypes and a putative dominant locus conferring anti-HIV-1 immune responses in the exposed but uninfected individuals. Distributions of linkage disequilibrium across chromosome 22 also differed between the exposed but uninfected and two other phenotypic groups. CONCLUSIONS: The data indicated the presence of a new genetic factor associated with the HIV-1-exposed but uninfected status.     

Left atrial thrombus causing pulmonary embolism by passing through an atrial septal defect.

A 66-year-old woman admitted with dyspnea on exertion had atrial fibrillation and left ventricular dysfunction. Echocardiography revealed an atrial septal defect (ASD) and a soft, easily deformable thrombus in the dilated left atrium. The atrial mass suddenly disappeared on the 10th day after admission, and contrast-enhanced chest computed tomography and pulmonary blood flow scintigraphy showed that the thrombus had detached from the left atrium, floated into the right atrium through the ASD and caused pulmonary embolism. This is the first documented case of a left atrial thrombus causing pulmonary embolism by passing through an ASD. When an ASD is present, it is important to consider not only paradoxical thromboembolism (from the right to the left atrium), but also pulmonary embolism caused by thromboembolism from the left to the right atrium.     

Termination of Living Anionic Polymerization of Butyl Acrylate with α‐(Chloromethyl)acrylate for End‐Functionalization and Application to the Evaluation of Monomer Reactivity

Anionic polymerization of n‐butyl acrylate (nBA) in toluene initiated with a binary initiator, isopropyl α‐lithioisobutyrate/ethylaluminum bis(2,6‐di‐tert‐butylphenoxide) at ?60 °C, is terminated with ethyl α‐(chloromethyl)acrylate (ECMA) to afford a poly(nBA) possessing an acryloyl group at the terminal with 80% of termination efficiency. The reactivity of nBA against a polymer anion of methyl methacrylate formed under identical conditions is estimated relative to the termination with ECMA by reacting a mixture of nBA and ECMA followed by ¹H NMR spectroscopic chain‐end analysis; the relative reactivity of nBA is found 80 times or more higher than ECMA.

     

MgH2–CoO: a conversion-type composite electrode for LiBH4-based all-solid-state lithium ion batteries

Several studies have demonstrated that MgH₂ is a promising conversion-type anode toward Li. A major obstacle is the reversible capacity during cycling. Electrochemical co-existence of a mixed metal hydride-oxide conversion type anode is demonstrated for lithium ion batteries using a solid-state electrolyte. 75MgH₂·25CoO anodes are obtained from optimized mixing conditions avoiding reactions occurring during high-energy ball-milling. Electrochemical tests are carried out to investigate the cycling capability and reversibility of the on-going conversion reactions. The cycling led to formation of a single-plateau nanocomposite electrode with higher reversibility yield, lowered discharge–charge hysteresis and mitigated kinetic effect at high C-rate compared to MgH₂ anodes. It is believed that reduced diffusion pathways and less polarized electrodes are the origin of the improved properties. The designed composite-electrode shows good preservation and suitability with LiBH₄ solid electrolyte as revealed from electron microscopy analyses and X-ray photoelectron spectroscopy.

The findings point to a means of guided formation of MgH₂–CoO conversion-type nanocomposite electrode for all-solid-state Li-ion batteries.     

Influence of Bleeding Risk on Outcomes of Radial and Femoral Access for Percutaneous Coronary Intervention: An Analysis From the GLOBAL LEADERS Trial

BackgroundRadial artery access has been shown to reduce mortality and bleeding events, especially in patients with acute coronary syndromes. Despite this, interventional cardiologists experienced in femoral artery access still prefer that route for percutaneous coronary intervention. Little is known regarding the merits of each vascular access in patients stratified by their risk of bleeding.MethodsPatients from the Global Leaders trial were dichotomized into low or high risk of bleeding by the median of the PRECISE-DAPT score. Clinical outcomes were compared at 30 days.ResultsIn the overall population, there were no statistical differences between radial and femoral access in the rate of the primary end point, a composite of all-cause mortality, or new Q-wave myocardial infarction (MI) (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.42-1.15). Radial access was associated with a significantly lower rate of the secondary safety end point, Bleeding Academic Research Consortium (BARC) 3 or 5 bleeding (HR 0.55, 95% CI 0.36-0.84). Compared by bleeding risk strata, in the high bleeding score population, the primary (HR 0.47, 95% CI 0.26-0.85; P = 0.012; P_interaction = 0.019) and secondary safety (HR 0.57, 95% CI 0.35-0.95; P = 0.030; P_interaction = 0.631) end points favoured radial access. In the low bleeding score population, however, the differences in the primary and secondary safety end points between radial and femoral artery access were no longer statistically significant.ConclusionsOur findings suggest that the outcomes of mortality or new Q-wave MI and BARC 3 or 5 bleeding favour radial access in patients with a high, but not those with a low, risk of bleeding. Because this was not a primary analysis, it should be considered hypothesis generating.     

A Rare Case of Ectopic Adrenocorticotropic Hormone Syndrome with Recurrent Olfactory Neuroblastoma

A 40-year-old woman who had a history of recurrent olfactory neuroblastoma presented with full moon face, central obesity, buffalo hump, impaired glucose tolerance and bilateral cervical lymph node swelling. Laboratory tests showed morbidly elevated levels of adrenocorticotropic hormone (ACTH) and cortisol, which were not suppressed by high-dose (8 mg) dexamethasone. Biopsies of the enlarged cervical lymph nodes revealed ACTH-positive metastatic olfactory neuroblastoma, and ectopic ACTH syndrome was diagnosed. Metyrapone was used to suppress cortisol production and resulted in decreased levels of ACTH and cortisol. Bilateral cervical tumor resection further reduced the ACTH and cortisol levels, accompanied by a reduction in the metyrapone dosage. Cushing''s syndrome was alleviated through ACTH-producing tumor removal.