Differential effects of teriparatide on regional bone formation using 18F‐fluoride positron emission tomography

Teriparatide increases skeletal mass, bone turnover markers, and bone strength, but local effects on bone tissue may vary between skeletal sites. We used positron emission tomography (PET) to study ¹⁸F‐fluoride plasma clearance (K_i) at the spine and standardized uptake values (SUVs) at the spine, pelvis, total hip, and femoral shaft in 18 postmenopausal women with osteoporosis. Subjects underwent a 1‐hour dynamic scan of the lumbar spine and a 10‐minute static scan of the pelvis and femurs at baseline and after 6 months of treatment with 20 µg/day teriparatide. Blood samples were taken to derive the arterial input function and lumbar spine K_i values evaluated using a three‐compartment model. SUVs were calculated for the spine, pelvis, total hip, and femoral shaft. After 6 months treatment with teriparatide, spine K_i values increased by 24% (p = .0003), while other model parameters were unchanged except for the fraction of tracer going to bone mineral (k₃/[k₂ + k₃]), which increased by 23% (p = .0006). In contrast to K_i, spine SUVs increased by only 3% (p = .84). The discrepancy between changes in K_i and SUVs was explained by a 20% decrease in ¹⁸F^? plasma concentration. SUVs increased by 37% at the femoral shaft (p = .0019), 20% at the total hip (p = .032), and 11% at the pelvis (p = .070). Changes in bone turnover markers and BMD were consistent with previous trials. We conclude that the changes in bone formation rate during teriparatide treatment as measured by ¹⁸F^? PET differ at different skeletal sites, with larger increases in cortical bone than at trabecular sites. © 2011 American Society for Bone and Mineral Research.     

Basic fibroblast growth factor antagonizes transforming growth factor beta-mediated erythroid differentiation in K562 cells

Basic fibroblast growth factor (bFGF) and transforming growth factor- beta 1 (TGF-beta) have both been shown to act on hematopoietic progenitor cells. bFGF is a hematopoietic cytokine that acts on progenitor cells in concert with other cytokines to promote their proliferation. TGF-beta induces erythroid differentiation in K562 cells. To determine whether bFGF might act on progenitor cells by antagonizing the effects of cytokines that induce differentiation, we determined the effects of bFGF on the TGF-beta-mediated induction of hemoglobin synthesis in K562 cells. bFGF antagonized the TGF-beta- mediated induction of hemoglobin in a dose-dependent manner, with 0.1 ng/mL bFGF inhibiting hemoglobin induction by 40% and 10 ng/mL bFGF completely abrogating hemoglobin production. bFGF was most effective at antagonizing the TGF-beta-mediated induction of hemoglobin if it and TGF-beta were added simultaneously to K562 cells, but delayed addition of bFGF to TGF-beta-treated cultures still resulted in significant inhibition of hemoglobin synthesis. The inhibitory effects of bFGF on hemoglobin production were fully reversible, showing that bFGF did not permanently alter the phenotype of K562 cells. The hemin-mediated induction of hemoglobin synthesis in K562 cells was only partially negated by bFGF. bFGF also diminished the expression of glycophorin A on the surface of K562 cells. These results indicate that bFGF might increase progenitor/stem cell numbers by antagonizing the effects of cytokines that induce differentiation, thereby increasing the pool of proliferating progenitor/stem cells.     

Stray dog trade fuelled by dog meat consumption as a risk factor for rabies infection in Calabar,southern Nigeria

Background

Rabies is a preventable zoonosis with the highest case fatality of any disease in the world. In the developing world, it is transmitted mainly by dog bites. In parts of southern Nigeria, dog meat is a delicacy.

Objective

To highlight trade in stray dogs as a major risk factor for rabies in animals and humans in south-south Nigeria.

Method

Patients admitted into the University of Calabar Teaching Hospital (UCTH) with a diagnosis of rabies between July and October 2012 were analysed for risk factors, post exposure prophylaxis (PEP), health seeking behaviour and outcome. Focused group interview were also conducted among traders/handlers of stray dogs.

Results

Ten cases of rabies in subjects aged 3 to 52 years were recorded in these five months period. Eight of the cases were male and apparently got infected directly or indirectly through the trade in stray dogs for human consumption. None had proper PEP and all patients died.

Conclusion

Stray dog trade, fuelled by eating of dog meat, is a risk factor for human and animal rabies in Calabar, southern Nigeria. Culling of stray dogs, control of stray dogs'' trade and public enlightenment on PEP is recommended.     

Neutrophil interaction with influenza-infected epithelial cells

An in vitro model system was used to study the early neutrophil response to influenza-infected epithelia. In the absence of serum, neutrophil adherence to influenza-infected confluent monolayers of Madin-Darby canine kidney epithelial cells (MDCK) was approximately 590 times greater than neutrophil binding to control cultures. The leukocytes bound specifically to virus-infected cells. Neutrophil adherence to influenza-infected MDCK cells was monitored during the course of one replication cycle, and binding began at a time (4.5 hours) that coincided with viral protein insertion in the apical cell membrane. Ultrastructural examination at 4.5 hours showed that greater than 90% of the neutrophils adhered to the epithelial cell membrane in the absence of budding virus and, at 6.5 hours, 100% of the neutrophils adhered to the epithelium with emerging virions. The number of neutrophils bound to influenza-infected MDCK cells was not affected by the presence or absence of calcium or magnesium but did depend on the amount of viral inoculum and on the temperature of the culture. In direct contrast to hemadsorption of RBCs, neutrophil binding to influenza-infected MDCK cells was 100% greater at 37 degrees C than at 4 degrees C. The neutrophil surface molecules that bound influenza virus appeared to become functionally polarized because the adherence of neutrophils to budding influenza virus or to a virus-coated surface inhibited the neutrophils from binding additional influenza virus to their nonadherent surface.     

Increased heat sensitivity of red blood cells in hereditary elliptocytosis with acquired cobalamin (vitamin B12) deficiency

Structural membrane proteins were studied from erythrocytes (RBC) of a patient with a nonhemolytic form of hereditary elliptocytosis (HE) who developed a microcytic anemia with fragmented RBC while cobalamin (B12) deficient. Evidence is presented for qualitative changes in the patient's RBC membranes not related to a loss of structural proteins. Sensitivity of RBC to heat treatment was studied as well as quantitative changes in proteins by densitometry of 1% SDS--10% PAGE gels. Fractions of RBC of various sizes from the patient while B12 deficient all possessed a marked degree of heat sensitivity when compared to RBC from the patient after B12 repletion, normal family members, HE controls, B12-deficient controls, anemic controls, and normal controls. Because loss of spectrin (bands 1 + 2) from heat- sensitive RBC membranes in hereditary pyropoikilocytosis has been reported, the amount of spectrin relative to band 3 was measured. No decrease in the ratio of bands (1 + 2)/3 was found. In addition, no chromatographically abnormal membrane proteins were found by SDS-PAGE of the patient's RBC while B12 deficient. Our findings indicate that B12 deficiency results in an abnormal membrane with enhanced instability in some forms of HE. Since protein loss was not found, we conclude that an alteration in membrane protein interaction may be involved.     

Gleason score and tumor laterality in radical prostatectomy and transrectal ultrasound-guided biopsy of the prostate: a comparative study

We aimed to compare Gleason score and tumor laterality between transrectal ultrasound-guided biopsy of the prostate (TRUSBX) and radical prostatectomy (RP). Some factors that could cause a discrepancy in results between these two procedures were also evaluated. Among the 318 cases reviewed, 191 cases were selected for inclusion in this comparative study. We divided the patients into two groups using the Gleason score: an intermediate/high-grade group (≥7) and a low-grade group (<6). Exploratory analyses were conducted for comparisons between groups. We also performed comparisons between TRUSBX and RP for tumor laterality. TRUSBX overestimated 6% and underestimated 24% cases in comparison with RP for Gleason score, and overestimated 2.6% and underestimated 46% cases compared with RP for tumor laterality. Biopsy specimens were slightly smaller in TRUSBX cases with underestimated tumor laterality (P < 0.05), and no relationship between the biopsy specimen size and underestimated Gleason score in TRUSBX was found. Prostatic volume showed no statistical correlation with the likelihood of under or overestimation (P > 0.05). Thus, our study showed that TRUSBX has a high likelihood of underestimating both the Gleason score and tumor laterality in prostate cancer (PCa). The size of the fragment appears to be an important factor influencing the likelihood of laterality underestimation and Gleason score overestimation via TRUSBX. Due to the high likelihood of underestimation of the Gleason score and tumor laterality by 12-core prostate biopsy, we conclude that this type of biopsy should not be used alone to guide therapy in PCa.     

The Mitochondrial Genome And Human Mitochondrial Diseases

To date, more than 100 point mutations and several hundreds of structural rearrangements of mitochondrial DNA (mtDNA) are known too be connected with characteristic neuromuscular and other mitochondrial syndromes varying from those causing death at the neonatal stage to diseases with late ages of onset. The immediate cause of mitochondrial disorders is a defective oxidative phosphorylation. Wide phenotypic variation and the heteroplasmy phenomenon, which some authors include in mutation load, are characteristic of human mitochondrial diseases. As the numbers of cases identified and pedigrees described increase, data on the genotype-phenotype interaction and the structure and frequency of pathogenic and conditionally pathogenic mtDNA mutations in human populations are rapidly accumulated. The data on the genetics and epidemiology of mitochondrial diseases are not only important for differential diagnosis and genetic counseling. Since both neutral and mildly pathogenic mutations of mtDNA are progressively accumulated in maternal phyletic lines, molecular analysis of these mutations permits not only reconstruction of the genealogical tree of modern humans, but also estimation of the role that these mutations play in natural selection.     

Beraprost: a review of its pharmacology and therapeutic efficacy in the treatment of peripheral arterial disease and pulmonary arterial hypertension.

Beraprost sodium (beraprost) is a stable, orally active prostacyclin analogue with vasodilatory, antiplatelet and cytoprotective effects. Beraprost acts by binding to prostacyclin membrane receptors ultimately inhibiting the release of Ca2+ from intracellular storage sites. This reduction in the influx of Ca2+ has been postulated to cause relaxation of the smooth muscle cells and vasodilation. Data from a large, randomised, double-blind, multicentre study indicated that beraprost was as efficacious as ticlopidine in the treatment of patients with peripheral arterial disease (Buerger's disease and arteriosclerosis obliterans). Most patients receiving beraprost exhibited reduction of ulcer size, reported improvement of granulation appearance of the tissue and showed improvement of pain at rest and sensation of cold in the extremities. In a large pivotal clinical trial in patients with intermittent claudication, beraprost treatment was associated with statistically significant increases in pain-free and absolute walking distances compared with those in patients receiving placebo. Statistically significant differences in the incidence of critical cardiovascular events among both treatment groups were not observed but patients receiving beraprost were more likely to be satisfied with changes in their quality of life. However, while preliminary unpublished data from a large, phase III, placebo-controlled study in the US suggested a trend toward fewer critical cardiovascular events (no specific data presented), this study did not confirm the positive results from the European phase III trial and statistical significance was not achieved in the study's endpoints relating to exercise. A series of small, noncomparative clinical trials of patients with the rare condition of pulmonary arterial hypertension (PAH) demonstrated that substantial reductions of pulmonary arterial pressure and resistance, increase of cardiac output, and increase of exercise capacity appeared to be associated with beraprost therapy; however, these data are very limited and in most instances are not fully published. Beraprost is a well tolerated agent. Overall, the main adverse events include headache, hot flushes, diarrhoea and nausea. However, patients with PAH showed higher incidence of adverse events than those with peripheral arterial disease. CONCLUSION: Beraprost, an orally administered PGI2 analogue, is generally well tolerated and appears to be an effective agent in the treatment of patients with Buerger's disease and arteriosclerosis obliterans. Comparative data from a large randomised trial indicated that the drug appears as effective as ticlopidine in patients with these conditions. In patients with intermittent claudication, significant benefits of beraprost compared with placebo were reported in a randomised clinical trial; however, the use of beraprost in these patients is not supported by recent preliminary unpublished data from a large, phase III, placebo-controlled study. Limited data suggest some efficacy with long-term beraprost treatment of patients with PAH, where options are few and where oral administration of the drug could be a considerable advantage over intravenous prostacyclin (PGI2) therapy. Additional well-designed and, where possible, large trials with active comparators are necessary to define more precisely the place of beraprost in the treatment of patients with PAH, Buerger's disease and arteriosclerosis obliterans.     

Eyelid discoid lupus erythematosus and contact dermatitis: a case report

We report a patient with discoid lupus erythematosus (DLE) and associated allergic contact dermatitis (ACD) in the eyelids. In women, ACD caused by nail varnish is frequent and often seen in the eyelids. ACD caused by drugs (e.g. neomycin) is also frequent in this region. However, DLE with periorbital presentation without evidence of systemic or other cutaneous involvement is rare.