Smad5 is dispensable for adult murine hematopoiesis

Smad5 is known to transduce intracellular signals from bone morphogenetic proteins (BMPs), which belong to the transforming growth factor-beta (TGF-beta) superfamily and are involved in the regulation of hematopoiesis. Recent findings suggest that BMP4 stimulates proliferation of human primitive hematopoietic progenitors in vitro, while early progenitors from mice deficient in Smad5 display increased self-renewal capacity in murine embryonic hematopoiesis. Here, we evaluate the role of Smad5 in the regulation of hematopoietic stem cell (HSC) fate decisions in adult mice by using an inducible MxCre-mediated conditional knockout model. Surprisingly, analysis of induced animals revealed unperturbed cell numbers and lineage distribution in peripheral blood (PB), bone marrow (BM), and the spleen. Furthermore, phenotypic characterization of the stem cell compartment revealed normal numbers of primitive lin(-)Sca-1(+)c-Kit(+) (LSK) cells in Smad5(-)(/)(-) BM. When transplanted in a competitive fashion into lethally irradiated primary and secondary recipients, Smad5-deficient BM cells competed normally with wild-type (wt) cells, were able to provide long-term reconstitution for the hosts, and displayed normal lineage distribution. Taken together, Smad5-deficient HSCs from adult mice show unaltered differentiation, proliferation, and repopulating capacity. Therefore, in contrast to its role in embryonic hematopoiesis, Smad5 is dispensable for hematopoiesis in the adult mouse.     

Single nucleotide polymorphisms predict the change in left ventricular mass in response to antihypertensive treatment

BACKGROUND: Our aim was to determine whether the change in left ventricular (LV) mass in response to antihypertensive treatment could be predicted by multivariate analysis of single nucleotide polymorphisms (SNPs) in candidate genes reflecting pathways likely to be involved in blood pressure control. METHODS: Patients with mild to moderate primary hypertension and LV hypertrophy were randomized in a double-blind fashion to treatment with either the angiotensin II type 1 receptor antagonist irbesartan (n = 48) or the beta1 adrenoreceptor blocker atenolol (n = 49). A microarray-based minisequencing system was used for genotyping 74 SNPs in 25 genes. These genotypes were related to the change in LV mass index by echocardiography, after 12 weeks treatment as monotherapy, using stepwise multiple regression analysis. RESULTS: The blood pressure reductions were similar and significant in both treatment groups. Two SNPs in two separate genes (the angiotensinogen T1198C polymorphism, corresponding to the M235T variant and the apolipoprotein B G10108A polymorphism) for those treated with irbesartan, and the adrenoreceptor alpha2A A1817G for those treated with atenolol, significantly predicted the change in LV mass. The predictive power of these SNPs was independent of the degree of blood pressure reduction. CONCLUSION: SNPs in the angiotensinogen, apolipoprotein B, and the alpha2 adrenoreceptor gene predicted the change in LV mass during antihypertensive therapy. These results illustrate the potential of using microarray-based technology for SNP genotyping in predicting individual drug responses.     

A pilot study of complete edentulous rehabilitation with immediate function using a new implant design: case series

Background: The current investigation focuses on new implant designs for increased predictability in clinically demanding situations. Microtextured implant surfaces create favorable conditions for enhanced osseointegration of dental implants compared to implants with a smooth surface, and the macroscopic implant design may influence implant stability. Purpose: The aim of the present study was to retrospectively evaluate the clinical performance of a novel implant design in the rehabilitation of completely edentulous jaws and in combination with an immediate function protocol. Materials and Methods: Forty‐six consecutive patients received 189 study implants (NobelSpeedy^TM concept implant, Nobel Biocare AB, Göteborg, Sweden) supporting 53 full‐arch all‐acrylic prostheses (44 maxilla, 9 mandible). The majority (66%) of the reconstructions were supported by four implants, of which the two posterior implants were tilted. All patients were followed for a minimum of 1 year. Radiographic assessment of the marginal bone level was performed. Results: Two implants were lost in two patients, rendering a 1‐year cumulative clinical survival rate of 98.9%. The marginal bone level was, on average, situated 1.2 ± 0.7 mm below the implant‐abutment interface after 1 year of loading. Good soft tissue health and overall esthetic outcome was reported. Conclusions: The results of the present pilot study indicate that fully edentulous jaws with various types of bone can be treated with high success and good esthetics using immediately loaded implants with the presented design, and that favorable marginal bone levels can be maintained.     

Different proliferative responses of Gi/o-protein-coupled receptors in human myometrial smooth muscle cells

The majority of studies investigating the proliferative effect of G_i/o-protein-coupled receptor agonists are performed in recombinant receptor systems or cell lines. In these systems the relative stoichiometry of receptors compared to other cell components might be changed, which may lead to anomalies in cellular responses in contrast to natural occurring systems. In the present study, we have used primary cultures of smooth muscle cells (SMCs) isolated from human myometrium to characterize the proliferative effects of agonists binding to two different G protein-coupled receptors. Treatment of quiescent SMCs with lysophosphatidic acid (LPA) and noradrenaline resulted in significant increases in [³H]thymidine incorporation. However, LPA was almost four times more effective than noradrenaline in this respect. The proliferative effects of the agonists could be completely blocked by pertussis toxin, indicating that the response are mediated through G_i/o-proteins. The selective α₂-adrenergic receptor (α₂-AR) antagonist yohimbine dose-dependently reduced the effect of noradrenaline suggesting that the proliferative response was mediated through α₂-ARs. The proliferative effects induced by LPA and noradrenaline was markedly reduced in SMCs treated with the tyrosine kinase inhibitor genistein and the cAMP elevating compound forskolin. However, LPA but not noradrenaline induced rapid rises in the cytosolic free Ca²⁺ concentration [Ca²⁺]_i. The ability to increase Ca²⁺ might be one explanation why LPA produce a more pronounced proliferative response than noradrenaline in primary cultures of human myometrial SMCs.     

Population pharmacokinetics of rifapentine and its primary desacetyl metabolite in South African tuberculosis patients

This study was designed to describe the population pharmacokinetics of rifapentine (RFP) and 25-desacetyl RFP in a South African pulmonary tuberculosis patient population. Special reference was made to studying the influence of previous exposure to rifampin (RIF) and the variability in pharmacokinetic parameters between patients and between occasions and the influence of different covariates. Patients were included in the study if they had been receiving first-line antimycobacterial therapy (rifampin, isoniazid, pyrazinamide, and ethambutol) for not less than 4 weeks and not more than 6 weeks and were divided into three RFP dosage groups based on weight: 600 mg, <45 kg; 750 mg, 46 to 55 kg; and 900 mg, >55 kg. Participants received a single oral dose of RFP together with concomitant antimycobacterial agents, excluding RIF, on study days 1 and 5 after they ingested a soup-based meal. The RFP and 25-desacetyl RFP concentration-time data were analyzed by nonlinear mixed-effect modeling using NONMEM. The pharmacokinetics of the parent drug were modeled separately, and the individual pharmacokinetic parameters were used as inputs for the 25-desacetyl RFP pharmacokinetic model. A one-compartment disposition model was found to best describe the data for both the parent and the metabolite, and the metabolite was assumed to be formed only from the central compartment of the parent drug. Prior treatment with RIF did not alter the pharmacokinetics of RFP but appeared to increase the excretion of 25-desacetyl RFP in a nonlinear fashion. The RFP oral clearance and volume of distribution were found to increase by 0.049 liter/h and 0.691 liter, respectively, with a 1-kg increase from the median weight of 50 kg. The oral clearance of 25-desacetyl RFP was found to be 35% lower in female patients. The model developed here describes the population pharmacokinetics of RFP and its primary metabolite in tuberculosis patients and includes the effects of prior administration with RIF and covariate factors.     

Visual function,ocular motility and ocular characteristics in patients with mitochondrial complex I deficiency

Purpose: The aims of the present study were to investigate visual function, ocular motility and ocular characteristics in children and young adults with complex I deficiency. Material and Methods: In a prospective study with longitudinal follow‐up, the visual and ocular outcome in 13 patients with deficiency in complex I [nicotine‐amide adenine dinucleotide (NADH) dehydrogenase] in the mitochondrial respiratory chain is presented. The patients were diagnosed during 1995–2007 and assessed during 1997–2009 at a median age of 12.8 years (range 3.1–23.4). Results: Twelve of 13 patients had visual impairment and/or ocular pathology. Four of 10 patients who co‐operated in visual assessment had a best corrected decimal visual acuity of ≤0.5 in one or both eyes. Cataract surgery was performed in one patient and another patient showed retinal pigmentations and ptosis. Eleven patients demonstrated ocular motility problems, mainly saccade deficiencies. Five patients had optic atrophy (OA), which was bilateral in four patients. In four siblings, the OA showed a similarity to Leber’s Hereditary Optic Neuropathy. These patients also had the 11778 G→A mutation in mitochondrial DNA. Only one patient had normal visual acuity and ocular outcome including refraction and visual fields. Follow‐up time was median 3.0 years (range 0–11). Conclusion: Visual impairment, ocular motility problems and OA are common in children and young adults with complex I deficiency and should prompt the paediatric ophthalmologist to consider mitochondrial disorders.