Physical activity combined with massage improves bone mineralization in premature infants: a randomized trial.

BACKGROUND: Osteopenia of prematurity is a known source for morbidity in preterm infants. Premature infants have shown favorable outcomes in response to massage and physical activity. Whether such intervention can stimulate bone formation or decrease bone resorption is yet to be determined. OBJECTIVE: To test the hypothesis that massage combined with physical activity can stimulate bone formation and ameliorate bone resorption in premature infants. DESIGN/METHODS: A prospective double-blinded randomized trial was conducted at the Neonatal Intensive Care Unit of Ain Shams University in Cairo, Egypt. Thirty preterm infants (28 to 35 weeks' gestation) were randomly assigned to either control group (Group I, n=15) or intervention group (Group II, n=15). Infants in the intervention group received a daily protocol of combined massage and physical activity. Serum type I collagen C-terminal propeptide (PICP) and urinary pyridinoline crosslinks of collagen (Pyd) were used as indices for bone formation and resorption, respectively. PICP and Pyd were measured at enrollment and at discharge for all subjects. t-Test, ANOVA and linear regression analysis were used for statistical analyses. RESULTS: There was no difference between groups I and II in gestational age (32.1+/-1.8 vs 31.5+/-1.4 weeks) or birth weight (1.429+/-0.148 vs 1.467+/-0.132 g). In the control group, serum PICP decreased over time from 82.3+/-8.5 to 68.78+/-14.6 (p<0.01), while urinary Pyd increased from 447.7+/-282.8 to 744.9+/-373.6 (p<0.01) indicating decreased bone formation and increased bone resorption, respectively. In the intervention group, serum PICP increased over time from 62.5+/-13.8 to 73.84+/-12.9 (p<0.01). Urinary Pyd also increased over time from 445.7+/-266.5 to 716.8+/-301.8 (p<0.01). In a linear regression model including gestational age and intervention, serum PICP increased significantly in the intervention group (regression coefficient 18.8+/-4.6, p=0.0001) while urinary Pyd did not differ between groups (regression coefficient=5.6+/-114.3, p=0.961). CONCLUSIONS: A combined massage and physical activity protocol improved bone formation (PICP) but did not affect bone resorption (Pyd). Pyd increased over time in both groups, possibly due to continuous bone resorption and Ca mobilization.     

Gamma scintigraphic evaluation of the fate of hydroxypropyl methylcellulose capsules in the human gastrointestinal tract

The fate (movement and disintegration) of hard novel hydroxypropyl methylcellulose (HPMC) two-piece capsules in the human gastrointestinal tract was investigated using a gamma scintigraphic imaging method. Two different prolonged-release formulations without an active ingredient were used. The capsules contained different viscosity grades of HPMC powder (HPMC K100 and HPMC K4M). The aim was to determine the main reason why the pharmacokinetic profiles of model drugs change when the diluent was changed to a higher viscosity grade. The results were compared with our previous pharmacokinetic studies with corresponding capsules containing metoclopramide hydrochloride or ibuprofen as a model drug. The first observation was that the HPMC capsules had a tendency to attach to the oesophagus. Therefore, it is recommended that the HPMC capsules as well as gelatine capsules be taken with a sufficient amount of water (150–200 ml) in an upright position and maintaining the upright position for several minutes. The viscosity grade of the HPMC did not affect the transit times of the capsules in the GI tract. The major differences between the two formulations were the complete disintegration times of the capsules and the spreading of the capsules to the large intestine. Most of the HPMC K100-based capsules were completely disintegrated during the 8 h study, whereas the HPMC K4M-based capsules still exhibited plug formations in the large intestine. Also the HPMC K100-based capsules spread better to the ascending colon than the HPMC K4M-based capsules. The faster disintegration of the HPMC K100-based capsules explains the differences in the pharmacokinetic profiles of the model drugs between the HPMC K100- and K4M-based capsules in our previous studies. The main absorption site of the drugs from the capsules studied here is probably the large intestine when taken in a fasting state.     

Pharmacokinetics of levosimendan and its active metabolite OR-1896 in rapid and slow acetylators.

OBJECTIVE: The purpose of this study was to investigate the pharmacokinetics of levosimendan and to determine the primary pharmacokinetic parameters of the pharmacologically active metabolite OR-1896 in rapid and slow acetylators. METHODS: Levosimendan was administered as a constant rate (0.1 microg/(kg min)) i.v. infusion for 24h in six rapid and six slow acetylators based on N-acetyltransferase 2 genotyping. At the end of the infusion, a small amount (2.5 microg/kg) of (13)C-labeled OR-1896 was administered by i.v. infusion for 10 min. Blood samples were taken at predefined sampling points 14 days post-infusion and levosimendan and its metabolite concentrations were determined by LC-MS/MS. RESULTS: Steady-state concentrations of levosimendan were achieved within 4-8h and no differences were found in the pharmacokinetics of the parent compound between the rapid and slow acetylators. The maximum concentrations of amino phenylpyridazinone metabolite OR-1855 and N-acetylated conjugate OR-1896 were observed approximately 24h after terminating the infusion. AUC of OR-1896 was approximately 3.5 times higher in the rapid acetylators compared to the slow acetylators (P = 0.002, 95% confidence interval for group ratio from 2.0 to 8.2). The mean +/- S.D. fraction of levosimendan metabolized to OR-1896 was 6.8 +/- 2.8% in the rapid and 4.3 +/- 2.4% in the slow acetylators (P = 0.12). (13)C-OR-1855 concentrations were detected in plasma after administration of (13)C-OR-1896 indicating deacetylation from OR-1896 to OR-1855. CONCLUSIONS: Plasma OR-1896 levels during and after levosimendan treatment are dependent on the acetylation status of the subject-rapid acetylators having 3.5 times higher concentrations than slow acetylators.     

Sister-to-sister oocyte donation: couples’ experiences with regard to genetic ties

Objective: This study aimed to gain an in-depth understanding of the experiences of genetic ties in intrafamily oocyte donation families. Background: Previous research has shown that most mothers have a good and stable relationship with their donor. Little is known about the meaning of the difference in genetic ties for parents who conceived through sister-to-sister oocyte donation. Methods: An Interpretative Phenomenological Analysis was performed and focused on both individual experiences and couple experiences with regard to genetic ties. Ten participants were recruited via an infertility clinic and took part in semistructured couple interviews. Results: Our analysis revealed that the donation was seen as a way to equal genetic parenthood. Participants struggled with this prevailing ideal of genetic parenthood and questioned the legitimacy of their motherhood. Several dynamics were identified when couples tried to deal with the imbalance in genetic ties: they acknowledged each other, convinced one another, or pushed away the difference in genetic ties. Couples also managed the presence of a genetic tie with the donor by negotiating the closeness in their family relationships. Conclusion: The lack of a full genetic tie remained a meaningful absence for some mothers and the way couples dealt with this varied. We plead that the option of post-donation care should be offered to support couples with the complexities they try to deal with.     

Improving safety of gene therapy

Gene therapy has progressed from early clinical trials to first commercial gene therapy drugs. While there is a long history with the side-effects and adverse effects of pharmaceutical drugs, drugs based on gene delivery have presented new challenges for researchers, clinicians and regulatory authorities. On the path from early pre-clinical research to final commercial products, gene therapy tools and production methods have undergone tremendous changes to improve safety and efficacy. Deletion of adenovirus replication genes E1 and E3 has progressed to gutless adenoviruses with all viral genes removed; similarly evolution of lentiviral vectors has progressed from first generation viruses to safer third generation self-inactivating vectors. Improved chromatographic methods have eased the purification of viruses and delivery reservoirs, such as collagen or silicon collars for cardiovascular gene transfer have decreased systemic leakage of viruses; together with tissue-specific promoters and imaging of the biodistribution of viral particles, gene therapy specificity and safety can be improved even further. This review will introduce gene delivery vectors used in gene therapy and highlight key approaches used to improve their safety.     

Modulation of ghrelin axis influences the growth of colonic and prostatic cancer cells in vitro

BackgroundThe risk of different cancers seems to be associated with obesity. Moreover, low ghrelin levels observed in obese people may be implicated in cancer development and progression. The aim of this study was to examine the direct effects of both forms of ghrelin (acylated and unacylated) and ghrelin receptor type 1a antagonist (D-Lys-GHRP-6) on the growth of murine colon cancer MC38 and human prostate cancer DU145 cell lines in vitro.MethodsThe cells were cultured for 72 h in the presence of rat or human acylated ghrelin (rG, hG), human unacylated ghrelin (hUAG), D-Lys-GHRP-6 (GHS-RA) applied either alone or jointly. The cell line growth was assessed by the colorimetric Mosmann method.ResultshUAG (10^?6, 10^?7 and 10^?10 M) inhibited MC38 cancer cell growth and, at some concentrations (10^?8, 10^?9, 10^?10 M), enhanced the antineoplastic effect of GHS-RA (10^?4 M). In turn, GHS-RA evoked a biphasic effect on MC38 cancer growth: inhibitory at 10^?4 M and stimulatory at 10^?5 and 10^?6 M. Moreover, GHS-RA at the highest examined concentration (10^?4 M) enhanced the cytostatic effect of FU. Human acylated and unacylated ghrelin and GHS-RA inhibited DU145 cancer growth with moderate and different potencies. A dose-response effect was observed for the inhibitory action of hG together with the synergistic effect of hUAG and GHS-RA.ConclusionThe obtained results indicate an involvement of the ghrelin axis in the growth regulation of colon and prostate cancers and may suggest new therapeutic options for these neoplasms.     

Head and neck squamous carcinomas with exophytic and endophytic type of growth have the same prognosis after surgery and adjuvant radiotherapy

Head and neck squamous cell carcinomas (HNSCC) are characterized by exophytic or endophytic growth. We hypothesized that the growth pattern predicts outcome and associates with distinct clinical and immunological profiles. Tumors obtained from 60 HNSCC patients treated with surgery and adjuvant radiotherapy were identified as exophytic or endophytic. Recurrence-free survival (RFS) at 42 months was determined. In a subsets of 30 patients (22 exophytic and 8 endophytic) tumor stroma and parenchyma were evaluated for infiltrating CD4⁺ and CD8⁺ T, dendritic, myeloid and FOXP3⁺ regulatory T cells (Treg) and expression of immunosuppressive cytokines by immunohistochemistry. The localization and frequency of positive cells were determined microscopically and analyzed by hierarchical clustering to distinguish exophytic versus endophytic tumors. 34/60 patients had exophytic and 26/60 endophytic tumors. No differences in clinicopathologic data, disease progression or RFS were seen between the two cohorts. Infiltrates of CD3⁺CD8⁺ T cells were larger in endophytic than exophytic tumors, while FOXP3⁺ Treg, TGF-β⁺, IL-10⁺, Arg-1⁺, CD11b⁺ cells were equally prominent in both. FOXP3⁺ Treg accumulated in endophytic tumor nests, while the exophytic tumor stroma was enriched in IL-10⁺ cells (both at p < 0.05). Hierarchical clustering based on immunophenotyping failed to identify different clusters in these two tumor types. However, CD68⁺ macrophages and FOXP3⁺ Treg showed a distinct distribution. The HNSCC growth pattern did not predict RFS. Although higher numbers and differences in localization of immunosuppressive cells in endophytic versus exophytic tumors were observed, no significant relationship was established between the growth pattern and the immune profile of infiltrating lymphocytes.