Visual internal urethrotomy for management of urethral strictures in boys: a comparison of short-term outcome of holmium laser versus cold knife

Purpose

To compare efficacy and safety of visual internal urethrotomy (VIU) using holmium laser (Ho:YAG) (group A) versus cold knife (group B) in children with urethral strictures. It may be the first comparative study on this issue in children.

Methods

This study compared Ho:YAG group, which was evaluated prospectively from January 2014 till January 2016, versus cold knife group, which was a historical control performed from March 2008 till February 2010. Children ≤ 13 years old with urethral strictures ≤ 1.5 cm were included successively. Recurrent cases, congenital obstructions and cases with complete arrest of dye in voiding cystourethrography were excluded. Scar tissue was incised at twelve o’clock. Outcome was compared using Student’s t, Mann–Whitney, Chi-square or Fisher exact tests as appropriate.

Results

Each group included 21 patients. Mean age was 6.27 ± 3.23 (2–13) years old. Mean stricture length was 1.02 versus 1 cm in group A versus B, respectively (p = 0.862). Ten cases of penile/bulbous strictures and another 11 cases of membranous strictures were found in each group. There was no significant difference between both groups in preoperative data. Success rate for initial VIU was 66.7% in group A versus 38% in group B (p = 0.064). This was associated with significantly higher Q_max in group A (mean 16.52 vs 12.09 ml/s; p = 0.03). Success rate after two trials of VIU was 76.2% for group A and 47.61% for group B (p = 0.057). No complications were reported in both groups.

Conclusion

Laser VIU has a higher success rate than cold knife VIU for urethral strictures ≤ 1.5 cm in children with significantly higher Q_max. Both are easy to perform, low invasive and safe.

     

Modulation of calcium-activation in control and pressure--overload hypertrophied ferret hearts: effect of DPI 201-106 on myofilament calcium responsiveness.

We examined the relationship between free Ca2+ and developed force in chemically skinned fibers from control and pressure-overload hypertrophied (POH) hearts of ferrets in the absence and presence of DPI 201-106 (4-([3-(4-diphenyl-methyl-l-piperazinyl)-2-hydroxypropoxy]-1H-indole-2- carbonitrile), a positive inotropic and negative lusitropic agent. Force production in both control and hypertrophied fibers increased with Ca2+ concentration ([Ca2+]) over a range from 10(-7) M to 10(-4) M, and did not differ significantly in response to Ca2+ under isometric conditions. The [Ca2+] required for half-maximal activation ([Ca2+]50%) was estimated to be 1.84 x 10(-6) M in control muscles and 1.76 x 10(-6) M in POH muscles. The maximal Ca2(+)-activated force was significantly higher in the POH group (3.68 +/- 0.27 g/mm2) as compared to the control muscles (2.41 +/- 0.56 g/mm2. A DPI concentration of 10(-6) M shifted the force-pCa relation leftward by 0.13-0.18 pCa units in the control hearts, and by 0.40-0.45 pCa units in the hypertrophied hearts. In the concentration range between 10(-8) M and 10(-5) M, DPI induced a concentration dependent increase in force production that reached about 40% in the hypertrophied hearts and only 18% in the control hearts at pCa 6. The influence of DPI on the myofibrillar Ca2+ binding may be due to the effect of the drug on the troponin T-tropomyosin complex. In view of our results, we propose that hypertrophied hearts may demonstrate an adaptational change in the contractile proteins at the level of the thin myofilaments. This adaptational change may result in altered contractile performance and response to agents that potentially act at the level of the myofilaments. Further, alteration at the level of the myofilaments may not be detected by standard force-[Ca2+] relationships.     

Interplay of formulation and process methodology on the extent of nifedipine molecular dispersion in polymers

The aim of this study is to evaluate effects of formulation and process technology on drug molecular dispersibility in solid dispersions (SDs). Nifedipine solid dispersions with ethylcellulose (EC) and/or Eudragit RL (RL) prepared by co-precipitation, co-evaporation, and fusion methods were characterized with FTIR, DSC, and XRPD for the content of nifedipine as molecular dispersion, amorphous and/or crystalline suspensions. A method was developed based on regular solution and Flory-Huggins theories to calculate drug-polymer interaction parameter in solid dispersion systems. A synergic effect of RL and EC on nifedipine molecular dispersibility in solid dispersions was observed. Increasing RL/EC ratio resulted in a higher degree of drug-polymer interaction that thermodynamically favored molecular dispersion, which, however, was counteracted by a corresponding decrease in the matrix glass transition point that kinetically favored phase-separation. Process methodology was found to play an important role in the formation of amorphous SD. The ranking of technologies with respect to the extent of molecular dispersion from high to low is fusion > co-evaporation > co-precipitation, wherein the solidification rate of polymeric solution and non-solvent effects were linked to kinetic entrapment of drug molecules in polymeric networks. Since nifedipine molecular dispersibility in EC/RL polymer(s) is a result of interplay between thermodynamic and kinetic factors, nifedipine molecular dispersions prepared for this study are thermodynamically metastable systems. To explore those supersaturation systems for use in drug delivery of poorly water soluble drugs, it is critical to balance drug-polymer interactions and matrix glass transition point and to consider a process technology with a fast solidification rate during formulation and process development of amorphous SD.     

Volumetric interpretation of protein adsorption: interfacial packing of protein adsorbed to hydrophobic surfaces from surface-saturating solution concentrations

The maximum capacity of a hydrophobic adsorbent is interpreted in terms of square or hexagonal (cubic and face-centered-cubic, FCC) interfacial packing models of adsorbed blood proteins in a way that accommodates experimental measurements by the solution-depletion method and quartz-crystal-microbalance (QCM) for the human proteins serum albumin (HSA, 66 kDa), immunoglobulin G (IgG, 160 kDa), fibrinogen (Fib, 341 kDa), and immunoglobulin M (IgM, 1000 kDa). A simple analysis shows that adsorbent capacity is capped by a fixed mass/volume (e.g. mg/mL) surface-region (interphase) concentration and not molar concentration. Nearly analytical agreement between the packing models and experiment suggests that, at surface saturation, above-mentioned proteins assemble within the interphase in a manner that approximates a well-ordered array. HSA saturates a hydrophobic adsorbent with the equivalent of a single square or hexagonally-packed layer of hydrated molecules whereas the larger proteins occupy two-or-more layers, depending on the specific protein under consideration and analytical method used to measure adsorbate mass (solution depletion or QCM). Square or hexagonal (cubic and FCC) packing models cannot be clearly distinguished by comparison to experimental data. QCM measurement of adsorbent capacity is shown to be significantly different than that measured by solution depletion for similar hydrophobic adsorbents. The underlying reason is traced to the fact that QCM measures contribution of both core protein, water of hydration, and interphase water whereas solution depletion measures only the contribution of core protein. It is further shown that thickness of the interphase directly measured by QCM systematically exceeds that inferred from solution-depletion measurements, presumably because the static model used to interpret solution depletion does not accurately capture the complexities of the viscoelastic interfacial environment probed by QCM.     

Bioengineering embryonic stem cell microenvironments for exploring inhibitory effects on metastatic breast cancer cells

The recreation of an in vitro microenvironment to understand and manipulate the proliferation and migration of invasive breast cancer cells may allow one to put a halt to their metastasis capacity. Invasive cancer cells have been linked to embryonic stem (ES) cells as they possess certain similar characteristics and gene signatures. Embryonic microenvironments have the potential to reprogram cancer cells into a less invasive phenotype and help elucidate tumorigenesis and metastasis. In this study, we explored the feasibility of reconstructing embryonic microenvironments using mouse ES cells cultured in alginate hydrogel and investigated the interactions of ES cells and highly invasive breast cancer cells in 2D, 2&1/2D, and 3D cultures. Results showed that mouse ES cells inhibited the growth and tumor spheroid formation of breast cancer cells. The mouse ES cell microenvironment was further constructed and optimized in 3D alginate hydrogel microbeads, and co-cultured with breast cancer cells. Migration analysis displayed a significant reduction in the average velocity and trajectory of breast cancer cell locomotion compared to control, suggesting that bioengineered mouse ES cell microenvironments inhibited the proliferation and migration of breast cancer cells. This study may act as a platform to open up new options to understand and harness tumor cell plasticity and develop therapeutics for metastatic breast cancer.     

In vivo antihyperlipidemic activity of a new series of N-(benzoylphenyl) and N-(acetylphenyl)-1-benzofuran-2-carboxamides in rats

A new series of N‐(benzoylphenyl) and N‐(acetylphenyl)‐1‐benzofuran‐2‐carboxamides ( 3a – 3d and 4a ′– 4c ′) were synthesized. Compounds ( 3a , 3b , and 4a ′– 4c ′) were tested in vivo using Triton‐WR‐1339‐induced hyperlipidemic rats as an experimental model for their hypolipidemic activity. The tested animals were divided into eight groups: control, hyperlipidemic, 3a , 3b , 4a ′, 4b ′, 4c ′, and bezafibrate. At a dose of 15 mg/kg, the elevated plasma triglyceride (TG) levels were significantly reduced in compounds 3b (p <0.0001) and 4c ′ (p <0.05) after 12 and 24 h compared to the normal control group. Furthermore, high‐density lipoprotein‐cholesterol levels were remarkably increased in compounds 3b (p <0.001) and 4c ′ (p <0.05). Meanwhile, compound 4b ′ slightly reduced the TG levels after 12 and 24 h. The present study demonstrated new properties of the novel series of benzofuran‐2‐carboxamides 3b and 4c ′ as potent lipid‐lowering agents. It is, therefore, reasonable to assume that compounds 3b and 4c ′ may have a promising potential in the treatment of hyperlipidemia and coronary heart diseases.     

Antisolvent crystallisation is a potential technique to prepare engineered lactose with promising aerosolisation properties: Effect of saturation degree

Engineered lactose particles were prepared by anti-solvent crystallisation technique using lactose solutions with different saturation degrees. In comparison to commercial lactose, engineered lactose particles exhibited less elongated and more irregular shape (large aggregates composed of smaller sub-units), rougher surface texture, higher specific surface area, and different anomer form. Engineered lactose powders demonstrated smaller bulk density, smaller tap density, and higher porosity than commercial lactose powder. Dry powder inhaler (DPI) formulations containing engineered lactose and salbutamol sulphate as a model drug demonstrated improved drug content homogeneity and higher amounts of drug delivered to lower airway regions. Higher fine particle fraction of drug was obtained in the case of lactose powders with higher porosity, higher specific surface area and higher fine particle content (<5μm). The results indicated that the higher the saturation degree of lactose solution used during crystallisation the smaller the specific surface area, the higher the amorphous lactose content, and the higher the β-lactose content of engineered lactose particles. Also, lactose powders obtained from lactose solution with higher degree of saturation showed higher bulk and tap densities and smaller porosity. Engineered lactose powders crystallized from lower saturation degree (20% and 30% w/v) deposited higher amounts of drug on lower airway regions. In conclusion, this study demonstrated that it is possible to prepare engineered lactose particles with favourable properties (e.g. higher fine particle fraction and better drug content homogeneity) for DPI formulations by using lactose solutions with lower degree of saturation during crystallisation process.     

Molecular analysis of the membrane insertion domain of proteinase 3, the Wegener's autoantigen, in RBL cells: implication for its pathogenic activity

PR3, also called myeloblastin, is a neutrophil serine protease that promotes myeloid cell proliferation by cleaving the cyclin-dependent kinase inhibitor p21(cip1/waf1). In addition, it is the target of ANCA in GPA, a necrotizing vasculitis. Anti-PR3 ANCA binding to membrane-expressed PR3 triggers neutrophil activation, potentiating vascular inflammation. This study performed in RBL cells identifies the structural motifs of PR3 membrane anchorage and examines its impact on PR3 proinflammatory and proliferative functions. With the use of MD simulations and mutagenesis, we demonstrate that the mutations of four hydrophobic (F180, F181, L228, F229) or four basic (R193, R194, K195, R227) amino acids abrogated PR3 membrane anchorage. The hydrophobic patch-deficient PR3 mutant (PR34H4A) was still able to cleave the synthetic substrate Boc-Ala-Pro-Val in cell lysates. However, in contrast to WT PR3, PR34H4A was not expressed at the plasma membrane after degranulation and failed to cleave extracellular fibronectin, was not externalized after apoptosis and did not impair macrophage phagocytosis of apoptotic cells, did not promote myeloid cell proliferation and failed to cleave p21/waf1. PR3 membrane insertion appears to be pivotal for its proinflammatory activities, such as extracellular proteolysis and impairment of apoptotic cell clearance, but also for myeloid cell proliferation. Targeting membrane-associated PR3 might constitute a novel, anti-inflammatory therapeutic strategy in inflammatory disease especially in vasculitis, but this approach has to be validated in mature neutrophils.