2,4-Disubstituted pyridine derivatives are effective against intracellular and biofilm-forming tubercle bacilli.

It was recently reported that 4-substituted picolinohydrazonamides carrying hydrophilic cyclic amines, such as morpholine and pyrrolidine, at the end of their thiosemicarbazide chain have potent antimycobacterial activity in vitro at concentrations below 1 µg/ml. Here, two selected compounds, 2,4-disubstituted pyridine derivatives 11 and 15, revealed significant bactericidal activity against Mycobacterium tuberculosis localized intracellularly within human macrophages, as well as against biofilm-forming tubercle bacilli. Mutants were selected that were resistant to the investigated compounds at an efficiency similar to that identified in the presence of the first line antituberculosis drug rifampicin. The resistant mutants were viable in the presence of the tested compounds exclusively on solid media. Genome-wide sequencing of the mutants selected in the presence of compound 11 revealed the accumulation of nonsynonymous mutations in the mmpR5 gene encoding a transcriptional repressor of the MmpS5-MmpL5 efflux pump, whose upregulation has been associated with bedaquiline resistance. The depletion of MmpR5 in wild-type M. tuberculosis using CRISPR-Cas9 technology increased the resistance of this strain to compound 11. Mass spectrometry-based proteomics (LC-MS/MS) of wild-type tubercle bacilli growing in subinhibitory concentrations of compounds 11 or 15 revealed 15 overproduced proteins not detectable in the control cells, including virulence-related proteins.

BioSCOOP - Biobank Sample Communication Protocol. New approach for the transfer of information between biobanks.

Dynamic development of biobanking industry (both business and science) resulted in an increased number of IT systems for samples and data management. The most difficult and complicated case for the biobanking community was cooperation between institutions, equipped with different IT systems, in the field of scientific research, mainly data interchange and information flow. Tools available on the market relate mainly to the biobank or collection level. Efficient and universal protocols including the detailed information about the donor and the sample are still very limited. Here, we have developed BioSCOOP, a communication protocol in the form of a well documented JSON API. The main aim of this study was to harmonize and standardize the rules of communication between biobanks on the level of information about the donor together with information about the sample. The purpose was to create a communication protocol for two applications: to transfer the information between different biobanks and to allow the searching and presentation of the sample and data sets.

Sports hernias: a systematic literature review.

This review summarises the existing knowledge about pathogenesis, differential diagnosis, conservative treatment, surgery and post-surgical rehabilitation of sports hernias. Sports hernias occur more often in men, usually during athletic activities that involve cutting, pivoting, kicking and sharp turns, such as those that occur during soccer, ice hockey or football. Sports hernias generally present an insidious onset, but with focused questioning a specific inciting incident may be identified. The likely causative factor is posterior inguinal wall weakening from excessive or high repetition shear forces applied through the pelvic attachments of poorly balanced hip adductor and abdominal muscle activation. There is currently no consensus as to what specifically constitutes this diagnosis. As it can be difficult to make a definitive diagnosis based on conventional physical examination, other methods, such as MRI and diagnostic ultrasonography are often used, primarily to exclude other conditions. Surgery seems to be more effective than conservative treatment, and laparoscopic techniques generally enable a quicker recovery time than open repair. However, in addition to better descriptions of surgical anatomy and procedures and conservative and post-surgical rehabilitation, well-designed research studies are needed, which include more detailed serial patient outcome measurements in addition to basing success solely on return to sports activity timing. Only with this information will we better understand sports hernia pathogenesis, verify superior surgical approaches, develop evidence-based screening and prevention strategies, and more effectively direct both conservative and post-surgical rehabilitation.

Evaluation of emulsion stability by diffuse reflectance spectroscopy.

A new method is described for evaluating the stability of emulsion bases and active components contained within such emulsions. Diffuse reflectance spectroscopy (DRS) is a technique that has the capability of detecting changes in particle size, surface properties, or drug quality of emulsions as a function of time without disturbance of the system. Such physical or chemical changes are monitored by changes in the visible and UV wavelength spectral characteristics of the emulsified systems. Four basic emulsion systems were prepared and analyzed for physical stability for 6 months by three techniques: visible coalescence, particle counting measurement, and DRS. Two drugs, aspirin and ascorbic acid, were then incorporated within stable emulsion bases, and the chemical stability of these drugs was monitored by DRS for 6 months. Results were compared with concomitant quantitative drug assay procedures. Good agreement was observed when data from DRS and analytical measurements were compared. The DRS technique may be used as a supportive method, offering simplicity and expedience, with other methods of evaluating emulsion stability and drug stability within emulsified systems.

In vitro adsorption of various pharmaceutical to montmorillonite.

Dissolution and dialysis studies showed that cationic drugs and certain nonionic drugs bind strongly to montmorillonite clay. The quantity of drug bound by one unit of clay varied considerably. Anionic drugs were weakly bound, and less bioavailabilty problems would be anticipated with these medicinals. The mechanism of binding of cationic drugs to montmorillonite was proposed as a two-step process: a cation-exchange reaction followed by strong surface chemisorption.

Sustained-release applications of montmorillonite interaction with amphetamine sulfate.

Urinary recovery studies showed that montmorillonite significantly affects the initial therapeutic levels of amphetamine sulfate. The combination of a 1:20 drug-montmorillonite complex with pure drug in a 1:1 ratio, based on amphetamine content, resulted in recovery profiles resembling those obtained from prolonged-release dosage forms. The 1:20 complex, pure drug, and combination formulations showed comparable bioavailability after 48 hr.

Corneal penetration behavior of beta-blocking agents III: In vitro-in vivo correlations.

Aqueous humor levels were determined over time after the topical administration to rabbit eyes of 1% isotonic buffered (pH 7.3) solutions of three beta-blocking agents, acebutolol hydrochloride, timolol maleate, and bufuralol hydrochloride (arranged in order of increasing lipophilicity). Corneal permeability coefficients, determined from a previous in vitro study, were inversely related to the observed time to peak for the three drugs, as expected. Two of the drugs, bufuralol and timolol, did not give the expected rank order for Cmax and AUC, which could result from differences in distribution and/or elimination processes. Aqueous boundary layers were postulated for in vivo corneal permeability which suggested that bufuralol and timolol may have nearly identical effective permeability coefficients in vivo.

Corneal penetration behavior of beta-blocking agents II: Assessment of barrier contributions.

Rabbit corneas were excised and mounted in a chamber to determine the permeability characteristics of a group of beta-blocking agents. By measuring the permeability rate of each drug across intact cornea, stroma alone, epithelium-stroma, and stroma-endothelium, it was possible to determine the resistance to penetration for each corneal layer. The reciprocal of the sum of resistances for the epithelium, stroma, and endothelium equaled the experimentally determined permeability coefficient for the intact cornea (104 +/- 6.0%). Thus, the penetration of beta-blocking agents through the excised rabbit cornea could be treated as three barriers in series. For hydrophilic compounds, the epithelium was the rate-determining barrier. The endothelium offered less resistance, whereas the stroma offered only very minimal resistance. The lipophilic compounds penetrated the excised cornea more rapidly. However, the stroma became rate-determining for the most lipophilic compounds (penbutolol, bufuralol, bevantolol, and propranolol). Although the octanol-buffer (pH 7.65) distribution coefficient of these compounds varied over a fourfold logarithmic range, the permeability coefficient was considered nearly constant [3.4 X 10(-5) (+/- 0.34) cm/sec] for stroma. Also, the ratios of tortuosity to porosity for the stromal layer were 1.58 +/- 0.15. These results suggest that drug diffuses through an aqueous media of gel-like mucopolysaccharide interspersed by a matrix of collagen fibrils. From further analyses intra- and intercellular pathways for epithelium and endothelium were added to the model resulting in a sigmoidal representation of permeability coefficient versus distribution coefficient. However, the intercellular (pore) pathway could not be adequately quantified because of the variation in the data for very hydrophilic compounds.

Vascular injuries during lumbar laminectomy.

Vascular injury during lumbar laminectomy is an uncommon event. It is most often secondary to a biting instrument, such as a pituitary rongeur. Its diagnosis must be made rapidly in order to save the patient from exsanguination. This is well within the province of the general surgeon, who should be prepared to treat it at any time.

Microcalorimetric investigation of the complexation between 2-hydroxypropyl-beta-cyclodextrin and amine drugs with the diphenylmethyl functionality.

Solution calorimetry has been employed to evaluate the stability constants and standard-enthalpy changes (delta H degrees) associated with complex formation between 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and a group of amine compounds having the diphenylmethyl functionality in aqueous solution at 298.15 K. Data from microcalorimetric titrations of the compounds were analysed using a nonlinear least-squares method. Of the 12 compounds studied, only terfenadine.HCl formed a 1:2 (compound:HP-beta-CD) complex. All the others formed 1:1 complexes. The standard free energy decrease accompanying the formation of inclusion complexes is generally due to a negative delta H degrees. This exothermic delta H degrees can be interpreted as indicating that the binding forces for complexation include both the hydrophobic effect and strong van der Waals interactions. When a halogen substituent is in the aromatic ring, stability constants are higher and standard-entropy changes (delta S degrees) become positive, suggesting greater hydrophobic interaction. Both adiphenine.HCl and proadifen.HCl form more stable complexes, suggesting that hydrogen bonding to the carbonyl oxygen by the hydroxyl-group on the rim of the CD ring could be an important contributor to the complexation. Substitution on the aliphatic carbon of the diphenylmethyl group was also found to be important in determining the ability of compounds to bind with HP-beta-CD. The independence of the thermodynamic constants on the degree of protonation in the case of bifunctional amines indicates that the amine functional groups do not penetrate into the HP-beta-CD cavity.

[Congenital anomalies in the material of City Hospital in Bydgoszcz during the period of 1995-1999]. / Analiza wad rozwojowych noworodków w materiale Szpitala Miejskiego w Bydgoszczy w latach 1995-1999.

OBJECTIVE: The analysis occurrence of developmental defects of newborns in the City Hospital in Bydgoszcz during the period 1995-1999. MATERIALS AND METHODS: Over the period of 5 years, 14,943 newborns delivered in City Hospital in Bydgoszcz. The group of 358 (2.40%) with developmental anomalies was analysed retrospectively. The subject of the study was to estimate the types of malformations and their frequency. RESULTS: In our material cardiovascular anomalies (29.05%), reproductive system anomalies (20.11%) and muscosceletal anomalies (18.72%) were most frequent. Breech-presented or transverse lie fetuses had double the risk of any anomalies. In addition, pre-term delivery were not positively associated with any newborn defects. The frequency of occurrence cesarean sections was positively correlated with presence of congenital malformations.

[Changes in the methods of cesarean section]. / Zmiany w technice operacji ciecia cesarskiego.

OBJECTIVE: To evaluate the effects of leaving the visceral peritoneum open and hysterotomy closing by a one-layer continuous locked. MATERIALS AND METHODS: The analysis of 868 women underwent caesarean section had been performed. All operated patients were divided into three compared groups. 268 women operated between 01.05.96 and 31.01.97, belonged into I group, which had the visceral peritoneum sutured during caesarean section, in comparison to the II group operated between 01.05.97-31.01.98 (n = 280), which had only one modification in surgical procedure--the visceral peritoneum was left unsutured and to the group operated between 01.05.98-31.01.99 (n = 320) with second modification--the hysterotomy was closed by a one-layer continuous locked. RESULTS: The average operating time was significantly shorter at group II and III. After surgery we have not observed significant differences in frequency of febrile morbidity (6.34% in I group, 8.93% in second group and 8.44% in third group) and postoperative complications (respectively 9.33; 11.07 and 10.63%). CONCLUSIONS: Non-closure of the visceral peritoneum and closure of the hysterotomy by a one-layer continuous locked has no influence on the number of the post surgical complications. Modifications method of cesarean section showed significantly decreased operative time and chirurgical materials use.

[Intestinal parasites in four Warsaw kindergarten children in 1994-1996]. / Wystepowanie pasozytów jelitowych u dzieci w czterech przedszkolach warszawskich w latach 1994-1996.

In 1994/96 there were examined 588 children attending four Warsaw's kindergartens. Investigations were made by means of a standard coprological methods and by ELISA method for the presence of coproantigens of Giardia. The extensiveness of the infection was about 12.5%. It seems that now only oxyuriosis is the most important epidemiological problem among these children. The complexity of diagnosis and treatment of infected children and some health's education may improve their health and prevent the spreading of invasion.

Efficacy of albendazole against Trichinella pseudospiralis and Trichinella spiralis in mice.

Albendazole (Smith Kline, Beecham) in a dose of 20 mg/kg/day was given to B6C3F1 mice exposed to 300 larvae of T. pseudospiralis or T. spiralis. The drug was introduced on days 2, 3 and 4; or 4, 5 and 6; or 18, 19 and 20 after infection. It limited the intensity of intestinal and muscle phases of trichinellosis. Given at the stage of maturation of adult forms and production of new-born larvae, the drug caused almost total elimination of both species from the intestines of mice and a decrease in the numbers of muscle larvae, with a tendency towards a greater reduction of larvae and adults of T. pseudospiralis. The drug did not change the course of infection when given at the phase of infectivity of larvae.