Polymorphism of nucleotide sequences of human genomic DNA linked to a mucoviscidosis locus

Polymorphism in the restriction fragments length of human DNA sequences linked to mucoviscidosis locus was studied in the healthy control group and in the families affected by mucoviscidosis. The plasmid clones metH, pJ3.11,XV-2c and pKM.19 were used as hybridization probes. The allelic frequencies of the polymorphic loci were determined for total population and for affected families. The linkage disequilibrium between the disease locus and linked polymorphic loci detectable with XV-2c (TaqI endonuclease) and pKM.19 (PstI endonuclease) was demonstrated. The high informational value of DNA-diagnosis of mucoviscidosis in the family studies with the use of four DNA probes combination has been demonstrated.     

Comparative morphological analysis of the articular cartilage, epiphyseal plate, spongy bone, and synovial membrane of the knee joint in children treated and not treated with ciprofloxacin]

Comparative data on he postmortem morphological examination of the knee joint in children treated and not treated with ciprofloxacin while alive are presented. Nine children were ill with mucoviscidosis and 8 children were ill with aplastic anemia. The patients were ill with mucoviscidosis and 8 children were ill with aplastic anemia. The patients were treated with ciprofloxacin in a daily dose of 20 to 40 mg/kg body weight at the average for 148 days. The condition of the articular cartilage, growth area, spongy bone and synovial membrane of the knee joint was examined visually, histologically and morphologically. It was revealed that ciprofloxacin had no chondrotoxic effect. The structure affected in some cases by the ciprofloxacin treatment was the synovial membrane which developed subacute synovitis not clinically manifested (latent) in life. The phenomenon is explained.     

Rational use of antibiotics in mucoviscidosis pediatric cases with an account of local microbiological monitoring]

The results of local microbiological monitoring of bronchial secretion in 482 children with mucoviscidosis observed within 2000-2004 in the Republican Centre of Mucoviscidosis are presented. The results provided development of recommendations for rational use of antibiotics in the treatment of infectious processes in pediatric patients with mucoviscidosis. Since the emergence of MRSA in such patients is low, it is recommended to use antistaphylococcal betalactams (oxacillin, cefazolin, amoxycillin/clavulanate) for the treatment of infections due to S. aureus. For the treatment of infections due to some other pathogens, except S. maltophilia, the most active betalactams were carbapenems (imipenem and meropenem). Ciprofloxacin was active against numerous etiological agents causing low respiratory tract infections in children with mucoviscidosis except S. maltophila and A. xylosoxidans subsp. xylosoxidans. For the treatment of infections due to P. aeruginosa, P. aeruginosa muc. and K. pneumoniae the most active aminoglycosides were amikacin and tobramycin (for P. aeruginosa and P. aeruginosa muc.), while gentamicin was not active in such cases. As for antibiotics of other groups, high activity against S. aureus in the treatment of children with mucoviscidosis was recarded with the use of vancomycin, fusidic acid and rifampicin. Azithromycin and co-trimoxazole were active against H. influenzae. Chloramphenicol was active against S. maltophilia, B. cepacia and H. influenzae in the treatment of such patients.     

Efficacy and safety of cefoperazone/sulbactam in the treatment of children with mucoviscidosis during exacerbation of the bronchopulmonary process]

The use of cefoperazone/sulbactam in combination with amikacin in the treatment of 20 patients with mucoviscidosis and exacerbation of bronchopulmonary pathological process resulted in marked positive dynamics of the clinical and functional indices of the lungs state. The bacteriological effect with respect to the main pathogens in the cases of mucoviscidosis was strain-dependent: eradication of 10 (83.4%) out of 12 Staphylococcus aureus strains and only 3 (15.8%) out of 19 Pseudomonas aeruginosa strains. The most frequent adverse reaction was diarrhea (5 children) successfully corrigated by loperamide. Discontinuation of the drug use was required in 3 patients because of macrohematuria (1 child) and allergic eruption.     

Evaluation of tolerance and efficacy of pefloxacin in the treatment and prevention of severe infections in children with mucoviscidosis and aplastic anemia]

Pefloxacin (Abaktal) efficacy and safety were investigated at 21 children (7-16 years old) randomized in 2 groups: children with mucoviscidosis and children with aplastic anemia. The drug was used at the dose 15-20 mg/kg per day bid for 14-28 days. Pefloxacin was used in combination with ceftazidime and amikacin. Combined therapy demonstrated good clinical efficacy. Bacteriological efficacy was not uniform: staphylococci were not isolated from sputum since the 7th day of treatment, but pseudomonads were cultured even on the 14th day of the treatment (the sensitivity to pefloxacin remained). The only but frequent side-effect was arthropathy. The background and some peculiarities of arthropathy development were analyzed. This phenomenon is called quinolone-induced synovitis. The risk group for quinolone-induced synovitis was estimated--children elder than 10 years with allergic anamnesis. Good clinical efficacy and tolerability of pefloxacin at the children with mucoviscidosis or aplastic anemia is a reason and base to cancel the limits to its use in pediatrics.     

On fluoroquinolones treatment safety in children (clinical, morphological and catamnesis data)]

Results of prospective comparative investigation of monofluoroquinolones (ciprofloxacin, ofloxacin, pefloxacin) arthropathy are presented. The trial was performed at 144 children with mucoviscidosis (aged 0.5-16) and at 37 children with aplastic anemia (aged 1.75-15). Two groups differ by necessary antibacterials regimes and hence by different abilities for arthropathy development: patients with mucoviscidosis were treated with fluoroquinolones followed by repeated short courses in combination with other antibacterials; patients with aplastic anemia--were treated permanently for a long time with low doses as monotherapy for autoinfection prophylaxis. Analysis was performed on the base of catamnesis, year growth rate, postmortal morphological investigation of the right knee joint. It was shown that quinolone arthropathy development didn't depend on treatment duration, as it developed during the first three weeks of the fluoroquinolone use, but depended on the drug, patient age and nosology. Arthropathy has favourable prognosis and was fully resolved at the period from 7 days to 3 month according to the arthropathy form (arthrologic, arthritic). Quinolones arthropathy at the children has specific features, the main one is absence of cartilage damage confirmed by morphological analysis.     

Pefloxacin in the treatment of patients with mucoviscidosis]

It was shown that microbial flora isolated from the bronchial secretion of 39 patients with mucoviscidosis in 1999-2001 consisted in one third (32.8%) of S. aureus strains. Evaluation of pefloxacin efficacy in the case of monoinfection and pathogens association revealed potent antistaphylococcal effect of the drug. Positive result was demonstrated in 82.3% cases by the 7th day. Among the side effects dominated arthropathy which disappeared at the period from 3 days to 3 months after drug administration was stopped.     

Clinical and bacteriological efficacy and tolerability of meropenem in the treatment of bronchopulmonary affections in children with mucoviscidosis]

Meropenem (in combination with amikacin) was used in the treatment of children and adolescents with mucoviscidosis and severe exacerbation of bronchopulmonary affections. The drug showed satisfactory clinical and moderate bacteriological effects (48.3%) as dependent on the severity and duration of the disease and the microbial flora. Meropenem was well tolerated: no side effects were observed during the treatment, whereas it was used in high doses (60-105 mg/kg daily).     

Difficulties of diagnosing gluten enteropathies in adults

Seven cases of adult patients with gluten enteropathy (1 male and 6 female patients, including 1 patient with Duhring's disease) are presented. These patients suffered from diarrhoea lasting for 1-10 years prior to the diagnosis of gluten enteropathy. Transient diarrhoea was noted in one female patient in her childhood. Blood calcium levels were lowered in all patients and were accompanied by tetany in five and osteomalacia in two patients. One patient's sister is suffering from mucoviscidosis. Earlier, coeliac disease was not diagnosed in any patient. Previous diagnoses included enteritis, hypoparathyroidism or neuro- and myopathies of unknown etiology. The authors suggest that the difficulties in diagnosing gluten enteropathies in adults are due to the lack of biopsy capsules, low acquaintance of physicians with this disease, and indications to small intestine biopsy.     

The efficacy and safety of ciprofloxacin in treating children with mucoviscidosis]

Ciprofloxacin clinical and bacteriological efficacies, as well as tolerability mainly with respect to chondrotoxicity were evaluated in the treatment of children with mucoviscidosis. The drug was shown to have high clinical and moderate bacteriological efficacies. As for its tolerability, adverse reactions chiefly associated with affection of the gastrointestinal tract, i.e. nausea, stomach pain, diarrhea, increased transaminase levels were recorded. The arthrotoxicity episode was single and transitory. The use of ciprofloxacin had no negative effect on the children growth. No chondrotoxic effect of ciprofloxacin in the treatment of children was observed which is explained in the paper. It is concluded that ciprofloxacin is in general an efficient and safe antibiotic useful for the treatment of children.     

Comparative yearly growth rate of children with mucoviscidosis treated and not treated with ciprofloxacin:clinicomorphological comparisons]

The results of the prospective and comparative investigation of the linear growth of children at the age of 4 to 16 years with mucoviscidosis treated with ciprofloxacin in combination with a cephalosporin or an aminoglycoside in the main group and a cephalosporin or an aminoglycoside alone in the control group are presented. The children were observed for 3 and 5 years. It was shown that in spite of the treatment term with ciprofloxacin the yearly growth rate in the children in the main and control groups did not significantly differ. The morphological investigation did not reveal any injury of the armicular cartilage and growth zone. The hyperplastic reaction in the tegmental cartilage was states and considered as a physiological one in response to the presence of ciprofloxacin and therefore reversible. No chondrotoxicity of the fluoroquinolones and ciprofloxacin, particularly in the children, is explained.     

Fluorine level in the bone and cartilage in children treated with ciprofloxacin (data obtained from the femur distal part]

Comparative data on the content of fluorine in various sections of the left femur distal part, i.e. spongy bone, process zone and articular cartilage are presented. The examination was performed on postmortem sections from 10 pediatric cases (the average age of 9.5 years) with mucoviscidosis or aplastic anemia treated before the death for up to 12 months with ciprofloxacin in a dose of 20 to 40 mg/kg body weight. The control postmortem sections were from 10 practically healthy children (the average age of 10.4 years) killed in a car accident. The sections were subjected to 2-stage dry ashing with ionometric determination of the fluorine ions. The results were treated according to the V.Yu. Urbach procedure. It was shown that the content of fluorine in the sponge bone and process zone in both the groups did not significantly differ. A comparatively high content of fluorine was detected only in the postmortem sections of the articular cartilage from the children of the main group who however had no chondrotoxic symptoms while alive. That means that the difference is statistically and clinically insignificant.     

Efficacy and safety of cefepime in the treatment of bronchopulmonary disease exacerbation in pediatric patients with mucoviscidosis]

Clinicobacteriological effect of cefepime (in combination with amikacin) was studies in 25 pediatric patients of the age of 7 to 17 years with a mixed form of mucoviscidosis at the stage of the bronchopulmonary infection exacerbation. The basic pathogens isolated from the sputum were: Pseudomonas aeruginosa sm., P. aeruginosa muc. (67.5%) and Staphylococcus aureus (29.1%). The 2-week treatment course resulted in a marked clinical effect with improvement of the lung functional indices and eradication of the majority of the S. aureus strains (81.2%) and half of the P. aeruginosa strains (49.6%). The only side effect was moderate diarrhea not requiring discontinuation of the drug use.     

Evaluation of the influence of the bacterial vaccines Pneumo-23 and Act-HIB on the course of the chronic inflammatory process of the respiratory organs in children

The effectiveness and safety of vaccination of children having chronic inflammatory lung diseses with Pneumo-23 and Act-HIB were evaluated. The group under study included 38 children having chronic pneumonia, congenital defects of lung development, Kartagener's syndrome, mucoviscidosis; of these children, 25 were vaccinated with Pneumo-23 and 13--with Act-HIB. For comparison a group of 40 children with the same pathology, but not vaccinated, was used. A favorable course of the postvaccinal period was noted. Prior to vaccination Streptococcus pneumoniae in association with Haemophilus influenzae were isolated from all patients; in a year after vaccination with Pneumo-23 these microorganisms were isolated only in monoculture: S. pneumoniae in 3 out of 25 cases (88% elimination) and H. influenzae in 10 out of 25 cases (60% elimination).     

Evaluating Strategies to Normalise Biological Replicates of Western Blot Data

Western blot data are widely used in quantitative applications such as statistical testing and mathematical modelling. To ensure accurate quantitation and comparability between experiments, Western blot replicates must be normalised, but it is unclear how the available methods affect statistical properties of the data. Here we evaluate three commonly used normalisation strategies: (i) by fixed normalisation point or control; (ii) by sum of all data points in a replicate; and (iii) by optimal alignment of the replicates. We consider how these different strategies affect the coefficient of variation (CV) and the results of hypothesis testing with the normalised data. Normalisation by fixed point tends to increase the mean CV of normalised data in a manner that naturally depends on the choice of the normalisation point. Thus, in the context of hypothesis testing, normalisation by fixed point reduces false positives and increases false negatives. Analysis of published experimental data shows that choosing normalisation points with low quantified intensities results in a high normalised data CV and should thus be avoided. Normalisation by sum or by optimal alignment redistributes the raw data uncertainty in a mean-dependent manner, reducing the CV of high intensity points and increasing the CV of low intensity points. This causes the effect of normalisations by sum or optimal alignment on hypothesis testing to depend on the mean of the data tested; for high intensity points, false positives are increased and false negatives are decreased, while for low intensity points, false positives are decreased and false negatives are increased. These results will aid users of Western blotting to choose a suitable normalisation strategy and also understand the implications of this normalisation for subsequent hypothesis testing.     

Subglacial cetaceans and other mathematical mysteries: a Commentary on “A quantitative test of the thermogenesis hypothesis of cetacean brain evolution,using phylogenetic comparative methods” by C. Maximino

A recent paper published in this Journal purported to provide a quantitative test of the thermogenetic hypothesis of cetacean brain evolution. While using appropriate statistical analyses that account for phylogenetic inertia, errors in the raw data and in interpretation of the thermogenetic hypothesis raise concerns about the validity of the statistical results and the conclusions of the paper. In this commentary the errors in raw data, mathematical approaches, the lack of inclusion of certain data points and misinterpretation of the thermogenetic hypothesis are detailed. The conclusion being that the thermogenetic hypothesis has not been correctly tested by the study.     

Testing a covariotide model of DNA substitution

The concomitantly variable codons hypothesis of DNA substitution argues that at any time only a fraction of the codons in a gene are capable of accepting a mutation. However, as mutations are fixed at some positions in a gene, the sites that are potentially variable also change because of changed functional constraints. This hypothesis has been termed the "covarion" hypothesis or when the model is applied to nucleotides, the "covariotide" hypothesis. The covarion-covariotide model has proven to be remarkably difficult to test. Here I examine a covariotide hypothesis for 11 genes using a likelihood ratio test. I show that in nine of the genes examined a covariotide model provides a better explanation of the data than a model that does not allow constraints to change over time.     

The genetic hypothesis for susceptibility to lepromatous leprosy

Summary Evidence for genetic influence of the host response to infection with Mycobacterium leprae is reviewed. A complex segregation analysis is performed on data for 91 families from Mactan, Philippines, in each of which at least one offspring developed lepromatous leprosy. The data are not found to be inconsistent with an autosomal recessive hypothesis for susceptibility to lepromatous leprosy. Heritability estimates in the range of 80% were calculated for sib-sib pairs under the multifactorial hypothesis for susceptibility. It is argued that the multifactorial hypothesis is more in keeping with available immunologic, epidemiologic, and demographic data than is the single gene hypothesis.     

Evolution of Endocrine Regulation of Metamorphosis in Lower Vertebrates

Metamorphosis commonly occurs in lower vertebrates, but itsendocrine regulation is not well known outside of the Amphibia.Paedomorphosis (progenesis and neoteny) is a frequent occurrenceas well. The only endocrine-related hypothesis is that of Etkinfor amphibians. This hypothesis has been modified to accommodatesome of the recent findings, but other data have not been incorporatedand still other parts remain untested. Presumably, the hypothesisrelies entirely on endogeneous factors, and the importance ofexternal factors needs to be examined. Facultative neotenicamphibians may be useful animals for testing certain aspectsof the Etkin hypothesis. There are insufficient data for fishesat this time to evaluate the possible universality of the amphibianhypothesis.     

Postembryonic dimensional allometry of the human femur

Developmental constraints can affect evolution. McMahon's (1973, 1975a) hypothesis of elastic similarity is tested as an epigenetic rule. This is an ontogenetic hypothesis that previously has not been tested with ontogenetic data. Cross-sectional data from the human femur are analyzed. Length-diameter relationships for phases of growth and aging are calculated with bivariate allometry. McMahon's hypothesis cannot be rejected, although most of the calculations are not consistent with it. Ontogenetic skeletal allometry is complex because both material and geometric properties change during development.