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PubMed2004

A systematic review of medical therapy for anal fissure.

PURPOSE: This is a meta-analysis of randomized, controlled trials to assess the efficacy and morbidity of medical therapies for anal fissure. METHODS: Medline and the Cochrane Controlled Trials Register and the Cochrane Colorectal Cancer Review Groups Controlled Trials Register were searched using the terms "anal fissure randomized" from 1966 to 2002. Studies in which participants were randomized to a nonsurgical therapy for anal fissure were the focus of this review. Comparison groups included an operative procedure, an alternate medical therapy, or placebo. Chronic fissure, acute fissure, and fissure in children were included in the review, however, atypical fissure associated with inflammatory bowel disease, cancer, or anal infection were excluded. Data were abstracted from published reports and meeting abstracts, assessing method of randomization, blinding, "intention to treat" and dropouts, therapies, supportive measures, dosing and frequency, and crossovers. Outcome measures included nonhealing of the fissure and adverse events. RESULTS: Twenty one different comparisons of medical therapies to heal anal fissure have been reported in 31 trials, including 9 agents-glyceryl trinitrate, isosorbide dinitrate, botulinum toxin, diltiazem, nifedipine, hydrocortisone, lidocaine, bran, placebo-as well as anal dilators and surgical sphincterotomy. Glyceryl trinitrate was favored in the analysis over placebo (odds ratio = 0.55, 95 percent confidence interval, 0.41-0.74). After excluding two studies from analysis because of placebo response rates >2 standard deviations below the mean for all studies, the advantage of glyceryl trinitrate over placebo was no longer statistically significant (odds ratio = 0.78; 95 percent confidence interval, 0.56-1.08). Nifedipine and diltiazem did not differ from glyceryl trinitrate in their ability to cure fissure (0.66; 0.22-2.01). Botulinum toxin compared with placebo showed no significant efficacy (0.75; 0.32-1.77), and was also no better than glyceryl trinitrate (0.48; 0.21-1.10). Surgery was more effective than medical therapy in curing fissure (0.12; 0.07-0.22). CONCLUSIONS: Medical therapy for chronic anal fissure, acute fissure, and fissure in children may be applied with a chance of cure that is only marginally better than placebo, and for chronic fissure, far less effective than surgery.

Adult↗
PubMed1993

Targeting the site of RNA-RNA recombination in brome mosaic virus with antisense sequences.

It has been postulated that local hybridizations between viral RNAs can mediate recombination in brome mosaic virus (BMV) and in poliovirus. To test this model, a 3' fragment of BMV RNA1 was inserted into the 3' noncoding sequence of BMV RNA3 in an antisense orientation. This resulted in high-frequency nonhomologous crossovers at or near the hybridized region. Insertion of the same RNA1 fragment in a positive-sense orientation did not promote recombination. Modification of the antisense insert by deletion of 3' portions did not affect the sites of crossover. However, modification of the 5' portion shifted the crossovers toward the central part of the heteroduplex region. Our results provide experimental evidence that recombinant crosses can be primed by hybridization between viral RNA molecules.

Base Sequence↗
PubMed2001

Termini of human chromosomes display elevated rates of mitotic recombination.

The strand-specific in situ hybridization technique of CO-FISH was used to probe telomeres of human mitotic cells in order to determine the spontaneous frequency of crossover. This approach allowed the detection of recombinational crossovers occurring anywhere along the length of individual chromosomes, including reciprocal events taking place between sister chromatids. Although the process of sister chromatid exchange (SCE) is the most prominent type of recombination in somatic mammalian cells, our results show that SCEs accounted for less than a third of the recombinational events revealed by CO-FISH. It is concluded that chromosomal regions near the termini of chromosome arms undergo extraordinarily high rates of spontaneous recombination, producing terminal crossovers whose small size precludes detection by standard cytogenetic methods. That similar results were observed for transformed epithelial cells, as well as primary fibroblasts, suggests that the phenomenon is a common characteristic of human cells. These findings are noteworthy because, although telomeric and subtelomeric DNA is known to be preferentially involved in certain types of recombination, the tips of somatic mammalian chromosomes have not previously been identified as preferred sites for crossover. Implications of these results are discussed in terms of limitations imposed on CO-FISH for its proposed use in directional hybridization mapping.

Chromosomes, Human↗
PubMed2003

Reexamination of the evolution of the dynamic susceptibility of the glass former glycerol.

The dielectric data of glycerol compiled by Lunkenheimer et al. [Contemp. Phys. 41, 15 (2000)] are reanalyzed within a phenomenological approach on the one hand, and within mode coupling theory (MCT), on the other. We present a complete interpolation of the dielectric data covering 17 decades in frequencies. The crossover temperature extracted from the phenomenological analysis of the slow response at low temperatures and defined by the emergence of the excess wing upon cooling agrees well with the critical temperature extracted from a MCT analysis of the dynamics at high temperatures including data that were not used in the first MCT analysis of glycerol by Lunkenheimer et al. [Phys. Rev. Lett. 77, 318 (1996)]. The crossover temperature is found to be T(c)=288+/-3 K, which is significantly higher than previously reported. Extracting the nonergodicity parameter f, the characteristic anomaly is only found when 1-f is inspected, since f is very close to 1. No difference for the evolution of the dynamic susceptibility is observed for the nonfragile system glycerol with respect to fragile glass formers provided that the evolution of the dynamics is studied as a function of the correlation time tau(alpha).

Journal Article↗
PubMed1993

High-efficiency gene inactivation and replacement system for gram-positive bacteria.

A system for high-efficiency single- and double-crossover homologous integration in gram-positive bacteria has been developed, with Lactococcus lactis as a model system. The system is based on a thermosensitive broad-host-range rolling-circle plasmid, pG+host5, which contains a pBR322 replicon for propagation in Escherichia coli at 37 degrees C. A nested set of L. lactis chromosomal fragments cloned onto pG+host5 were used to show that the single-crossover integration frequency was logarithmically proportional to the length of homology for DNA fragments between 0.35 and 2.5 kb. Using random chromosomal 1-kb fragments, we showed that homologous integration can occur along the entire chromosome. We made use of the reported stimulatory effect of rolling-circle replication on intramolecular recombination to develop a protocol for gene replacement. Cultures were first maintained at 37 degrees C to select for a bacterial population enriched for plasmid integrants; activation of the integrated rolling-circle plasmid by a temperature shift to 28 degrees C resulted in efficient plasmid excision by homologous recombination and replacement of a chromosomal gene by the plasmid-carried modified copy. More than 50% of cells underwent replacement recombination when selection was applied for the replacing gene. Between 1 and 40% of cells underwent replacement recombination when no selection was applied. Chromosomal insertions and deletions were obtained in this way. These results show that gene replacement can be obtained at an extremely high efficiency by making use of the thermosensitive rolling-circle nature of the delivery vector. This procedure is applicable to numerous gram-positive bacteria.

DNA Replication↗
PubMed2000

Frequent homologous recombination events between molecules of one RNA component in a multipartite RNA virus.

Brome mosaic bromovirus (BMV), a tripartite plus-sense RNA virus, has been used as a model system to study homologous RNA recombination among molecules of the same RNA component. Pairs of BMV RNA3 variants carrying marker mutations at different locations were coinoculated on a local lesion host, and the progeny RNA3 in a large number of lesions was analyzed. The majority of doubly infected lesions accumulated the RNA3 recombinants. The distribution of the recombinant types was relatively even, indicating that both RNA3 counterparts could serve as donor or as acceptor molecules. The frequency of crossovers between one pair of RNA3 variants, which possessed closely located markers, was similar to that of another pair of RNA3 variants with more distant markers, suggesting the existence of an internal recombination hot spot. The majority of crossovers were precise, but some recombinants had minor sequence modifications, possibly marking the sites of imprecise homologous crossovers. Our results suggest discontinuous RNA replication, with the replicase changing among the homologous RNA templates and generating RNA diversity. This approach can be easily extended to other RNA viruses for identification of homologous recombination hot spots.

Bromovirus↗
PubMed1995

Allelic associations and homozygosity at loci from HLA-B to D6S299 in genetic haemochromatosis.

Haemochromatosis (GH) is an autosomal recessive disorder in which increased iron absorption causes iron overload. The gene (HFE) is closely linked to HLA-A on chromosome 6 (6p21.3) but has not yet been identified. We have examined eight polymorphic loci, HLA-B (most centromeric), I82, D6S265, HLA-A, D6S128, HLA-F, D6S105, and D6S299 (most telomeric) in 37 unrelated patients and 60 control subjects. There are also significant positive associations between GH and alleles at all loci except D6S299. Analysis of 48 GH chromosomes in which haplotypes could be established showed that the most common haplotype was I82-2:D6S265-1:HLA-A3:D6S128-2:HLA-F1:D6S105-8. This was present in 28 of 48 chromosomes. In 14 the haplotype included HLA-B7 but only in seven did this extend beyond the telomere to D6S299-2 (the most common allele on GH chromosomes at this locus). In 36 out of 48 chromosomes the two locus haplotype, F1:D6S105-8 was present. Since haemochromatosis appears to originate from a founder mutation we have examined linkage disequilibrium between these various loci and GH using calculations of pexcess. The maximum value (0.72, 95% CI 0.55-0.85) is given by D6S105-8 but is not significantly different from values for HLA-A3 and HLA-F1 (0.50, 95% CI 0.34-0.61 and 0.49, 0.25-0.66 respectively). However, both HLA-A and D6S105 give a value for pexcess which is significantly higher than that for the most centromeric marker, HLA-B (0.17, 95% CI 0.02-0.30). We have counted the number of patients who are homozygous for the common allele at each locus. At D6S105, 22 patients are homozygous for allele 8, with 18 homozygous for HLA-F1 and 10 homozygous for A3. The pattern of cumulative homozygosity suggests a gene location closer to D6S105 than HLA-A. We have also analysed our data for divergence from the apparent founder haplotype (A3:F1:105-8) and have calculated the theoretical frequencies of crossovers between loci. These data suggest a location telomeric to D6S105. A more precise localisation of the gene may be possible with the identification of new markers around D6S105.

Adolescent↗
PubMed1994

A prospective, randomized study of spinal cord stimulation versus reoperation for failed back surgery syndrome: initial results.

Spinal cord stimulation (SCS) has been reported to be effective treatment for the failed back surgery syndrome in a number of retrospective case series. Its retrospectively reported results compare favorably with those of neurosurgical treatment alternatives, such as reoperation and ablative procedures. There has been no direct prospective comparison, however, between SCS and other techniques for pain management. We have undertaken a prospective, randomized comparison of SCS and reoperation in patients with persistent radicular pain, with and without low back pain, following lumboscral spine surgery. Patients selected for reoperation by standard criteria have been randomly assigned to initial treatment by one or the other technique. The primary outcome measure is the frequency of crossover to the alternative procedure, if the results of the first have been unsatisfactory after 6 months. Results for the first 27 patients reaching the 6-month crossover point show a statistically significant (p = 0.018) advantage for SCS over reoperation. This is one of many potentially important outcome measures, which are to be followed long-term as a larger overall study population accrues.

Back Pain↗
PubMed1995

Randomized study of sulfamethoxazole-trimethoprim versus aerosolized pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia in patients with AIDS.

In a prospective, randomized open-label trial, the efficacy of sulfamethoxazole-trimethoprim (SMX-TMP) 400/80 mg b.i.d. was compared with the efficacy of aerosolized pentamidine (AP) 60 mg every 2nd week as secondary prophylaxis (SP) against recurrence of Pneumocystis carinii pneumonia (PCP) in AIDS patients. 94 patients participated in the study, 47 in each group. The patients were observed for a mean period of 17.2 months. PCP recurred in the AP group in 8 cases, while 1 relapse occurred in the SMX-TMP group. The one-year cumulative relapse rate was 9.0% (95% CI 0-19%) in the AP group compared with 2.4% (95% CI 0-8%) in the SMX-TMP group (p < 0.05). The odds ratio was 4.2 (95% CI 0.5-39.8) in favour of SMX-TMP. Furthermore, we found a tendency towards a protective effect against toxoplasmosis in the SMX-TMP group, though there was no difference in survival between the two groups. There was no statistical difference in frequency of crossover from one therapy form to the other. Based on these data we recommend SMX-TMP for secondary PCP prophylaxis.

AIDS-Related Opportunistic Infections↗
PubMed1992

A genetic linkage map of human chromosome 21: analysis of recombination as a function of sex and age.

A genetic linkage map of human chromosome 21 has been constructed using 22 anonymous DNA markers and five complementary DNAs (cDNAs) encoding the amyloid beta protein precursor (APP), superoxide dismutase 1 (SOD1), the ets-2 proto-oncogene (ETS2), the estrogen inducible breast cancer locus (BCEI), and the leukocyte antigen, CD18 (CD18). Segregation of RFLPs detected by these DNA markers was traced in the Venezuelan Reference Pedigree (VRP). A comprehensive genetic linkage map consisting of the 27 DNA markers spans 102 cM on the long arm of chromosome 21. We have confirmed our initial findings of a dramatically increased rate of recombination at the telomere in both females and males and of significantly higher recombination in females in the pericentromeric region. By comparing patterns of recombination in specific regions of chromosome 21 with regard to both parental sex and age, we have now identified a statistically significant downward trend in the frequency of crossovers in the most telomeric portion of chromosome 21 with increasing maternal age. A less significant decrease in recombination with increasing maternal age was observed in the pericentromeric region of the chromosome. These results may help in ultimately understanding the physical relationship between recombination and nondisjunction in the occurrence of trisomy 21.

Adolescent↗
PubMed1990

Detailed genetic linkage map of human chromosome 21: patterns of recombination according to age and sex.

A detailed genetic linkage map of human chromosome 21 will allow the rapid regional assignment of future genes and DNA markers to this autosome. It will also facilitate the precise mapping of the genes responsible for the DS phenotype and the defect causing FAD. This map can also be used to implicate genes involved with specific features of the DS phenotype by permitting the delineation of finite regions of chromosome 21 which are duplicated in patients with partial trisomy 21, and who manifest select symptoms of the DS phenotype. In the case of FAD, most pedigrees are not ideally structured for genetic linkage analysis since affected individuals die relatively soon (6-8 years) after the onset of symptoms. By first establishing the genetic relationships of DNA markers in the vicinity of the FAD defect, multipoint analyses of these markers can then be performed in FAD families. Multipoint analysis carries a greater probability of identifying markers flanking the FAD locus thereby providing landmarks for cloning attempts aimed at isolating and characterizing the FAD gene defect. We have confirmed our initial findings of a dramatically increased rate of recombination at the telomere in both females and males, and significantly higher recombination in females in the pericentromeric region between D21S1/S11 and D21S13/S16. By comparing patterns of recombination in specific regions of chromosome 21 with regard to both parental sex and age, we have identified a statistically significant downward trend in in the frequency of crossovers in the most telomeric portion chromosome 21 with increasing maternal age. A less significant decrease in recombination with increasing maternal age was observed in the sub-centromeric region of the chromosome where recombination in females is overall higher than in males. Future confirmation of these results in combination with investigations aimed at deciphering the role played by recombination in promoting normal segregation during meiosis should help to elucidate the potential relevance of these findings to the etiological basis of nondisjunction.

Chromosome Mapping↗
PubMed1996

Mechanism of relief of tachypnea during pressure support ventilation.

Pressure support ventilation (PSV) provides a range of ventilatory support from partial respiratory muscle unloading, where inspiratory work is shared between the patient and the mechanical ventilator, to total respiratory muscle unloading, where inspiratory work is performed solely by the ventilator. This study is designed to determine if minimizing work fully accounts for relief of tachypnea during PSV. We examined respiratory parameters over a range of PSV that includes the crossover from partial to total respiratory muscle unloading. Eight studies were obtained on seven intubated patients in respiratory failure. Ventilation, occlusion pressure (P0.1), and patient inspiratory work (WOBinsp) were measured while PSV was varied. In all patients, WOBinsp decreased as PSV increased. The level of PSV where WOBinsp was minimized was identified; this marked the crossover from partial to total respiratory muscle unloading. Frequency decreased with increasing PSV but remained elevated (range, 22 to 38 breaths/min) at the crossover. Frequency was normalized only at PSV levels 131 to 193% of the levels of pressure at the crossover. Tidal volume (VT) changed little during partial support and averaged 5.9 mL/kg at the crossover. VT increased only on PSV providing total unloading. Six of seven patients exhibited increasing static compliance with increasing VT suggesting alveolar recruitment. P0.1 tracked WOBinsp over the entire range of PSV (r = 0.95, p < 0.001). The normalization of frequency observed above the crossover coincided with increasing VT rather than decreasing work. These observations suggest that reflexes resulting from increased VT and/or alveolar recruitment may have contributed to the normalization of frequency.

Adult↗
PubMed2005

Persistence and loss of meiotic recombination hotspots.

The contradiction between the long-term persistence of the chromosomal hotspots that initiate meiotic recombination and the self-destructive mechanism by which they act strongly suggests that our understanding of recombination is incomplete. This "hotspot paradox" has been reinforced by the finding that biased gene conversion also removes active hotspots from human sperm. To investigate the requirements for hotspot persistence, we developed a detailed computer simulation model of their activity and its evolutionary consequences. With this model, unopposed hotspot activity could drive strong hotspots from 50% representation to extinction within 70 generations. Although the crossing over that hotspots cause can increase population fitness, this benefit was always too small to slow the loss of hotspots. Hotspots could not be maintained by plausible rates of de novo mutation, nor by crossover interference, which alters the frequency and/or spacing of crossovers. Competition among hotspots for activity-limiting factors also did not prevent their extinction, although the rate of hotspot loss was slowed. Key factors were the probability that the initiating hotspot allele is destroyed and the nonmeiotic contributions hotspots make to fitness. Experimental investigation of these deserves high priority, because until the paradox is resolved all components of the mechanism are open to doubt.

Alleles↗
PubMed1988

Models of multilocus recombination: nonrandomness in chiasma number and crossover positions.

Cytological evidence indicates that genetic interference can be partitioned into two empirical components: nonrandomness in the number of chiasmata that occur and nonrandomness in the locations of multiple chiasmata. Previous studies have incorporated the first effect into genetic models for analyzing multipoint data. An extension to this approach is presented which allows for the second component of interference by modeling the probability density function of the locations of multiple crossovers. Results of reanalyses of multilocus data for the Drosophila X chromosome show that models that incorporate only the first effect give a better fit to these data than do standard mapping functions and that the extended model significantly improved the fit by decreasing the predicted frequency of multiple crossovers in nearby regions. Our results demonstrate that chiasma-based models of multilocus recombination, which are unique in incorporating direct estimates of the frequency of multiple crossovers for a chromosome region, can provide a powerful and realistic means of accounting for genetic interference when applied to the problems of gene localization, locus ordering, and exclusion mapping.

Chromosome Mapping↗
PubMed2004

Effects of meal frequency and high-fibre rye-bread diet on glucose and lipid metabolism and ileal excretion of energy and sterols in ileostomy subjects.

OBJECTIVE: To investigate the effect of a rye, high-fibre diet (HFD) vs a wheat, low-fibre diet (LFD), meal frequency, nibbling (Nib, seven times a day) or ordinary (Ord, three times a day), and their combined effects on blood glucose, insulin, lipids, urinary C-peptide and ileal excretion of energy, cholesterol and bile acids in humans. DESIGN: LFD period with Nib or Ord meal frequency followed by an HFD diet with Nib or Ord meal frequency in randomized, crossover design. SETTING: Outpatients of ileostomy volunteers were called for an investigation in research word. SUBJECTS: A total of 10 subjects (two female subjects, age 34 and 51 y; eight males, mean age 54.4 y, range 43-65 y) participated in the experiment. All subjects were proctocolectomized for ulcerative colitis (mean 16.0 y, range 8-29 y before the study). INTERVENTION: In total, 10 ileostomy subjects started with LFD for 2 weeks, the first week on either Nib (five subjects) or Ord (five subjects) and the second week on the other meal frequencies, in a crossover design, followed by a wash-out week, and continued with HFD period for 2 weeks in the same meal frequency manner. All foods consumed in both Nib or Ord regimens were identical and a high-fibre rye bread was used in the HFD period and a low-fibre wheat bread in the LFD period. MAIN OUTCOME MEASURES: Day-profiles of blood glucose, insulin and lipids, blood lipids before and after dietary intervention, and excretion of steroids in the effluents and C-peptide in the urine. RESULTS: During the Nib regimen, plasma glucose and insulin peaks were lower at the end of the day with HFD compared with LFD. Urinary C-peptide excretion was significantly higher in the day-time on LFD compared with HFD (LFD-Ord vs HFD-Ord, P < 0.01; LFD-Nib vs HFD-Nib, P < 0.01). Plasma free-cholesterol, total cholesterol, triglycerides and phospholipids were significantly higher (P < 0.05) after LFD than after HFD with the Nib regimen. A higher excretion of energy (P < 0.05) and chenodeoxycholic acid (P < 0.05) were observed with HFD compared with LFD regardless of meal frequency. A higher daily excretion of cholic acid, total bile acids, cholesterol, net cholesterol and net sterols (P < 0.05) was observed on HFD compared with LFD with the Nib regimen. CONCLUSIONS: An HFD decreased insulin secretion measured as a decreased excretion of C-peptide in urine and as decreased plasma insulin peaks at the end of the day during a Nib regimen. The smoother glycaemic responses at the end of the day during a Nib regimen may be a consequence of a second meal phenomenon, possibly related to the nature of dietary fibre complex.

Adult↗
PubMed2004

Collective modes of trapped gases at the BEC-BCS crossover.

The collective mode frequencies in isotropic and deformed traps are calculated for general polytropic equation of states, P proportional n(gamma+1), and expressed in terms of gamma and the trap geometry. For molecular and standard Bose-Einstein condensates and Fermi gases near Feshbach resonances, the effective power gamma approximately 0.5-1.3 is calculated from Jastrow type wave-function ansatz, and from the crossover model of Leggett. The resulting mode frequencies are calculated for these phases around the BEC-BCS crossover.

Journal Article↗
PubMed1996

Complete interference and nonrandom distribution of meiotic crossover in a mollusc, Mulinia lateralis (Say).

In gene mapping, the genetic distance between two genes is measured by the frequency of meiotic crossovers occurring between them. It is generally assumed that there is more than one crossover per chromosome, and the distribution of crossovers along chromosomes is random and follows a Poisson distribution (no interference), or that interference is inversely correlated with distance. Although those assumptions may be correct for some organisms, we report here a novel exception in the marine mollusc Mulinia lateralis Say. Using segregation analysis of gynogenetic diploids, we found surprisingly high gene-centromere recombinant frequencies for most of the 13 allozyme loci studied. For at least six loci, there was always one and only one crossover occurring between the gene and its centromere, suggesting complete interference where the occurrence of one crossover completely suppressed the occurrence of another. The complete interference was confirmed by the cytogenetic observation that there was only one chiasma for all bivalents. Further, sites of the single crossover seem not to be randomly distributed along chromosomes, but preferentially located in a recombination hot-region proximal to the centromere. The restricted distribution of a single crossover per chromosome provides one explanation for the unique phenomenon of heterozygote deficiency in M. lateralis and other molluscs.

Animals↗
PubMed2000

EXO1 and MSH4 differentially affect crossing-over and segregation.

The 5'-3' exonuclease Exo1p from Saccharomyces cerevisiae is required for wild-type levels of meiotic crossing-over and normal meiotic chromosome segregation as is the meiosis-specific MutS homologue, Msh4p. Mutations in both genes reduce crossing-over by approximately two-fold, but deltamsh4 strains have significantly lower viability and a higher frequency of meiosis I non-disjunction. Epistasis analysis indicates a complex interaction between the two genes. Although crossing-over was not detectably lower in the double mutant, viability was significantly worse than either single mutant. Such a result suggests that the two genes are affecting meiotic viability by distinct mechanisms. We propose that deltaexo1 affects chromosome segregation by reducing crossing-over, while deltamsh4 affects both the frequency and distribution of crossovers. Mutation in EXO1 reduces gene conversion frequencies significantly at some but not all loci, suggesting that other enzymes are also involved in DNA resection. We propose that Exo1p plays an early role in establishing some recombination intermediates by generating single-stranded tails. The role of Msh4p is suggested to be in determining whether some recombination intermediates are resolved as crossover events and in generating crossover interference. The synergistic effect of deltaexo1deltamsh4 on spore viability suggests that the two genes have partially compensatory roles in a process affecting meiotic success.

Alleles↗