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PubMed1998

Bacteriology of preserved stallion semen and antibiotics in semen extenders.

Three experiments were conducted to evaluate the effects of different antibiotics in a milk-glucose semen extender on motility of equine sperm and elimination of bacteria following storage of extended semen in vitro. In Experiment 1, 7 antibiotics were compared: amikacin, gentamicin, streptomycin, potassium penicillin, sodium penicillin, ticarcillin, and polymixin B. In Experiment 2, 3 antibiotic treatments were compared: potassium penicillin G, amikacin, or a combination of potassium penicillin G and amikacin. In Experiment 3, 3 antibiotic treatments were compared: potassium penicillin G-amikacin, ceptiofur, and a combination of ticarcillin and clavulanic acid (Timentin). Control treatments (antibiotic-free extender) were included in each experiment. Six motility variables were evaluated: percentage of motile sperm; percentage of progressively-motile sperm; percentage of rapidly-motile sperm; mean curvilinear velocity; mean average path velocity; and mean straight-line velocity. In Experiment 1, mean percentages of motile, progressively motile and rapidly motile sperm were lower (P < 0.05) in semen exposed to polymixin B then in other treatments. Mean average-path velocity of sperm in extender containing polymixin B was lower (P < 0.05) than that of all other treatments, with exception of control or ticarcillin. Mean straight-line velocity of sperm in extender containing polymixin B was lower (P < 0.05) than that of all other treatments, with exception of control, streptomycin or ticarcillin. Semen samples containing gentamicin, amikacin, streptomycin, or potassium penicillin were more effective (P < 0.05) at eliminating bacterial growth than those samples containing polymixin B. Semen samples containing gentamicin were also more effective (P < 0.05) at eliminating bacterial growth than those samples containing ticarcillin or sodium penicillin. In Experiment 2, mean percentage of rapidly-motile sperm, and mean curvilinear, average-path, and straight-line velocities were greater (P < 0.05) for potassium penicillin-amikacin than values for all other treatments. In 2 of 3 stallions, an effect of treatment on percentage of motile sperm was detected (P < 0.05). For one stallion, mean motility of potassium penicillin-amikacin was greater (P < 0.05) than that of all other treatment groups. For another stallion, mean motility of the control was lower (P < 0.05) than that of the other treatments. Following storage, potassium penicillin (16/18 [89%]) or potassium penicillin-amikacin (17/19 [94%]) were more effective (P < 0.05) at controlling aerobic and anaerobic bacterial isolates in semen specimens than was amikacin (10/18 [56%]). In Experiment 3, a difference among treatment groups for motility variables was not detected (P < 0.05). No bacterial growth was recovered in antibiotic-treated semen, with exception of Micrococcus sp. (2 colonies) which were isolated from one semen specimen treated with ceptiofur.

Amikacin↗

PubMed1999

Fertility in bitches artificially inseminated with extended, chilled semen.

Sixteen bitches were artificially inseminated with either fresh, 24 h-chilled or 48 h-chilled extended semen over 38 estrous cycles. A commercial system for extending, chilling and transporting semen commonly used in the equine industry was used Pregnancy rates and litter sizes of the bitches inseminated with extended, chilled semen (19/20, 95%; litter size = 7.1) were not significantly different from those observed in bitches inseminated with fresh semen (17/18, 94%; litter size = 7.2; P > or = 0.89). These results show that a commercial system for extending, chilling and transporting equine semen is an attractive and efficient method of shipping canine extended chilled semen.

Analysis of Variance↗

PubMed1999

Fertility after vaginal or uterine deposition of dog semen frozen in a tris extender with or without Equex STM paste.

Twenty-five bitches were artificially inseminated with semen that was frozen-thawed using an egg yolk-Tris-glucose-citrate extender containing 5% glycerol with, or without the addition of 0.5% Equex STM Paste. Semen was collected on 2 occasions from 11 dogs, pooled, and evaluated for sperm motility, morphology and plasma membrane integrity. Each pool was then divided in 2 parts, diluted with 1 of the 2 extenders, and frozen in 0.5-mL straws. In the bitches, plasma progesterone was assayed daily during late proestrus and estrus. Artificial insemination (AI) was performed twice on Days 3 and 5 after the estimated LH peak. For each insemination, 200x10(6) spermatozoa were used. Ten bitches were inseminated with semen frozen without Equex: In 5 females, semen was deposited transcervically into the uterus with the aid of a fiberoptic endoscope and a urethral catheter, while the remaining 5 bitches were inseminated in the cranial vagina using a Norwegian catheter. Fifteen bitches were inseminated with semen frozen-thawed with Equex: Two groups of 5 bitches were inseminated according to the techniques described above, while 5 bitches were inseminated vaginally using the Osiris catheter. Pregnancy was diagnosed and the number of fetuses counted by ultrasound examination. Post-thaw, spermatozoa frozen with Equex tended to have higher total and progressive motility and to survive longer in vitro than when the extender without Equex was used. Spermatozoal concentration, age of the bitches, duration of heat and estrus, and progesterone concentration at LH peak and at the first and second AI did not differ among the 5 groups. The overall pregnancy rate of 84% (21/25) was close to what can be expected from well controlled natural matings. For both freezing extenders tested, 5/5 bitches were pregnant after uterine deposition of semen and 4/5 were pregnant when semen was deposited in the anterior vagina using the Norwegian catheter. With the Osiris catheter, 3/5 inseminations resulted in a pregnancy. No significant differences in pregnancy rate or number of fetuses were found between groups, site of deposition or freezing extender.

Animals↗

PubMed2001

Extended-duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of the randomised trials.

BACKGROUND: The optimum duration of prophylaxis against venous thromboembolism after total hip or knee replacement is uncertain. Our primary objective was to establish the efficacy of extended-duration prophylaxis on symptomatic venous thromboembolic events. METHODS: We identified randomised trials comparing extended-duration prophylaxis using heparin or warfarin with placebo or untreated control in patients undergoing elective total hip or knee replacement by searching electronic databases (MEDLINE, EMBASE), references from retrieved articles, and abstracts from conference proceedings, and by contact with pharmaceutical companies and investigators. Two reviewers independently extracted data on study design, symptomatic and symptomless venographic venous thromboembolism, death, and bleeding outcomes. Results from individual trials were combined with the Mantel-Haenszel method. FINDINGS: Nine studies met our inclusion criteria (3999 patients), eight with low molecular weight heparin, and one with unfractionated heparin. Extended-duration prophylaxis for 30-42 days significantly reduced the frequency of symptomatic venous thromboembolism (1.3% vs 3.3%, OR 0.38; 95% CI 0.24-0.61, numbers needed to treat [NNT]=50), with no statistical evidence of heterogeneity (x(2) test, p=0.69). There was a greater risk reduction in patients undergoing hip replacement (1.4% vs 4.3%, 0.33; 0.19-0.56, 34) compared with knee replacement (1.0% vs 1.4%, 0.74; 0.26-2.15, 250). A significant reduction in symptomless venographic deep vein thrombosis was also observed (9.6% vs 19.6%, 0.48; 0.36-0.63, 10). There was no increase in major bleeding but extended-duration prophylaxis was associated with excess minor bleeding (3.7% vs 2.5%, 1.56; 1.08-2.26, numbers needed to harm [NNH]=83). INTERPRETATION: Among patients undergoing total hip or knee replacement, extended-duration prophylaxis significantly reduces the frequency of symptomatic venous thromboembolism. The reduction in risk is equivalent to about 20 symptomatic events per 1000 patients treated.

Anticoagulants↗

PubMed2000

Simulated effects on dairy cattle health of extending the voluntary waiting period with recombinant bovine somatotropin.

We simulated the effect of extending the voluntary wait period by 100 days on disorder-frequency measures that were based on cow-years (from lactations completed during the 4-year simulation horizon), metric tons of milk yield, and lactational incidence risks. A dynamic stochastic discrete-event simulation model that focuses on clinical and subclinical intramammary infections (IMI), plus clinical metabolic (left-displaced abomasum, ketosis, milk fever) and reproductive (cystic ovarian disease, dystocia, retained placenta, twinning, uterine infection) disorders in dairy herds was used. Although the voluntary wait period was increased by 100 days (50 vs. 150), the predicted difference in simulated days to conception was only 89 days for the extended voluntary wait-period group (which we attributed to higher fertility later in lactation). Herds that had a voluntary wait period of 150 days (compared to the control herds' voluntary wait period of 50 days) were predicted to have significantly lower rates of metabolic and reproductive disorders and clinical mastitis on both cow-year and milk-yield bases. Simulated control herds, on average, produced 8539 kg of milk in an average lactation of 325 days and simulated herds with a 150-day voluntary wait period 10893 kg of milk in an average lactation of 409 days. There was a significantly lower predicted rate and risk of culling for reproductive failure in the extended voluntary wait period group. The predicted lactational incidence risks for subclinical IMI were 18% higher for the extended voluntary wait period group - but extending the voluntary wait period by 100 days was predicted not to increase the risk of any of the other 10 disorders.

Algorithms↗

PubMed2000

The FK520 gene cluster of Streptomyces hygroscopicus var. ascomyceticus (ATCC 14891) contains genes for biosynthesis of unusual polyketide extender units.

FK520 (ascomycin) is a macrolide produced by Streptomyces hygroscopicus var. ascomyceticus (ATCC 14891) that has immunosuppressive, neurotrophic and antifungal activities. To further elucidate the biosynthesis of this and related macrolides, we cloned and sequenced an 80kb region encompassing the FK520 gene cluster. Genes encoding the three polyketide synthase (PKS) subunits (fkbB, fkbC and fkbA), the peptide synthetase (fkbP), the 31-O-methyltransferase (fkbM), the C-9 hydroxylase (fkbD) and the 9-hydroxyl oxidase (fkbO) had the same organization as the genes reported in the FK506 gene cluster of Streptomyces sp. MA6548 (Motamedi, H., Shafiee, A., 1998. The biosynthetic gene cluster for the macrolactone ring of the immunosuppressant FK506. Eur. J. Biochem. 256, 528-534). Disruption of a PKS gene in the cluster using the φC31 phage vector, KC515, led to antibiotic non-producing strains, proving the identity of the cluster. Previous labeling data have indicated that FK520 biosynthesis uses novel polyketide extender units (Byrne, K.M., Shafiee, A., Nielson, J., Arison, B., Monaghan, R.L., Kaplan, L., 1993. The biosynthesis and enzymology of an immunosuppressant, immunomycin, produced by Streptomyces hygroscopicus var, ascomyceticus. Dev. Ind. Microbiol. 32, 29-45). Genes in the flanking regions of the FK520 cluster were identified that appear to be involved in synthesis of these extender units. All but two of these genes were homologous to genes with known function. In addition to a crotonyl-CoA reductase gene (fkbS), at least two other genes are proposed to be involved in biosynthesis of the atypical PKS extender unit ethylmalonyl-CoA, which accounts for the ethyl side chain on C-21 of FK520. A set of five contiguous genes (fkbGHIJK) is proposed to be involved in biosynthesis of an unusual PKS extender unit bearing an oxygen on the alpha-carbon, and leading to the 13- and 15-methoxy side chains. These putative precursor synthesis genes in the flanking regions of the FK520 cluster are not found in the flanking regions of the rapamycin cluster (Molnár, I., Aparicio, J.F., Haydock, S.F., Khaw, L.E., Schwecke, T., König, A., Staunton, J., Leadlay, P.F., 1996. Organisation of the biosynthetic gene cluster for rapamycin in Streptomyces hygroscopicus: analysis of genes flanking the polyketide synthase. Gene 169, 1-7), consistent with labeling data showing that rapamycin biosynthesis uses only malonyl and methylmalonyl extender units.

Acyl Coenzyme A↗

PubMed2002

Motility and fertility of bull sperm in whole milk extender containing antioxidants.

Bull sperm are exposed to aerobic conditions during processing before freezing, and they have little endogenous antioxidant to protect them against reactive oxygen species that may be present. Seventeen laboratory studies and two field trials were conducted with 174 semen collections from bulls in an artificial breeding cooperative. More than 250 combinations and concentrations of reduced glutathione (GSH), superoxide dismutase (SOD), ascorbic acid, hypotaurine (HPT), 2,2,6,6-tetramethylpeperidine-1-oxyl (Tempo) and 4-hydroxy-2, 2, 6, 6-tetramethylpeperidine (Tempol) were tested by adding these compounds to fresh semen, and to a whole milk (WM) glycerol extender. Semen packaged in straws in the WM extender was frozen with liquid nitrogen. The motility of frozen-thawed sperm during storage at 25 or 5 degrees C after freezing was compared with semen stored without freezing. Antioxidants generally were not beneficial, except the percentage of motile sperm was improved by 6-11% units (P<0.05) when sperm were stored unfrozen or after freezing when 0.5mM of GSH with or without SOD was added. In two field trials, non-return rates were 71.9, 69.5 and 70.9% (P>0.05) with WM containing 0.0, 0.5 and 1.0mM of GSH, respectively, and 74.0 and 73.9% with WM and WM plus 0.5mM of GSH and 100U/ml of SOD (P>0.05). WM contains an abundant supply of casein which is an antioxidant, and additional antioxidants were ineffective in improving motility of sperm immediately after freezing and thawing or in affecting fertility. However, sperm responses were different in egg yolk-Tris extender. Sperm in this egg yolk extender tolerated substantial concentrations of Tempo and Tempol compared with toxic effects in WM (P<0.05). Therefore, optimal combinations of antioxidants tested here may have more useful applications in organizations using an egg yolk-based semen extender.

Animals↗

PubMed1998

Outcomes of extended radical esophagectomy for thoracic esophageal cancer.

BACKGROUND: Great controversy exists concerning the adequate extent of esophagectomy for cure in patients with esophageal cancer. Extended radical esophagectomy combined with three-field lymphadenectomy has been performed to improve the cure rates for patients with the disease in Japan. The purposes of this study were to assess the mortality and morbidity rates after extended radical esophagectomy and to determine the oncologic indications for this procedure. STUDY DESIGN: We reviewed 190 patients who underwent extended radical esophagectomy for invasive esophageal cancer. The procedures were performed prospectively between 1982 and 1996. RESULTS: The 30-day mortality, in-hospital mortality, and morbidity rates were 1.6%, 4.7%, and 58.4%, respectively. The most common postoperative complication was vocal-cord paralysis (45.3%), followed by major pulmonary complications (21.6%). The overall survival rate for the 190 patients was 41.5% at 5 years, with a median followup period of 61 months. Some subgroups of patients had an extremely poor prognosis despite extended radical esophagectomy. Survival was < or = 5 years in all patients with five or more positive nodes; all patients with simultaneous metastases to the cervical, mediastinal, and abdominal lymph nodes; and all patients with cervical metastases from a lower esophageal tumor. CONCLUSIONS: Extended radical esophagectomy is potentially associated with high morbidity rates although the mortality rates are acceptable, suggesting the necessity of careful patient selection. This procedure is indicated oncologically only for patients with four or fewer metastatic nodes or with metastases confined to one or two of the three anatomic compartments (neck, mediastinum, and abdomen) from upper or midesophageal tumors.

Carcinoma, Squamous Cell↗

PubMed1999

Reduction in health care resource utilization associated with extended-release theophylline.

BACKGROUND: People with airway disease are high utilizers of health care resources. Few studies document the value of alternative therapies in reducing utilization. Studies examining theophylline, which demonstrate reduction in resource utilization, have been primarily of short duration in hospitalized settings with small samples. OBJECTIVE: The purpose of this study was to examine the role of oral extended-release theophylline in reducing health care utilization over an extended period of time when added to existing inhaler therapy for ambulatory patients with airway disease. METHODS: We used a retrospective, pretest/posttest design in examining the 1990-1993 South Carolina Medicaid database to compare health care utilization of 455 ambulatory patients for 4 months before and 6 months after extended-release theophylline was added to their treatment regimen. We assessed the following three outcomes: inhaler use, physician office visits, and emergency department visits, all measured in units/person/month. RESULTS: Our sample consisted of patients taking beta2-agonist only (n = 393), steroid only (n = 25), and beta2-agonist plus steroid (n = 37). Inhaler use and physician office visits declined significantly among beta2-agonist users, as well as within the entire sample. Initiation of extended-release theophylline therapy was associated with a 30% decline in utilization of inhaler and physician office visits, influenced mostly by the decline with the beta2-agonist group. CONCLUSION: The results of this effectiveness study using an administrative claims database are consistent with the published randomized clinical trials that document the value of extended-release theophylline when added to existing inhaler therapy.

Administration, Inhalation↗

PubMed2006

Randomized comparative study of the effects of treatment with once-daily, niacin extended-release/lovastatin and with simvastatin on lipid profile and fibrinolytic parameters in Taiwan.

Hyperlipidemia can be effectively treated either with niacin or HMG-CoA reductase inhibitor (statin), or a combination of both. Few reports showed the effects of the combination regimen with niacin and statin on hemostatic functions. We conducted a single-center, double-blind, double-dummy, randomized, two-arm study to assess the effects of the niacin extended-release/lovastatin therapy in a fixed-dose formulation and of simvastatin on lipid lowering and two fibrinolytic parameters, fibrinogen and d-dimer. All patients were enrolled according to NCEP-ATP III guidelines and underwent a placebo run-in period of 4 weeks before being randomized to either niacin extended-release/lovastatin tablets (500/20 mg) once daily (n = 36) or simvastatin capsule (20 mg) once daily (n = 34). After 16 weeks of treatment, both groups of patients showed significantly reduced low-density lipoprotein cholesterol and total cholesterol (LDL-C, p < 0.001 and < 0.001, respectively, p = 0.159 between the groups; TC, p < 0.001 and < 0.001, respectively, p = 0.018 between the groups). Both drugs were well tolerated. Only in the group treated with niacin extended-release/lovastatin was fibrinogen concentration significantly reduced after treatment (2.48 +/- 0.65 to 1.99 +/- 0.62 g/L, p = 0.008). No difference was found with d-dimer in either group. This study shows that both niacin extended-release/lovastatin and simvastatin are effective and well-tolerated lipid-lowering drugs in Taiwanese patients with dyslipidemia. A combinational treatment with niacin extended-release/lovastatin may provide additional benefit in fibrinolysis.

Aged↗

PubMed1999

Aberrant mRNAs with extended 3' UTRs are substrates for rapid degradation by mRNA surveillance.

The mRNA surveillance system is known to rapidly degrade aberrant mRNAs that contain premature termination codons in a process referred to as nonsense-mediated decay. A second class of aberrant mRNAs are those wherein the 3' UTR is abnormally extended due to a mutation in the polyadenylation site. We provide several observations that these abnormally 3'-extended mRNAs are degraded by the same machinery that degrades mRNAs with premature nonsense codons. First, the decay of the 3'-extended mRNAs is dependent on the same decapping enzyme and 5'-to-3' exonuclease. Second, the decay is also dependent on the proteins encoded by the UPF1, UPF2, and UPF3 genes, which are known to be specifically required for the rapid decay of mRNAs containing nonsense codons. Third, the ability of an extended 3' UTR to trigger decay is prevented by stabilizing sequences within the PGK1 coding region that are known to protect mRNAs from the rapid decay induced by premature nonsense codons. These results indicate that the mRNA surveillance system plays a role in degrading abnormally extended 3' UTRs. Based on these results, we propose a model in which the mRNA surveillance machinery degrades aberrant mRNAs due to the absence of the proper spatial arrangement of the translation-termination codon with respect to the 3' UTR element as defined by the utilization of a polyadenylation site.

3' Untranslated Regions↗

PubMed2001

Selective, high-affinity binding of ferric ions by glycine-extended gastrin(17).

Uptake of dietary iron is essential for replenishment of body stores. A role for the hormone gastrin in iron uptake as a chelator of ferric ions in the gastric lumen has been proposed previously [Baldwin, G. S. (1992) Med. Hypotheses 38, 70-74]. Here, spectroscopic evidence of selective, high-affinity binding of ferric ions to progastrin-derived peptides in aqueous solution at low pH is provided. The maximum at 281 nm in the absorption spectrum of glycine-extended gastrin(17) at pH 4.0 increased (2.07 +/- 0.30)-fold in the presence of > or =2 equiv of ferric ions. Titration of glycine-extended gastrin(17) with ferric ions under stoichiometric conditions indicated that the stoichiometry of binding was 2.00 +/- 0.28 mol of Fe(3+)/mol of peptide. Fluorescence quenching experiments yielded values for the stoichiometry and apparent dissociation constant of the ferric ion-glycine-extended gastrin(17) complex at pH 4.0 of 2.39 +/- 0.17 mol of Fe(3+)/mol and 0.62 +/- 0.19 microM, respectively. No interaction was detected with Co(2+), Cu(2+), Mn(2+), or Cr(3+). Electron paramagnetic resonance spectroscopy suggested that the iron ligands were either oxygen or sulfur atoms. Fluorescence quenching experiments with peptides derived from the glycine-extended gastrin(17) sequence indicated that one or more of the five glutamic acid residues were necessary for iron binding. The binding of ferric ions by glycine-extended gastrin(17) at low pH is consistent with a role for progastrin-derived peptides in iron uptake from the lumen of the gastrointestinal tract.

Binding Sites↗

PubMed1999

Dissecting the role of acyltransferase domains of modular polyketide synthases in the choice and stereochemical fate of extender units.

Modular polyketide synthases (PKSs), such as the 6-deoxyerythronolide B synthase (DEBS), are large multifunctional enzyme complexes that are organized into modules, where each module carries the domains needed to catalyze the condensation of an extender unit onto a growing polyketide chain. Each module also dictates the stereochemistry of the chiral centers introduced into the backbone during the chain elongation process. Here we used domain mutagenesis to investigate the role of the acyl transferase (AT) domains of individual modules in the choice and stereochemical fate of extender units. Our results indicate that the AT domains of DEBS do not influence epimerization of the (2S)-methylmalonyl-CoA extender units. Hence, stereochemical control of the methyl-branched centers generated by DEBS most likely resides in the ketosynthase (KS) domains of the individual modules. In contrast, several recent studies have demonstrated that extender unit specificity can be altered by AT domain substitution. In some of these examples, the resulting polyketide was produced at considerably lower titers than the corresponding natural product. We analyzed one such attenuated mutant of DEBS, in which the methylmalonyl transferase domain of module 2 was replaced with a malonyl transferase domain. As reported earlier, the resulting PKS produced only small quantities of the expected desmethyl analogue of 6-deoxyerythronolide B. However, when the same hybrid module was placed as the terminal module in a truncated 2-module PKS, it produced nearly normal quantities of the expected desmethyl triketide lactone. These results illustrate the limits to modularity of these multifunctional enzymes. To dissect the role of specific amino acids in controlling AT substrate specificity, we exchanged several segments of amino acids between selected malonyl and methylmalonyl transferases, and found that a short (23-35 amino acid) C-terminal segment present in all AT domains is the principal determinant of their substrate specificity. Interestingly, its length and amino acid sequence vary considerably among the known AT domains. We therefore suggest that the choice of extender units by the PKS modules is influenced by a "hypervariable region", which could be manipulated via combinatorial mutagenesis to generate novel AT domains possessing relaxed or altered substrate specificity.

Acyl Coenzyme A↗

PubMed2003

On the extended beta-conformation propensity of polypeptides at high temperature.

At room temperature, natural polypeptides exposed to high concentrations of a strong denaturant nearly attain the circular dichroism spectra characteristic of random coils. As temperature is increased, the spectra begin to show the signature of a substantial fraction of extended chain, the structure common in beta-sheets. This structural propensity at high temperature is not altered by concentration changes over a greater than 1000-fold range, so it is not caused by aggregation. Four proteins with different folds and varying amounts of alpha-helical and beta-sheet secondary structure, in the presence or absence of denaturant, all were subject to extended chain formation upon heating. This effect arises naturally from the steric constraints associated with polypeptides and is probably counteracted, not enhanced, by hydrophobic interactions. Molecular dynamics simulations in the 298-1000 K range reveal an attractive potential of mean force in the extended chain region of the Ramachandran diagram, which broadens as the temperature is raised. We also demonstrate a direct correlation between extended structure content and the rate of aggregation kinetics. Thus pre-existing extended structure could funnel proteins into aggregates.

Circular Dichroism↗

PubMed2003

In situ assembly of enzyme inhibitors using extended tethering.

Cysteine aspartyl protease-3 (caspase-3) is a mediator of apoptosis and a therapeutic target for a wide range of diseases. Using a dynamic combinatorial technology, 'extended tethering', we identified unique nonpeptidic inhibitors for this enzyme. Extended tethering allowed the identification of ligands that bind to discrete regions of caspase-3 and also helped direct the assembly of these ligands into small-molecule inhibitors. We first designed a small-molecule 'extender' that irreversibly alkylates the cysteine residue of caspase-3 and also contains a thiol group. The modified protein was then screened against a library of disulfide-containing small-molecule fragments. Mass-spectrometry was used to identify ligands that bind noncovalently to the protein and that also form a disulfide linkage with the extender. Linking the selected fragments with binding elements from the extenders generates reversible, tight-binding molecules that are druglike and distinct from known inhibitors. One molecule derived from this approach inhibited apoptosis in cells.

Apoptosis↗

PubMed1998

Three year in vivo investigation to determine the progression of approximal primary carious lesions extending into dentine.

OBJECTIVE: To investigate the proportion of a sample of approximal carious lesions extending up to 1 mm into dentine which progressed over a 3-year period and to examine factors which influenced that progression. DESIGN: Prospective, single centre, clinical study. SETTING: Restorative Clinic at Bristol Dental School, UK. SUBJECTS AND METHODS: Sixty-five adult patients were identified who each had an approximal carious lesion which extended up to 1 mm into the dentine and which were assessed at intervals of up to 36 months. All patients were given appropriate preventive advice. MAIN OUTCOME MEASURES: Progression of the lesions was determined by assessment of sequential bitewing radiographs. RESULTS: 29% of the lesions progressed within 8 months, 56% by 20 months and 69% by 36 months. After 36 months, lesions which extended over 0.5 mm and up to 1 mm into the dentine were significantly more likely to have progressed (92%) compared with shallower lesions which extended up to only 0.5 mm into dentine (50%). CONCLUSIONS: The depth of an approximal dentine lesion was the main clinical marker which related to its progression. It is recommended that operative intervention is considered for approximal lesions which extend deeper than 0.5 mm into the dentine, while preventive treatment and re-assessment may be considered for shallower lesions.

Adolescent↗

PubMed2001

Prospective analysis of the diagnostic yield of extended en bloc resection for adenocarcinoma of the oesophagus or gastric cardia.

BACKGROUND: The extent of lymph node dissection can affect tumour node metastasis staging. The resulting 'stage migration' might hamper stage-by-stage comparison between different forms of oesophageal resection. The aim of this study was to assess the diagnostic impact of extended en bloc lymphadenectomy in staging (adeno)carcinoma of the mid/distal oesophagus or gastric cardia. METHODS: This was a prospective study of 74 patients (67 men and seven women; median age 63 (range 40-78) years) who underwent extended oesophagectomy between 1994 and 2000. RESULTS: A median of 31 (range 15-78) lymph nodes was resected (and identified), with a median of 5 (range 0-31) positive nodes. Twenty-seven patients (36 per cent) had tumour-positive nodes in extended fields: 15 patients (20 per cent) in the abdomen and 15 patients (20 per cent) in the mediastinum. Subcarinal nodes were most affected (19 per cent). Extended resection led to tumour upstaging in 17 patients (23 per cent); two patients had isolated positive subcarinal nodes and 15 other tumours became M1a owing to positive nodes near the coeliac axis, hepatic artery or splenic artery. Tumour positivity in paratracheal or aortopulmonary nodes occurred in 8 per cent of patients, without influencing staging. CONCLUSION: Extended en bloc lymphadenectomy altered staging in 17 of 74 patients (23 per cent) with adenocarcinoma of the oesophagus or cardia, mainly into M1a owing to positive coeliac nodes (20 per cent).

Adenocarcinoma↗

PubMedDate not supplied

Venlafaxine extended release (XR) for the prophylaxis of migraine and tension-type headache: A retrospective study in a clinical setting.

OBJECTIVE: To assess the efficacy of extended-release venlafaxine in the prophylaxis of migraine and chronic tension-type headache. BACKGROUND: Venlafaxine, a structurally novel antidepressant, is a selective serotonin-norepinephrine reuptake inhibitor. This study is the first to test the effects of extended-release venlafaxine on headaches. METHODS: Patients were evaluated on a retrospective basis. Fifty-six patients with chronic tension-type headache and 114 patients with migraine were prescribed extended-release venlafaxine. Nearly all the study subjects had been resistant to several previous preventive medications. Patients took venlafaxine for an average of 6 months with a median dose of 150 mg (range, 37.5 to 300 mg). RESULTS: The mean frequency of headaches in the group with chronic tension-type headache fell from 24.0 to 15.2 per month (P <.0001). The group with migraine showed a reduction from 16.1 to 11.1 headaches per month (P <.0001). The medicine was well tolerated. CONCLUSIONS: This trial indicates that extended-release venlafaxine has potential in headache prophylaxis based on its efficacy and safety profile. We recommend a double-blind, placebo-controlled study to further assess the role of extended-release venlafaxine in headache prevention.

Adolescent↗