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Biomedical subjects

R Finch

Publications and source records attributed to R Finch.

At least 19 recordsLinked to original sources
PubMed2002

Bacterial resistance--the clinical challenge.

Resistance to antibacterial agents has increased among many species of bacterial pathogens in the last two decades. While this has been recognized and has been a matter of concern among those concerned with infectious diseases, it is only relatively recently that prescribing physicians have become aware of the problem. A range of official bodies, both national and international, have proposed a range of strategies for controlling this increase in resistance. The relationship between resistance and clinical efficacy or failure is unclear in many areas, although increasingly resistance can be seen to be associated with a less than optimal clinical response. Although the relationship between antibiotic use and resistance is complex, there is an assumption that excessive use of antibacterials may drive an increase in resistance. The term 'prudent prescribing' is frequently used in official documents, but it is not easy for the prescriber to determine exactly what is prudent prescribing. There have been efforts to reduce the unnecessary use of antibacterials in the treatment of many community respiratory infections where the etiological agent is likely to be viral. Guidelines for prescribing have been drawn up by governments and professional societies but their impact can be variable. They need to take account of the changing patterns of resistance, for example the rise in high-level penicillin resistance among pneumococci. They also need to be readily accessible to the practicing clinician. Surveillance systems are available in abundance and these may be local, national, or international. They often, however, suffer from drawbacks and are frequently selective. Frequently the prescriber does not have ready access to the most appropriate data. Integrated strategies to control resistance are urgently needed, as are improved rapid diagnostic facilities.

Anti-Bacterial Agents↗
PubMed2002

Randomized controlled trial of sequential intravenous (i.v.) and oral moxifloxacin compared with sequential i.v. and oral co-amoxiclav with or without clarithromycin in patients with community-acquired pneumonia requiring initial parenteral treatment.

The objective of the present trial was to compare the efficacy, safety, and tolerability of moxifloxacin (400 mg) given intravenously (i.v.) once daily followed by oral moxifloxacin (400 mg) for 7 to 14 days with the efficacy, safety, and tolerability of co-amoxiclav (1.2 g) administered by i.v. infusion three times a day followed by oral co-amoxiclav (625 mg) three times a day, with or without clarithromycin (500 mg) twice daily (i.v. or orally), for 7 to 14 days in adult patients with community-acquired pneumonia requiring initial parenteral therapy. A total of 628 patients were enrolled and assessed by evaluation of their clinical and bacteriological responses 5 to 7 days and 21 to 28 days after administration of the last dose of study medication. Although the trial was designed, on the basis of predefined outcomes, to demonstrate the equivalence of the two regimens, the results showed statistically significant higher clinical success rates (for moxifloxacin, 93.4%, and for comparator regimen, 85.4%; difference [Delta], 8.05%; 95% confidence interval [CI], 2.91 to 13.19%; P = 0.004) and bacteriological success rates (for moxifloxacin, 93.7%, and for comparator regimen, 81.7%; Delta, 12.06%; 95% CI, 1.21 to 22.91%) for patients treated with moxifloxacin. This superiority was seen irrespective of the severity of the pneumonia and whether or not the combination therapy included a macrolide. The time to resolution of fever was also statistically significantly faster for patients who received moxifloxacin (median time, 2 versus 3 days), and the duration of hospital admission was approximately 1 day less for patients who received moxifloxacin. The treatment was converted to oral therapy immediately after the initial mandatory 3-day period of i.v. administration for a larger proportion of patients in the moxifloxacin group than patients in the comparator group (151 [50.2%] versus 57 [17.8%] patients). There were fewer deaths (9 [3.0%] versus 17 [5.3%]) and fewer serious adverse events (38 [12.6%] versus 53 [16.5%]) in the moxifloxacin group than in the comparator group. The rates of drug-related adverse events were comparable in both groups (38.9% in each treatment group). The overall incidence of laboratory abnormalities was similar in both groups. Thus, it is concluded that monotherapy with moxifloxacin is superior to that with a standard combination regimen of a beta-lactam and a beta-lactamase inhibitor, co-amoxiclav, with or without a macrolide, clarithromycin, in the treatment of patients with community-acquired pneumonia admitted to a hospital.

Administration, Oral↗
PubMed2002

Novel cationic trypsinogen (PRSS1) N29T and R122C mutations cause autosomal dominant hereditary pancreatitis.

Hereditary pancreatitis (HP) is usually caused by mutations in the cationic trypsinogen (PRSS1) gene, especially R122H or N29I. We sequenced the PRSS1 gene in the proband of families without these common mutations. Novel R122C and N29T mutations were detected in independent families that segregated with the disease in an autosomal dominant fashion. The R122C mutation eliminates the arginine autolysis site as with R122H mutations. The N29T mutation may also enhance intrapancreatic trypsin activity as has been demonstrated in vitro. Identification of these new mutations requires special attention as commonly used detection methods may fail.

Adult↗
PubMed2001

Hereditary pancreatitis in North America: the Pittsburgh-Midwest Multi-Center Pancreatic Study Group Study.

BACKGROUND: Hereditary pancreatitis (HP) was defined on a clinical basis alone until the first cationic trypsinogen gene (PRSS1) mutation was discovered through the initial phase of the current Pittsburgh Midwest Multi-Center Pancreatic Study Group (MMPSG) HP study in 1996, making genetic testing available. AIM: To evaluate the regional distribution of HP in the United States, and to compare the study's gene mutation database with the pedigree databases to determine whether family history alone predicts the likelihood of detecting mutations in the cationic trypsinogen gene. METHODS: Probands of families with HP, familial pancreatitis and idiopathic chronic pancreatitis were recruited through referrals from MMPSG collaborating centers, other physicians and self-referral of patients who had learned of the study through the World Wide Web (www.pancreas.org). Pedigrees were constructed, detailed questionnaires were completed and a blood sample was drawn for each proband and participating family members. The birthplace and current location of each patient was recorded, DNA was analyzed for known mutations and the pattern of phenotype inheritance was determined from analysis of each pedigree. RESULTS: A total of 717 individuals were ascertained; 368 (51%) had clinical pancreatitis confirmed and the rest were primarily unaffected family members used for linkage studies. Forty-six clinically unaffected individuals were silent mutation carriers (11% of mutation-positive individuals). HP was most common in Minnesota, New York and the central mid-Atlantic states plus Kentucky and Ohio. One hundred and fifteen of 150 kindreds fulfilled the strict definition of an HP family, and 60 (52%) had PRSS1 mutations. Of the families with a detected mutation, 11% did not fulfill the clinical definition of an HP kindred. CONCLUSIONS: The distribution of HP within the United States shows major regional differences. The etiology of HP can be identified in a small majority of HP families through genetic testing. However, family history alone is not a good predictor of finding a mutation in the cationic trypsinogen (PRSS1) gene.

Databases, Factual↗
PubMed2001

Community-acquired pneumonia: the evolving challenge.

Community-acquired pneumonia (CAP) is a common disorder that has been the focus of a major international research effort to define its epidemiology, etiology and management. The microbial etiology of CAP is complex and severity assessment is important in identifying at-risk populations as well as defining therapeutic strategies. Laboratory investigations rarely influence initial therapy, which remains empirical. Guidelines have been developed in many countries in response to the need to optimize management and outcomes. However, many of these guidelines have been based on expert opinion rather than robust evidence. New evidence-based guidelines have been developed that take into account disease severity, the local distribution of pathogens and their likely susceptibility to antimicrobials, and that include newer treatment options. Macrolide and fluoroquinolone antimicrobials feature heavily in these new treatment recommendations. Promising new therapies continue to emerge that may offer advantages over fluoroquinolones and macrolides, in particular with regard to the problem of resistance. Of these, the ketolides are of special interest. Telithromycin, the first ketolide antibacterial, has been evaluated in the treatment of > 700 patients with CAP. A once-daily oral dose of telithromycin 800 mg for 7-10 days produces clinical and bacteriological success rates > 90% and equivalent to standard comparator agents, whilst maintaining efficacy against resistant pathogens.

Adolescent↗
PubMed2000

Chronic dysphagia following laparoscopic fundoplication.

BACKGROUND: Many surgeons practise tailored laparoscopic antireflux surgery in an attempt to prevent postoperative dysphagia. The aim of this study was to determine the effect of 360 degrees fundoplication (Nissen) or 270 degrees fundoplication (Toupet), and the influence of abnormal oesophageal peristalsis, upon postoperative dysphagia. METHODS: This was a cohort study from three tertiary referral centres, using dysphagia before laparoscopic fundoplication and 1 year after operation as the main outcome variable. Preoperative oesophageal manometry was performed on all patients. RESULTS: Some 761 patients underwent Nissen and 85 underwent Toupet fundoplication. Only 2 per cent reported severe postoperative dysphagia. There was a significant selection bias towards the Toupet operation for patients with abnormal oesophageal motility (P < 0.001). For patients whose oesophageal manometric findings were normal there was a significant improvement in dysphagia after Nissen fundoplication (P = 0.02), and no significant change following Toupet fundoplication. There was no significant change in the rate of dysphagia following either method of fundoplication amongst other subgroups in which oesophageal manometry was stratified as non-specific motor disorder, low-amplitude peristalsis, or aperistalsis. CONCLUSION: A tailored approach to the degree of fundoplication is unnecessary as patients with dysmotility suffer no more dysphagia after full laparoscopic Nissen fundoplication than those who have a partial Toupet wrap.

Chronic Disease↗
PubMed2000

SPINK1/PSTI polymorphisms act as disease modifiers in familial and idiopathic chronic pancreatitis.

BACKGROUND & AIMS: Gain-of-function trypsin mutations cause acute pancreatitis and chronic pancreatitis. Loss of trypsin inhibitor function may have similar effects. We investigated the prevalence of SPINK1 (PSTI) mutations in familial pancreatitis, idiopathic chronic pancreatitis, and controls. METHODS: Genetic-linkage studies were performed in 5 familial pancreatitis families. The entire SPINK1 gene was sequenced in 112 affected individuals and 95 control DNA samples, and exon 3 was sequenced in 95 additional controls. X-ray crystallography-based model building and statistical studies were performed. RESULTS: Significant linkage between pancreatitis and 5q31.1-2 was excluded. Novel SPINK1 mutations, one D50E mutation, one IVS3+125 C>A, and five IVS3+184 T>A intronic polymorphisms were identified. The N34S and P55S mutations were observed in 29 of 112 patients (25%) as N34S/N34S (n = 7), N34S/wt (n = 19), N34S/P55S (n = 2), and N34S/D50E (n = 1). Three hundred eighty control alleles revealed 3 N34S (0.77%), 2 P55S (0.53%), and no D50E mutations. Age of disease onset and severity were similar between homozygous and heterozygous patients. Structural modeling revealed several possible pathophysiologic mechanisms for the N34S mutation. CONCLUSIONS: SPINK1 mutations are common in the population (approximately 2%), but are clearly associated with pancreatitis. The mutation-associated risk is low. Modeling and familial clustering suggest that SPINK1 mutations are disease modifying, possibly by lowering the threshold for pancreatitis from other genetic or environmental factors, but by themselves do not cause disease.

Amino Acid Sequence↗
PubMed2000

The effects of exposure at constant (1 h) or exponentially decreasing concentrations of quinupristin/dalfopristin on biofilms of Gram-positive bacteria.

Using a biofilm model, infections by Staphylococcus aureus, coagulase-negative staphylococci and enterococci were studied. The biofilms were exposed to quinupristin/dalfopristin and five comparator antibiotics: ciprofloxacin, vancomycin, teicoplanin, flucloxacillin and erythromycin. Two methods of exposure to the drugs were used: constant for 1 h, and exponentially decreasing, with the rate of dilution being matched to the half-lives of the antibiotics. The effects of antibiotic exposure were monitored by performing viable counts on the cells eluted from the biofilms. The results are presented as the inhibitory or bactericidal effect (the reduction in numbers of bacteria eluted from the biofilms) and recovery times (the time taken for the number of cells eluted from the biofilms to return to the number eluted before the drug exposure). Quinupristin/dalfopristin was the most effective of the six antibiotics studied, especially against enterococci. However, there were no significant differences in the effects, inhibitory/ bactericidal or recovery times, produced by the two methods of exposure. The two glycopeptides showed a surprising lack of activity.

Biofilms↗
PubMed2000

Molecular analysis of the pmo (particulate methane monooxygenase) operons from two type II methanotrophs.

The particulate methane monooxygenase gene clusters, pmoCAB, from two representative type II methanotrophs of the alpha-Proteobacteria, Methylosinus trichosporium OB3b and Methylocystis sp. strain M, have been cloned and sequenced. Primer extension experiments revealed that the pmo cluster is probably transcribed from a single transcriptional start site located 300 bp upstream of the start of the first gene, pmoC, for Methylocystis sp. strain M. Immediately upstream of the putative start site, consensus sequences for sigma(70) promoters were identified, suggesting that these pmo genes are recognized by sigma(70) and negatively regulated under low-copper conditions. The pmo genes were cloned in several overlapping fragments, since parts of these genes appeared to be toxic to the Escherichia coli host. Methanotrophs contain two virtually identical copies of pmo genes, and it was necessary to use Southern blotting and probing with pmo gene fragments in order to differentiate between the two pmoCAB clusters in both methanotrophs. The complete DNA sequence of one copy of pmo genes from each organism is reported here. The gene sequences are 84% similar to each other and 75% similar to that of a type I methanotroph of the gamma-Proteobacteria, Methylococcus capsulatus Bath. The derived proteins PmoC and PmoA are predicted to be highly hydrophobic and consist mainly of transmembrane-spanning regions, whereas PmoB has only two putative transmembrane-spanning helices. Hybridization experiments showed that there are two copies of pmoC in both M. trichosporium OB3b and Methylocystis sp. strain M, and not three copies as found in M. capsulatus Bath.

Alphaproteobacteria↗
PubMed1999

Mammalian immunoassays for predicting the toxicity of malathion in a laboratory fish model.

This study describes the use of a panel of immune assays, originally developed by the National Toxicology Program for assessing xenobiotic-induced immunotoxicity in mice, to quantify the effects of sublethal malathion exposure on the immune responses of fish. For this study, Japanese medaka (Oryzias latipes) were exposed subchronically to the organophosphate pesticide malathion in a series of two experiments. In the first set of studies, fish were exposed for 7 or 14 d to untreated well water (i.e., controls) or to waterborne malathion at 0.2 or 0.8 mg/L. Following exposure, fish from each group were sacrificed and their kidneys (primary organ of leukopoiesis in fish and equivalent to mammalian bone marrow) were used to provide cells for assessing any malathion-induced effects upon nonspecific and acquired immune defense mechanisms. Effects upon humoral-mediated immunity were determined by enumerating antibody plaque-forming cell (PFC) numbers from a subset of fish exposed to malathion for 14 d and then injected intraperitoneally (ip) with sheep erythrocytes (sRBC). Results of these studies demonstrated that while malathion exposure had no significant effect upon hematocrit/leukocrit values or upon mitogen-stimulated T-cell lymphoproliferation, PFC numbers in the kidney of exposed fish were significantly reduced (compared to control fish) in a dose-dependent manner. In addition, total recoverable kidney cell numbers and viability, as well as superoxide anion production by kidney phagocytes, were reduced slightly (compared to control values) in fish exposed for 14 d to the highest malathion concentration tested. In the second set of experiments, medaka exposed for up to 21 d to either 0.1 or 0.3 mg malathion/L were challenged ip with an LD50 dose of the bacterial fish pathogen Yersinia ruckeri. Results from these infectivity studies demonstrated that exposure to either malathion concentration, for 14 or 21 d reduced host resistance against Yersinia infection. Taken together, these findings demonstrate the applicability of mammalian immune assays for predicting malathion-induced immunosuppression in a teleost fish, as well as the potential utility of a small laboratory fish to serve as an alternate model for mammals in immunotoxicological studies.

Animals↗
PubMed1998

Effects of r-metHuG-CSF on polymorphonuclear leucocyte kinetics and function in patients on continuous ambulatory peritoneal dialysis.

End-stage renal failure (ESRF) patients undergoing continuous ambulatory peritoneal dialysis (CAPD) are immunocompromised and exhibit abnormal circulating polymorphonuclear leucocyte (PMN) function, including reduced phagocytosis and intracellular killing. Six uraemic patients on CAPD were each given 300 microg granulocyte colony stimulating factor (G-CSF) every day for 5 d and PMN function tests were performed daily. By day 5 of the study CD11b expression was significantly decreased in response to N-formylmethionylleucylphenylalanine (fMLP) and opsonized Staphylococcus epidermidis stimulation, and expression of L-selectin (CD62L) was significantly decreased in response to opsonized Staphylococcus epidermidis stimulation. Further, superoxide anion production and Fc gammaRI (CD64) expression were found to be significantly increased and Fc gammaRII (CD16) expression was lowered. Circulating white cell and PMN counts were significantly elevated in response to treatment. Administration of G-CSF did not appear to have corrected the abnormalities in phagocytosis and intracellular killing. This study suggests that G-CSF does no harm to ESRF patients and influences uraemic PMN function in a manner that is comparable to its effects on PMN in non-uraemic subjects.

Adult↗
PubMed1998

Malaria and anaemia at different altitudes in the Muheza district of Tanzania: childhood morbidity in relation to level of exposure to infection.

Parallel monthly surveys of children aged 6-71 months were conducted in the Muheza district of Tanzania. The aim was to compare highland villages, where the mean, annual entomological inoculation rate (EIR) for malaria is 34 and mean annual prevalences of parasitaemia range from 33%-76%, with culturally similar villages of the lowlands, where the mean EIR is 405 and prevalences of parasitaemia range from 80%-84%. The total survey population could be divided into six geographical subgroups, which can be arranged in order of increasing prevalence of parasitaemia. The prevalences of dense parasitaemia, of febrile malaria, and of anaemia all increased in the same order across this series of groups, the trends being statistically significant. The results of previous studies have indicated a paradoxical effect whereby children in regions with a lower exposure to malarial infection suffer, in the long term, a higher incidence of severe attacks of malaria. In the present study there was no sign of any such paradoxical inverse relationship between the level of exposure and the prevalence of malarial illness or anaemia. However, child mortality rates are similar in the highlands and lowlands, as are the median ages of children admitted to hospital. Overall, the present findings indicate that, for the populations studied, an artificial reduction in EIR would be beneficial, even in the long term, with regard to the chronic effects of malaria. This does not necessarily conflict with previous studies reporting opposite conclusions with regard to the incidence of severe,acute effects.

Altitude↗
PubMed1995

Particulate methane monooxygenase genes in methanotrophs.

A 45-kDa membrane polypeptide that is associated with activity of the particulate methane monooxygenase (pMMO) has been purified from three methanotrophic bacteria, and the N-terminal amino acid sequence was found to be identical in 17 of 20 positions for all three polypeptides and identical in 14 of 20 positions for the N terminus of AmoB, the 43-kDa subunit of ammonia monooxygenase. DNA from a variety of methanotrophs was screened with two probes, an oligonucleotide designed from the N-terminal sequence of the 45-kDa polypeptide from Methylococcus capsulatus Bath and an internal fragment of amoA, which encodes the 27-kDa subunit of ammonia monooxygenase. In most cases, two hybridizing fragments were identified with each probe. Three overlapping DNA fragments containing one of the copies of the gene encoding the 45-kDa pMMO polypeptide (pmoB) were cloned from Methylococcus capsulatus Bath. A 2.1-kb region was sequenced and found to contain both pmoB and a second gene, pmoA. The predicted amino acid sequences of these genes revealed high identity with those of the gene products of amoB and amoA, respectively. Further hybridization experiments with DNA from Methylococcus capsulatus Bath and Methylobacter albus BG8 confirmed the presence of two copies of pmoB in both strains. These results suggest that the 45- and 27-kDa pMMO-associated polypeptides of methanotrophs are subunits of the pMMO and are present in duplicate gene copies in methanotrophs.

Amino Acid Sequence↗