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S W Martin

Publications and source records attributed to S W Martin.

At least 37 records · Page 2Linked to original sources
PubMed2001

Targeting peptide nucleic acid (PNA) oligomers to mitochondria within cells by conjugation to lipophilic cations: implications for mitochondrial DNA replication, expression and disease.

The selective manipulation of mitochondrial DNA (mtDNA) replication and expression within mammalian cells has proven difficult. One promising approach is to use peptide nucleic acid (PNA) oligomers, nucleic acid analogues that bind selectively to complementary DNA or RNA sequences inhibiting replication and translation. However, the potential of PNAs is restricted by the difficulties of delivering them to mitochondria within cells. To overcome this problem we conjugated a PNA 11mer to a lipophilic phosphonium cation. Such cations are taken up by mitochondria through the lipid bilayer driven by the membrane potential across the inner membrane. As anticipated, phosphonium-PNA (ph-PNA) conjugates of 3.4-4 kDa were imported into both isolated mitochondria and mitochondria within human cells in culture. This was confirmed by using an ion-selective electrode to measure uptake of the ph-PNA conjugates; by cell fractionation in conjunction with immunoblotting; by confocal microscopy; by immunogold-electron microscopy; and by crosslinking ph-PNA conjugates to mitochondrial matrix proteins. In all cases dissipating the mitochondrial membrane potential with an uncoupler prevented ph-PNA uptake. The ph-PNA conjugate selectively inhibited the in vitro replication of DNA containing the A8344G point mutation that causes the human mtDNA disease 'myoclonic epilepsy and ragged red fibres' (MERRF) but not the wild-type sequence that differs at a single nucleotide position. Therefore these modified PNA oligomers retain their selective binding to DNA and the lipophilic cation delivers them to mitochondria within cells. When MERRF cells were incubated with the ph-PNA conjugate the ratio of MERRF to wild-type mtDNA was unaffected, even though the ph-PNA content of the mitochondria was sufficient to inhibit MERRF mtDNA replication in a cell-free system. This unexpected finding suggests that nucleic acid derivatives cannot bind their complementary sequences during mtDNA replication. In summary, we have developed a new strategy for targeting PNA oligomers to mitochondria and used it to determine the effects of PNA on mutated mtDNA replication in cells. This work presents new approaches for the manipulation of mtDNA replication and expression, and will assist in the development of therapies for mtDNA diseases.

Binding Sites↗
PubMed2001

Development of a novel, nonimmunogenic, soluble human TNF receptor type I (sTNFR-I) construct in the baboon.

Pharmacokinetics and immunogenicity of six different recombinant human soluble p55 tumor necrosis factor (TNF) receptor I (sTNFR-I) constructs were evaluated in juvenile baboons. The constructs included either an sTNFR-I IgG1 immunoadhesin (p55 sTNFR-I Fc) or five different sTNFR-I constructs covalently linked to polyethylene glycol. The constructs were administered intravenously three times, and pharmacokinetics and immunogenicity were examined over 63 days. All of the constructs were immunogenic, with the exception of a 2.6-domain monomeric sTNFR-I. To evaluate whether the nonimmunogenic 2.6-domain monomeric construct could protect baboons against TNF-alpha-induced mortality, baboons were pretreated with 1, 5, or 10 mg/kg body wt and were compared with baboons receiving either placebo or 1 mg/kg body wt of the dimeric 4.0-domain sTNFR-I construct (n = 3 each) before lethal Escherichia coli bacteremia. The monomeric construct protected baboons and neutralized TNF bioactivity, although greater quantities were required compared with the dimeric 4.0-domain sTNFR-I construct. We conclude that E. coli-recombinant-derived human sTNFR-I constructs can be generated with minimal immunogenicity on repeated administration and still protect against the consequences of exaggerated TNF-alpha production.

Amino Acid Sequence↗
PubMed2001

The relationship between the occurrence of undifferentiated bovine respiratory disease and titer changes to bovine coronavirus and bovine viral diarrhea virus in 3 Ontario feedlots.

Serological evidence of previous viral exposure (titer at arrival) and current viral exposure (titer increase) during a 28-day study period, was used to determine if bovine coronavirus (BCV) or bovine viral diarrhea virus (BVDV) was associated with the occurrence of undifferentiated bovine respiratory disease (UBRD) in feedlot calves. Neutralizing antibody titers to BCV and BVDV were determined for 852 animals from 3 Ontario feedlots. Calves at 2 of the 3 feedlots (n = 753) received a modified live 4-way viral vaccine containing BVDV. On arrival at the feedlots, 90% of animals were seropositive for BCV, while 39% of animals were seropositive for BVDV. This evidence of previous exposure to both viruses was associated with reduced subsequent UBRD risk. Evidence of exposure to BCV during the study period was common, as 50% of animals showed a 16-fold or greater titer increase; however, treatment for UBRD was not associated with titer change. Although the majority of animals were vaccinated for BVDV at arrival, within a feedlot, animals treated for UBRD had larger titer increases to BVDV than non-treated animals. Based on our findings we infer that BCV was not causally related to UBRD occurrence, however consistent with other literature, BVDV may be causally related to UBRD occurrence.

Animals↗
PubMed2001

The relationship between the occurrence of undifferentiated bovine respiratory disease and titer changes to Haemophilus somnus and Mannheimia haemolytica at 3 Ontario feedlots.

The association between exposure to Haemophilus somnus and Mannheimia haemolytica (formerly Pasteurella haemolytica) and the risk of undifferentiated bovine respiratory disease (UBRD) was investigated using serological evidence of exposure coupled with a factorial design vaccine field trial. Measures of previous exposure (titer at arrival) and current exposure (titer increase in the study period) to these agents were used. The vaccine field trial involved systematic allocation of animals into groups that received either a M. haemolytica vaccine, an H. somnus vaccine, a combined M. haemolytica and H. somnus vaccine, and an unvaccinated control group. Serum was collected from the 852 animals enrolled to determine titers to H. somnus, M. haemolytica, bovine coronavirus and bovine viral diarrhea virus. Vaccination with H. somnus in combination with M. haemolytica and with M. haemolytica alone reduced the risk of UBRD. The odds ratio for vaccination with H. somnus alone and UBRD risk suggested some sparing effect, but the 95% confidence limits included unity. There was no association between serological evidence of concurrent exposure to M. haemolytica and UBRD occurrence. There was an association between titer change to H. somnus and UBRD risk. However, the association changed with time of BRD treatment; animals diagnosed and treated for UBRD on or after day 10 showed little evidence of exposure to H. somnus, despite evidence of natural H. somnus exposure in the unvaccinated group. The association between titer change to H. somnus and UBRD occurrence seen in this study may be a consequence of prolonged exposure to antibiotics, rather than a causal association.

Animals↗
PubMed2001

Evaluation of the importance of head and probe stabilisation in acoustic rhinometry.

As yet there is no established procedure to ensure the repeatability of acoustic rhinometry measurements although anecdotal evidence suggests that instrument fixation improves repeatability. The aim of this study is to validate the methodology of acoustic rhinometry and determine whether instrument fixation and head stabilisation is necessary. Four methods were compared in fifteen healthy volunteers, after nasal decongestion: A) Patient holding the probe (patient-held), B) Probe fixed in a probe stand (probe-stand), C) Probe fixed in stand and head stabilised in head rest (head-rest), D) Examiner holding the probe (examiner-performed). The two minimum cross-sectional areas and volume between 0 and 5 cm were recorded. The examiner-performed and probe-stand methods were consistently less variable than the other methods. With examiner-performed method, this was significant (p < 0.05) versus head-rest and patient-held methods for both measures of minimum cross-sectional area. For nasal volume the examiner-performed method was significantly (p < 0.05) less variable than the head-rest method. In conclusion, examiner-performed acoustic rhinometry is more repeatable than combined head stabilisation and instrument fixation and therefore the use of a head-rest may be unnecessary. Instrument fixation or examiner performed test is also preferable to allowing the patient to position the probe. The repeatability of the probe-stand method was similar to the examiner-performed method.

Adult↗
PubMed2000

Estimation of the under-reporting rate for the surveillance of Escherichia coli O157:H7 cases in Ontario, Canada.

Two models estimating the proportion of Escherichia coli O157:H7 cases not reported in the Ontario notifiable diseases surveillance system are described. The first model is a linear series of adjustments in which the total number of reported cases is corrected by successive underreporting coefficients. The structure of the second model is based on a relative difference in the proportion of E. coli O157:H7 cases which are hospitalized between the surveillance database and the underlying population. Based on this analysis, the rate of under-reporting of symptomatic cases of E. coli O157:H7 infection in Ontario ranges from 78 to 88% corresponding to a ratio of 1 reported case for approximately 4-8 symptomatic cases missed by the surveillance system. This study highlights the need to increase awareness among public health workers of the potential biases that may exist in the interpretation of routine surveillance data.

Escherichia coli Infections↗
PubMed2000

A dark, firm dry-like condition in turkeys condemned for cyanosis.

A case-control study (n = 130) was conducted on toms condemned for cyanosis. Color (CIE L*a*b*), pH, and physical characteristics were measured on the Pectoralis major at slaughter and after 24 h. Meat from carcasses condemned for cyanosis had dark, firm, dry-like traits. It was darker and redder and showed higher water-holding capacity, lower cooking loss, and higher gel strength than did controls. Perimortem pH was negatively correlated with the lightness (L*) of meat at the time of slaughter (r = -0.58) and at 24 h postmortem (r = -0.64), positively correlated with water-holding capacity (r = 0.73) and gel strength (r = 0.43) and negatively correlated with cooking loss (r = -0.50). Ultimate pH was negatively correlated with lightness (L*) of meat at slaughter time (r = -0.62) and at 24 h postmortem (r = 0.79) was positively correlated with water-holding capacity (r = 0.87) and gel strength (r = 0.61) and negatively correlated with cooking loss (r = -0.52). Tests based on pH and L* of the P. major were also assessed; tests based on pH had a sensitivity in the range of 0.79 to 0.89 and specificity (Sp) of 0.60 to 0.94. Tests based on L* showed sensitivity of 0.75 to 0.92, and specificity of 0.79 to 0.97. The repeatability of measurements varied from good (L*: rho = 0.6) to excellent (pH: rho = 0.92). Overall, turkey breast condemned for cyanosis showed dark, firm, dry-like traits. Tests based on color and pH are described as a means of identifying turkeys condemned for cyanosis.

Animals↗
PubMed2000

Spatial distribution of cannibalism mortalities in commercial laying hens.

The distribution of cannibalism cases in a flock of 19,776 Babcock White Leghorns was monitored from 21 to 54 wk of age. The hens were kept in a single-floor house consisting of four banks of two-deck stair-step cages. Each of the 4,944 cages held four hens at a density of 152 cm(2) (60 inches(2)) per hen. Each cage was assigned a number from 1 to 4,944, and each dead bird was tagged according to its cage of origin. Dead birds were collected daily, kept in a freezer, and necropsied weekly. Farm personnel routinely transferred a live hen from an end cage to a cage where a mortality had occurred. The cause of death, age, cage number, and cage location were recorded for each dead hen. Of the 1,173 hens that died during the study period, 253 (21.6%) died from egg peritonitis, 184 (15.7%) from hypocalcemia, 167 (14.1%) from cannibalism, 164 (14%) from neoplastic disease, and the rest from various other causes. Cannibalism cases were analyzed statistically for clustering. Cannibalism was defined as death from tissue trauma and hemorrhage inflicted by cage mates. A spatial analysis showed that cannibalism is not a random event but one that occurs in clusters. The incidence of cannibalism was also found to be significantly higher on the top rows of cages as compared with the bottom rows.

Age Factors↗
PubMed2000

Risk factors for abattoir condemnation of turkey carcasses due to cyanosis in southern Ontario.

Cyanosis is a category of condemnation for poultry, as defined by Agriculture and Agrifood Canada. A retrospective study to examine the seasonal patterns and trends for turkey cyanosis condemnation was conducted for the years 1987 to 1995 with the use of condemnation records made available by a single abattoir in Ontario. Condemnation for cyanosis had a significant seasonal pattern, with major losses occurring in the colder months (October to March). A prospective longitudinal study was conducted during January to March and October to December 1996 in the same abattoir and the 75 turkey farms that contracted to process their birds through it and all the 913 truckloads of turkeys processed in these two 3-mo periods. The data from this prospective study were used for multivariate modeling of the effects of potential risk factors on the incidence of cyanosis. Risk factors (at P < or = 0.05) included bird type (broiler age turkeys, mature toms, and mature hens compared to toms and hens), ambient temperature (cold: -9.9 to 0.0 C and very cold: < or =-10.0 C compared to mild: >0.0 C), clean-out lot (the last shipped from a poultry house), shipping time > or =8 h, and emaciation (proportion of turkeys in the lot condemned for insufficient muscle mass). The crate density was a sparing factor, and an increase in turkey density during shipping resulted in a lower incidence of cyanosis. This study suggested that the number of turkeys condemned for cyanosis was associated with cold, shipping stress, and subclinical syndromes.

Abattoirs↗
PubMed2000

Roaster breast meat condemned for cyanosis: a dark firm dry-like condition?

A case-control study (n = 68) of roaster chickens condemned for cyanosis was conducted. Color (CIE L*a*b*) and pH were measured at slaughter, and after 24 h aging on ice, at four predetermined sites of the Pectoralis major. Cyanotic carcasses (dark) had a higher pH than controls at the time of slaughter and at 24 h postmortem (P < 0.01). Perimortem pH was significantly correlated with pH at 24 h postmortem (r = 0.64) and also was correlated with lightness (L*) perimortem and postmortem (24 h; r = -0.36 and -0.50, respectively). Perimortem pH was not correlated with meat redness (a*) at slaughter time and after 24 h. Ultimate pH and lightness at 24 h postmortem were also correlated. Tests based on pH, L*, and a* of the P. major were assessed: the sensitivity and specificity at various cut-off points were, respectively, pH(6.3) = 76.47 and 88.24%, L*(41) = 91.18 and 79.41%, and a*(3) = 76.47 and 97.06%. The repeatability (p) of pH and color measurements was excellent and ranged from 0.87 to 0.98. Breast meat from roasters condemned for cyanosis had dark, firm, and dry (DFD)-like traits, and accurate tests based on color and pH could be described as a means of identifying chickens condemned for cyanosis.

Animals↗
PubMed2000

Bacteriological and histological profile of turkeys condemned for cyanosis.

Canadian Food Inspection Agency (CFIA) has adopted the term cyanosis to describe a category of condemnation for poultry that is dark but has no other condemnable lesions. Two case-control studies (n = 30 pairs; n = 65 pairs) of 18-wk-old tom turkeys were conducted. A case was defined as a carcass condemned by the veterinary inspector for cyanosis, and a control carcass was one that passed inspection. Microbiological tests were conducted on samples of Pectoralis major and Gastrocnemius lacteralis. A modified Rappaport Vassiliadis medium was used for Salmonella, and a Petrifilm method was used to assess aerobic counts, coliform counts, and Escherichia coli. The Salmonella (qualitative) test was negative for all cases and controls, and there were no significant differences between the aerobic counts, coliform counts, and E. coli counts of case and control carcasses. Two pathologists conducted a blind histopathological study: there were no lesions compatible with those of septicemia-toxemia, as defined by CFIA and the USDA, nor any significant histopathological differences between the skin, P. major, G. lateralis, kidney, liver, spleen, small intestine, pancreas, lung, and heart of cases and controls. The inter-rater agreement between pathologists ranged from good to excellent (Kappa = 0.7 to 1.0). In the absence of important lesions and microbial contamination, carcasses with this color change alone should be suitable for human consumption.

Animals↗
PubMed2000

Long-term regulation of renal Na-dependent cotransporters and ENaC: response to altered acid-base intake.

Increased systemic acid intake is associated with an increase in apical Na/H exchange in the renal proximal tubule mediated by the type 3 Na/H exchanger (NHE3). Because NHE3 mediates both proton secretion and Na absorption, increased NHE3 activity could inappropriately perturb Na balance unless there are compensatory changes in Na handling. In this study, we use semiquantitative immunoblotting of rat kidneys to investigate whether acid loading is associated with compensatory decreases in the abundance of renal tubule Na transporters other than NHE3. Long-term (i.e., 7-day) acid loading with NH(4)Cl produced large decreases in the abundances of the thiazide-sensitive Na-Cl cotransporter (TSC/NCC) of the distal convoluted tubule and both the beta- and gamma-subunits of the amiloride-sensitive epithelial Na channel (ENaC) of the collecting duct. In addition, the renal cortical abundance of the proximal type 2 Na-dependent phosphate transporter (NaPi-2) was markedly decreased. In contrast, abundances of the bumetanide-sensitive Na-K-2Cl cotransporter of the thick ascending limb and the alpha-subunit of ENaC were unchanged. A similar profile of changes was seen with short-term (16-h) acid loading. Long-term (7-day) base loading with NaHCO(3) resulted in the opposite pattern of response with marked increases in the abundances of the beta- and gamma-subunits of ENaC and NaPi-2. These adaptations may play critical roles in the maintenance in Na balance when changes in acid-base balance occur.

Acid-Base Equilibrium↗
PubMed2000

Phase I/II trial of recombinant methionyl human tumor necrosis factor binding protein PEGylated dimer in patients with active refractory rheumatoid arthritis.

OBJECTIVE: To evaluate the safety, immunogenicity, pharmacokinetics, and efficacy of intravenous administration of tumor necrosis factor binding protein (TNFbp) dimer in patients with rheumatoid arthritis (RA). METHODS: This phase I/II study was a multicenter, randomized, double blind, placebo controlled, ascending dose study evaluating TNFbp dimer administered by i.v. infusion. Thirty-three patients with RA divided into 3 cohorts received TNFbp dimer (30, 100, 300 microg/kg) or placebo during a 5 min infusion at baseline and at 3 and 6 weeks; patients were followed at routine intervals after each infusion through 77 days postinfusion. Pharmacokinetics were analyzed using a log-linear regimen and comparisons were made between half-life after first, 2nd, and 3rd doses. Plasma TNFbp dimer concentrations and serum antibody levels were used in the measurement of pharmacokinetics. RESULTS: Administration of 30 microg/kg of TNFbp dimer was generally well tolerated; the maximum tolerated dose was 100 microg/kg. No serious adverse events were reported. A significant antibody response affected the half-life and clearance of TNFbp dimer at each dose group. Anti-TNFbp antibodies were noncytotoxic and nonagonistic. Clinical evaluations provided evidence of in vivo activity of TNFbp dimer in these patients. CONCLUSION: TNFbp dimer administered to patients with long standing RA resulted in significant antibody production to the study drug. This effect reduced the half-life and clearance of the TNFbp. This TNFbp will not be a viable option for treating patients with RA secondary to immunogenicity.

Adult↗
PubMed2000

Canine heartworm testing in Canada: are we being effective?

Mass testing of dogs in Canada for the presence of Dirofilaria immitis has been ongoing since 1977. Since that time, there have also been changes in the diagnostic tests available to detect the presence of heartworm and changes in the therapy for heartworm, which necessitate a reevaluation of heartworm screening as currently practiced in Canada. The principles of evidence-based medicine were used to determine the prevalence of heartworm infection in various dog populations, and the effectiveness of screening these populations. The annual surveys of heartworm testing have shown that Canada is a low prevalence area (0.16%), with most of the test-positive dogs located in southern Ontario (0.19%), southern Manitoba (0.18%), southern Quebec (0.09%), and the southern Okanagan Valley (0.04%). Foci of higher prevalence are found within these 4 main geographic areas. Furthermore, the prevalence of heartworm infection is higher in the population of dogs not on preventative medication (0.62%), when compared to the population of dogs on preventative medication (0.04%). The evidence indicates that a heartworm diagnostic test applied to an asymptomatic dog on preventative medication contributes little information regarding the heartworm infection status of that dog. However, testing of a dog characterized as being high risk will provide clinically useful information. Recommendations regarding the testing of dogs for heartworm in Canada are derived on the basis of available evidence.

Animals↗
PubMed1999

Factors associated with being a bovine-virus diarrhoea (BVD) seropositive dairy herd in the Møre and Romsdal County of Norway.

Factors associated with being a bovine-virus diarrhoea (BVD) seropositive dairy herd were studied in a case-control study of 314 dairy herds in the Møre and Romsdal County of Norway. Information was collected through a mailed questionnaire, and associations were modeled using conditional logistic regression after selecting variables by a best-subset procedure. Purchasing of animals, use of common pasture, herd-to-herd contact over pasture fences, purchasing cattle with insufficient health (about BVD) documentation, and not using dairy advisors were associated with higher risk. In addition, younger farmers were more likely to have a bovine-virus diarrhoea seropositive herd than older farmers. 'Other animal traffic', including use of common animal housing in the summer months and exchange of calves between farmers were also risk factors. Collectively, these factors could explain 51% of the seropositive herds.

Animals↗
PubMed1999

Temporal and geographical distributions of reported cases of Escherichia coli O157:H7 infection in Ontario.

The distribution of 3001 cases of verocytotoxigenic Escherichia coli (VTEC) reported in the Province of Ontario, Canada, were examined to describe the magnitude of this condition geographically and to evaluate the spatial relationship between livestock density and human VTEC incidence using a Geographical Information System. Incidence of VTEC cases had a marked seasonal pattern with peaks in July. Areas with a relatively high incidence of VTEC cases were situated predominantly in areas of mixed agriculture. Spatial models indicated that cattle density had a positive and significant association with VTEC incidence of reported cases (P = 0.000). An elevated risk of VTEC infection in a rural population could be associated with living in areas with high cattle density. Results of this study suggested that the importance of contact with cattle and the consumption of contaminated well water or locally produced food products may have been previously underestimated as risk factors for this condition.

Agriculture↗