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Biomedical subjects

P Watson

Publications and source records attributed to P Watson.

At least 55 records · Page 3Linked to original sources
PubMed2000

Hyperinsulinemia enhances transcriptional activity of nuclear factor-kappaB induced by angiotensin II, hyperglycemia, and advanced glycosylation end products in vascular smooth muscle cells.

Pathogenesis of macrovascular complications of diabetes may involve an activation of the transcription factor nuclear factor-kappaB (NF-kappaB) by hyperglycemia and advanced glycosylation end products (AGEs). Activation of NF-kappaB is believed to be dependent on activation of the Rho family of GTPases. Although the precise mechanism of the Rho-mediated action is not completely understood, posttranslational modification of the Rho proteins by geranylgeranylation is required for their subsequent activation. We observed that in cultured vascular smooth muscle cells (VSMCs), insulin stimulated the activity of geranylgeranyltransferase (GGTase) I and increased the amounts of geranylgeranylated Rho-A from 47% to 60% (P:<0.05). GGTI-286, an inhibitor of GGTase I, blocked both effects of insulin. Increased availability of prenylated Rho-A significantly augmented the abilities of angiotensin II (Ang II), hyperglycemia, and AGEs to activate NF-kappaB, as measured by NF-kappaB response-element luciferase reporter activity. Preincubations of VSMCs with insulin for 24 hours doubled NF-kappaB transactivation by Ang II, hyperglycemia, and AGEs. This priming effect of insulin was completely inhibited by GGTI-286. We demonstrate for the first time, to our knowledge, that insulin potentiates NF-kappaB-dependent transcriptional activity induced by hyperglycemia, AGEs, and Ang II in VSMCs by increasing the activity of GGTase I and the availability of geranylgeranylated Rho-A.

Alkyl and Aryl Transferases↗
PubMed2000

Somatic mutation in MECP2 as a non-fatal neurodevelopmental disorder in males.

Rett syndrome is a cause of severe learning disability in girls and is associated with a characteristic history and movement disorder. It is an X-linked dominant condition associated with mutations of the MECP2 gene on the distal part of the X-chromosome. If present in a male conceptus, the mutation is usually lethal. We present evidence to show that males can be affected by Rett syndrome. In the boy presented, this situation came about because cells containing the MECP2 mutation existed alongside a normal cell line. Somatic mosaicism could explain the occurrence of other X-linked dominant disorders in males, when they would normally be lethal.

Chromosomal Proteins, Non-Histone↗
PubMed2000

Efficacy of selamectin against adult flea infestations (Ctenocephalides felis felis and Ctenocephalides canis) on dogs and cats.

Selamectin was evaluated in eight controlled studies (4 in dogs, 4 in cats) to determine the efficacy of a single topical unit dose providing the recommended minimum dosage of 6mgkg(-1) against Ctenocephalides felis felis and Ctenocephalides canis fleas on dogs and against C. felis on cats. In addition, the effect of bathing on the efficacy of selamectin against C. felis was evaluated. Identical studies were performed in Beagles and domestic shorthaired cats. For each study, animals were allocated randomly to treatments of 8-12 animals each. All studies (dog studies A, B, C, and D and cat studies A, B, C, and D) evaluated the efficacy of selamectin without bathing. In addition, study C in both dogs and cats evaluated efficacy with a shampoo bath at 24h after dosing, and study D evaluated the efficacy of selamectin with water soaking at 2h after dosing or with a shampoo bath at 2-6h after dosing. Dog study B evaluated efficacy against C. canis, whereas all other studies used C. felis. In each study, selamectin was administered on day 0 as a topical dose that was applied directly to the skin in a single spot at the base of the neck in front of the scapulae. Dogs and cats were infested with approximately 100 viable unfed C. felis or C. canis on days 4, 11, 18, and 27. On days 7, 14, 21, and 30, approximately 72h after infestation, a comb count of the number of viable fleas present on each animal was made. For C. felis and C. canis for dogs and cats, compared with controls, selamectin achieved significant reductions in geometric mean adult flea comb counts of > or =98.9% on days 7, 14, and 21 in all eight studies. On day 30, the reduction for C. felis remained at or above 98.0%. This included the dogs and cats that were soaked with water or bathed with shampoo at 2, 6, or 24h after treatment. There were no significant (P>0.05) differences between the flea counts from selamectin-treated animals in these studies, regardless of bathing status. On day 30, a significant reduction of 91.8% was achieved against C. canis on dogs. Thus, these studies demonstrated that a single topical unit dose of selamectin was highly effective against adult fleas on dogs and cats for at least 27 days.

Administration, Topical↗
PubMed2000

Efficacy of selamectin in the treatment and prevention of flea (Ctenocephalides felis felis) infestations on dogs and cats housed in simulated home environments.

The efficacy of selamectin, a novel avermectin, in protecting dogs and cats against experimentally induced environmental flea (Ctenocephalides felis felis) infestations, was evaluated in a series of controlled and masked studies. Purpose-bred shorthaired cats and Beagles were randomly allocated to treatment with either selamectin at a minimum dosage of 6mgkg(-1) of body weight in the commercial formulation or the negative control treatment (vehicle only), and housed in controlled simulated home environments capable of supporting the flea life cycle. Day 0 was defined as the first day of treatment. Treatments were administered topically in a single spot on the skin at the base of the neck in front of the scapulae. In environmental challenge studies, which were designed to evaluate the efficacy of selamectin in the treatment and control of established flea infestations, dogs and cats were each infested with 100 fleas on days -28 and -21 and placed in carpeted rooms in order to establish high levels of active flea infestation prior to day 0. Treatments were administered monthly for 3 months. Flea comb counts were performed on days 14, 29, 44, 59, 74, and 90. Reductions in geometric mean flea comb counts for selamectin, compared with vehicle, were >99% from day 14 onwards for dogs, and >92% on day 29 and >99% on days 44, 59, 74, and 90 for cats (P=0.0001). In prevention of environmental infestation studies, dogs and cats were placed in environments capable of supporting flea infestations and given monthly treatments for 2 months, commencing on day 0. Animals were infested with 100 fleas on days 1 and 7, and flea comb counts were performed on days 29, 44, and 60. Reductions in geometric mean flea comb counts for selamectin, compared with vehicle, were >99% on days 29, 44, and 60 (P=0.0001) for dogs and cats. Monthly administration of selamectin to dogs and cats housed in environments highly suited to completion of the flea life cycle was shown to be highly effective in the treatment and prevention of flea infestations, without the need for supplementary environmental control measures.

Administration, Topical↗
PubMed2000

Efficacy and safety of selamectin against fleas on dogs and cats presented as veterinary patients in Europe.

Two controlled and masked multi-centre studies were conducted to examine the efficacy of a novel topical avermectin, selamectin, against natural flea infestations on 418 dogs and 345 cats. Veterinary patients with viable flea infestations were enrolled in the studies, which were conducted in United Kingdom, France, Germany, and Italy. Animals were allocated randomly in a 2:1 ratio to one of two treatments: either selamectin alone at a minimum dosage of 6mgkg(-1) or fenthion at recommended dose rates. Concurrent use of an environmental spray (containing methoprene and either pyrethrins or permethrin) was permitted only for fenthion-treated animals. In-contact cats and dogs (animals living in the same home) received the same treatment as the first animal enrolled from the household, if recommended by the veterinarian. Study day 0 was defined as the day of first treatment. Animals were treated on days 0, 30, and 60, and flea comb counts and clinical evaluations were conducted on days 0, 14, 30, 60, and 90. Analysis of variance of ln(flea count+1) showed that values were significantly lower for selamectin alone compared with fenthion (with or without the concurrent use of an environmental spray) in dogs on days 30, 60, and 90 (P<0.05) and in cats on days 14, 30, 60, and 90 (P<0.01). For selamectin, the reductions in geometric mean flea counts on days 14, 30, 60, and 90, compared with day 0, were 92.5, 90.7, 98.1, and 99.1%, respectively, for dogs and 92.8, 92.7, 97.7, and 98.4%, respectively, for cats. Selamectin was shown to be safe and highly effective in the control of naturally acquired flea infestations on dogs and cats presented as veterinary patients in Europe.

Animals↗
PubMed2000

Prevention of experimentally induced heartworm (Dirofilaria immitis) infections in dogs and cats with a single topical application of selamectin.

In a series of six controlled studies (four in dogs, two in cats), heartworm-free dogs and cats were inoculated with Dirofilaria immitis larvae (L(3)) prior to topical treatment with the novel avermectin selamectin or a negative control containing inert formulation ingredients (vehicle). Selamectin and negative-control treatments were administered topically to the skin at the base of the neck in front of the scapulae. In dogs, selamectin was applied topically at dosages of 3 or 6mgkg(-1) at 30 days post-inoculation (PI), or of 3 or 6mgkg(-1) at 45 days PI, or of 6mgkg(-1) at 60 days PI. Cats were treated topically with unit doses providing a minimum dosage of 6mgkg(-1) selamectin at 30 days PI. Of the animals that were treated 30 days PI, some dogs were bathed with water or shampoo between 2 and 96h after treatment, and some cats were bathed with shampoo at 24h after treatment. Between 140 and 199 days PI, the animals were euthanized and examined for adult D. immitis. Adult heartworms developed in all control dogs (geometric mean count, 18.7 worms) and in 88% of control cats (geometric mean count, 2.1 worms). Selamectin was 100% effective in preventing heartworm development in dogs when administered as a single topical dose of 3 or 6mgkg(-1) at 30 days after infection, 3 or 6mgkg(-1) at 45 days after infection, or 6mgkg(-1) at 60 days after infection. Selamectin was 100% effective against heartworm infections in cats when administered as a single topical unit dose of 6mgkg(-1). Bathing with water or shampoo between 2 and 96h after treatment did not reduce the efficacy of selamectin as a heartworm prophylactic in dogs. Likewise, bathing with shampoo at 24h after treatment did not reduce the efficacy of selamectin in cats. These studies demonstrated that, at the recommended dosage and treatment interval, a single topical administration of selamectin was 100% effective in preventing the development of D. immitis in dogs and cats.

Administration, Topical↗
PubMed2000

The efficacy of selamectin in the treatment of naturally acquired aural infestations of otodectes cynotis on dogs and cats.

The efficacy of a novel avermectin, selamectin, was evaluated against naturally acquired aural infestations of Otodectes cynotis on dogs and cats. In four controlled and masked studies conducted in the USA and Europe, animals were allocated randomly to treatment with either selamectin at a minimum dosage of 6mgkg(-1) (range, 6-12. 5mgkg(-1)) or the vehicle only from the commercial formulation of selamectin (negative control). Treatments were administered topically in a single spot to the skin of each animal's back at the base of the neck in front of the scapulae. Cats were treated on day 0 only, and dogs were treated either on day 0 only or on days 0 and 30. The ears of dogs were examined otoscopically on day 14 for the presence of viable mites. Mite counts were conducted on day 30 for animals that had received one dose and on day 60 for animals that had received two doses. Percentage reductions in geometric mean mite counts for selamectin treatment compared with the vehicle were 100% for all animals on all count days. Analysis of variance, confirmed by Savage Scores, showed that ln(mite count+1) values were significantly (P< or =0.0015) lower for selamectin than for the vehicle for all animals on all count days. Thus, selamectin administered topically at a minimum dosage of 6mgkg(-1) was safe and 100% effective against naturally acquired aural infestations of O. cynotis in dogs and cats after a single dose or after two doses administered 1 month apart.

Administration, Topical↗
PubMed2000

Efficacy and safety of selamectin against Sarcoptes scabiei on dogs and Otodectes cynotis on dogs and cats presented as veterinary patients.

A series of randomized, controlled and masked field studies was conducted in veterinary patients to evaluate the efficacy of selamectin, a novel avermectin, in the treatment of naturally occurring Sarcoptes scabiei infestations on dogs and Otodectes cynotis infestations on dogs and cats. A total of 342 dogs and 237 cats participated in these studies, which were conducted at 40 veterinary practices in the USA and Europe. Animals were randomly assigned to treatment with selamectin or a positive-control product (existing approved products). Selamectin was administered as a unit dose providing a minimum of 6mgkg(-1) (range: 6-12mgkg(-1)) in a topical preparation applied to the skin in a single spot on day 0 (O. cynotis in cats, n=144), or on days 0 and 30 (O. cynotis and S. scabiei in dogs, n=83 and n=122, respectively). The presence of parasites was assessed before treatment and at 30 days (for all studies) and 60 days (for O. cynotis and S. scabiei dog studies) after first treatment. The animals were also evaluated clinically at each assessment period. Based on skin scrapings, the efficacy of selamectin against S. scabiei infestations on dogs was >95% by day 30, and 100% by day 60. Against O. cynotis, selamectin eliminated mites in 94-100% of cats by day 30, and in 90% of dogs by day 60. The positive-control products achieved similar results. Thus, selamectin was safe and effective against ear mites in dogs and cats and sarcoptic mange in dogs when used in field (veterinary patient) studies in dogs and cats of a wide variety of ages and breeds.

Administration, Topical↗
PubMed2000

Efficacy and safety of selamectin against gastrointestinal nematodes in cats presented as veterinary patients.

A series of randomized, controlled, masked, field (veterinary patient) studies were conducted in the USA and Europe to evaluate the efficacy of selamectin, a novel macrocyclic lactone of the avermectin subclass, in the treatment of naturally acquired gastrointestinal nematode infections in cats. After confirmation of ascarid and/or hookworm infection, 298 cats of various ages and breeds were randomly assigned to treatment with selamectin (n=202) or an existing commercially approved positive-control product (n=96). Unit doses of selamectin (providing a minimum dosage of 6mgkg(-1)) were administered topically to the skin in a single spot at monthly intervals. Quantitative fecal examinations were performed on days 0 (before treatment), 30, and 60. In the selamectin-treated cats, fecal ascarid egg counts were reduced by 99.6 to 100% on day 30, and by 99.9 to 100% on day 60. Fecal hookworm egg counts were reduced by 98.3% on day 30, and by 100% on day 60 in the selamectin-treated cats. The positive-control products achieved reductions in egg counts of 96.5 to 100% (ascarids) and 98.9 to 99.9% (hookworms). These studies have shown that monthly topical administration of selamectin is safe and highly effective in the treatment of naturally acquired ascarid and hookworm infections in cats.

Ancylostomatoidea↗
PubMed2000

Histology of prophylactically removed ovaries from BRCA1 and BRCA2 mutation carriers compared with noncarriers in hereditary breast ovarian cancer syndrome kindreds.

OBJECTIVE: The literature reports conflicting studies claiming premalignant histological features in benign ovaries from women who may have hereditary predilections for ovarian carcinoma. To test the veracity of these claims, this investigation studied ovaries prophylactically removed from members of hereditary breast ovarian cancer (HBOC) syndrome families who carry BRCA1 and BRCA2 mutations and compared these with the ovaries of mutation-negative women from the same HBOC syndrome kindred. METHODS: Sixty cases of women from HBOC syndrome families who had undergone prophylactic oophorectomies and whose BRCA1 and BRCA2 mutation status had been tested were selected from our database. Thirty had tested positive for BRCA1 mutations, 3 carried BRCA2 mutations, and 27 were negative for both BRCA1 and BRCA2 germline mutations. Histologic material from each case was examined by light microscopy blinded to the mutation status. Histologic features, previously reported to be possible precursor lesions for ovarian cancer, were quantified. Data from BRCA1 and BRCA2 mutation carriers were compared with those from mutation-negative cases in the direct line of genetic inheritance from the same HBOC syndrome families. RESULTS: Statistical analysis found that a more frequent occurrence of ovarian surface micropapillae in 87% of mutation carriers compared with just 55% of mutation-negative cases was the only histologic feature which was significantly different between the two groups (P = 0.39). Cortical clefts tended to be deeper in the ovaries of mutation carriers, but this did not reach significance (P = 0.051). There were no other significant histologic differences between the ovaries removed from mutation carriers and those from noncarriers. CONCLUSIONS: The results of our large and prospectively controlled, blinded study contrast with those reported from smaller, unblinded investigations. Except for the possible biological significance of surface micropapillae on ovaries from BRCA1 and BRCA2 mutation carriers, we found no histologic evidence for a genetically determined ovarian carcinoma precursor lesion.

Adult↗
PubMed2000

The nature and staging of attention dysfunction in early (minimal and mild) Alzheimer's disease: relationship to episodic and semantic memory impairment.

The development of cholinergic therapies for Alzheimer's disease (AD) has highlighted the importance of understanding the role of attentional deficits and the relationship between attention and memory in the earliest stages of the disease. Variability in the tasks used to examine aspects of attention, and in the disease severity, between studies makes it difficult to determine which aspects of attention are affected earliest in AD, and how attentional impairment is related to other cognitive modules. We tested 27 patients in the early stages of the disease on the basis of the MMSE (minimal 24-30 corresponding to minimal cognitive impairment, very mild or possible AD in other classifications; and mild 18-23) on a battery of attentional tests aimed to assess sustained, divided, and selective attention, plus tests of episodic memory, semantic memory, visuoperceptual and visuospatial function, and verbal short-term memory. Although the mildly demented group were impaired on all attentional tests, the minimally impaired group showed a preserved ability to sustain attention, and to divide attention based on a dual-task paradigm. The minimally demented group had particular problems with response inhibition and speed of attentional switching. Examination of the relationship between attention and other cognitive domains showed impaired episodic memory in all patients. Deficits in attention were more prevalent than deficits in semantic memory suggesting that they occur at an earlier stage and the two were partially independent. Impairment in visuoperceptual and visuospatial functions and verbal short-term memory were the least common. Although attention is impaired early in AD, 40% of our patients showed deficits in episodic memory alone, confirming that amnesia may be the only cognitive deficit in the earliest stages of sporadic AD.

Aged↗
PubMed2000

Pharmacokinetics of a hematoregulatory peptide (SK&F107647) in healthy male volunteers and in patients with colorectal or pancreatic adenocarcinoma not amenable to standard therapy.

PURPOSE: To describe the pharmacokinetics of SK&F 107647, a synthetic hematoregulatory peptide, in healthy volunteers and in patients with adenocarcinoma. METHODS: SK&F 107647 pharmacokinetics were evaluated in 2 dose-escalation studies. Volunteers received SK&F 107647 as single 15-minute iv infusion doses of 1, 10, 100, 500, and 1,000 microg/kg. Cancer patients received 2-hour iv infusions of 0.001, 0.01, 0.1 and 1 microg/kg once daily for 10 days. Drug concentrations were quantified in plasma and urine of healthy volunteers and on days 1 and 10 in plasma of cancer patients receiving the two top dose levels. RESULTS: In volunteers, mean clearance (CL) ranged from 76.7 to 101 ml/hour/kg; mean volume of distribution at steady-state (Vss) ranged from 175 to 268 ml/kg. Most of the administered dose was renally excreted as intact peptide within 24 hours postinfusion. In patients, mean CL was 57.6 ml/hour/kg, mean Vss ranged from 128 to 150 ml/kg and terminal half-life from 2.1 to 3.4 hours. There was little accumulation of drug. In both studies, linear pharmacokinetics was observed. Clearance approached normal glomerular filtration rate (GFR) in volunteers and correlated with creatinine clearance in cancer patients. CONCLUSIONS: SK&F 107647 exhibits linear pharmacokinetics, a small Vss, and clearance, primarily renal, approaching normal GFR.

Adenocarcinoma↗
PubMed2000

Monoclonal antibodies recognizing CD5, CD10 and CD23 in formalin-fixed, paraffin-embedded tissue: production and assessment of their value in the diagnosis of small B-cell lymphoma.

AIMS: Assessment of the expression of antigens CD5, CD10 and CD23 can be of value in the differential diagnosis of small B-cell lymphoma. Correct subclassification is important since optimal treatment regimes differ between the subtypes. The aim of this study was to generate monoclonal antibodies recognizing these antigens in paraffin-embedded tissue and to assess their efficacy using a panel of cases of small B-cell lymphoma of various subtypes. METHODS AND RESULTS: For each antibody synthetic recombinant protein and conventional murine hybridoma technology was employed. Monoclonal antibodies effective in formalin-fixed, paraffin-embedded tissue were successfully generated, designated NCL-CD5-4C7, NCL-CD10-270 and NCL-CD23-1B12, respectively. A series of 58 cases of small B-cell lymphoma including examples of each subtype (lymphocytic, follicle centre cell, mantle cell, marginal zone and lymphoplasmacytoid) was assembled and immunostaining for the respective antigens carried out using the monoclonal antibodies produced. Our results indicate that the antibodies are specific for their respective antigens and give the predicted phenotypic profile in the small B-cell lymphoma subtypes. CONCLUSIONS: These novel monoclonal antibodies may be of value in routine diagnostic practice.

Animals↗
PubMed2000

Endoscopic valvuloplasty for GERD.

BACKGROUND: The transoral, endoscopic route has been suggested as a possible approach for the correction of severe gastroesophageal reflux. Such a procedure would involve no mobilization of the cardia or other structures. The optimal placement, number, and configuration of sutures remains undefined. METHODS: With the use of a previously developed endoscopic sewing machine, this study was undertaken in baboons with two suture arrangements immediately below the lower esophageal sphincter. A linear arrangement (group I) and a circular arrangement (group II) were compared. During the 6 months after the procedure, the animals were evaluated using manometry, fluoroscopic barium swallow, upper gastrointestinal endoscopy, and a pressure volume test. RESULTS: A significant increase in lower esophageal sphincter length was demonstrated only in group II (p = 0. 010). A significant increase in lower esophageal sphincter pressure was demonstrated only in group I animals (p = 0.008). The abdominal length increased in group I (p = 0.004) and group II (p = 0.004). The yield pressure and yield volume did not differ significantly from those measured previously in control animals. No evidence of reflux, stricture formation, esophagitis, or other pathology was noted. CONCLUSIONS: Some manometric parameters associated with gastroesophageal reflux are altered by the endoscopic placement of sutures below the gastroesophageal junction, with no associated serious complications.

Animals↗
PubMed2000

Computer simulation evidence of the transient planar state during the homeotropic to focal conic transition in cholesteric liquid crystals

Previous experimental evidence has suggested the existence of a transient planar state during the transition from a homeotropic state to a focal conic state. This does not appear at first to be physically reasonable. Here we show a quantitative numerical model of this transition that shows the existence of the transient planar state and agrees well with measured data. We compared this simulation with two experimental samples: one with parallel boundary conditions, and one with perpendicular boundary conditions. Both samples had thickness to pitch ratios of 13.9. The agreement of the simulation with the experimental data gives further evidence that the system passes through the transient planar during the transition. Also shown here are preliminary results for the second part of the transition, the transition from the transient planar state to the focal conic state, that suggest a Helfrich-like undulation deformation.

Journal Article↗
PubMed2000

Twist-energy-driven helfrich modulations in cholesteric liquid crystals illustrated in the transient-planar to planar transition

The complete time evolution of a Helfrich-type instability that is driven by twist energy in a cholesteric liquid crystal is presented. The modulation is investigated using an initially uniform planar director configuration of a cholesteric liquid crystal (with helical axes uniformly aligned along the cell normal) whose pitch is substantially longer than the equilibrium value.

Journal Article↗