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Biomedical subjects

M Perkins

Publications and source records attributed to M Perkins.

At least 19 recordsLinked to original sources
PubMed1999

Lesions of midline midbrain structures leave medial forebrain bundle self-stimulation intact.

Previous work with psychophysically-based collision methods and pharmacological manipulation suggests a role in medial forebrain bundle (MFB) self-stimulation for neurons lying along the midline between the cerebral hemispheres, in the mid- and/or hindbrain. Also, recently-proposed models of the anatomical substrate for medial forebrain bundle stimulation reward suggest that at least part of the directly-activated axons of this substrate arise from mid- and/or hindbrain somata, bifurcate, and send bilateral projections to the MFB of each hemisphere. Branches of these axons are thought to cross the midline at some point near the ventral tegmental area. This study examines the effects on MFB stimulation reward of lesioning midbrain structures that lie along the midline between hemispheres. In 13 rats, lesions of the median raphe, the decussation of the superior cerebellar peduncle, or the interpeduncular nucleus were all ineffective in altering the stimulation frequency required to maintain half-maximal levels of operant responding for stimulation reward. These results are discussed in terms of implications for recent models of the anatomical substrate for brain stimulation reward.

Animals↗
PubMed1998

Lesions of pontomesencephalic cholinergic nuclei do not substantially disrupt the reward value of medial forebrain bundle stimulation.

This study examines the effects of lesioning the pedunculopontine tegmentum (PPTg) and laterodorsal tegmentum (LDTg) on the reward effectiveness of medial forebrain bundle (MFB) stimulation. Although the focus is on the effects of unilateral lesions made ipsilateral to stimulation sites in the hypothalamic and ventral tegmental MFB, the effects of contralateral lesions of both targets are also investigated. Reward effectiveness was assessed using the rate-frequency curve shift paradigm. In nine rats with unilateral PPTg lesions and five rats with unilateral LDTg lesions, the frequency required to maintain half-maximal response rats was generally not changed by more than 0.1 log units relative to prelesion baseline mean. In three rats with contralateral PPTg lesions and four rats with contralateral LDTg lesions, required frequency was also not substantially changed. The results are interpreted in terms of a previously proposed hypothesis regarding the role in MFB self-stimulation of ascending cholinergic input from the pontomesencephalon to ventral tegmental dopaminergic neurons.

Animals↗
PubMed1998

Midbrain periaqueductal lesions do not degrade medial forebrain bundle stimulation reward.

To investigate the possible role of the midbrain central grey and dorsal raphe in medial forebrain bundle (MFB) self-stimulation, 12 rats received monopolar stimulation electrodes in both the lateral hypothalamic and ventral tegmental MFB and an ipsilateral lesioning electrode in either the central grey or dorsal raphe. Baseline rate-frequency data were collected at several currents at each stimulation site until the frequency required to maintain half-maximal responding stabilized and then an electrolytic lesion was made by passing either 20 or 60 s of anodal constant current through the lesioning electrode. Post-lesion rate-frequency data indicated that lesions of the central grey and dorsal raphe had little appreciable effect on the rewarding nature of MFB stimulation. One rat's lesion damaged the median raphe and produced sustained downward shifts in required frequency, suggesting post-lesion enhancement of the stimulation's rewarding effect.

Animals↗
PubMed1998

Induction of the antigen 85 complex of Mycobacterium tuberculosis in sputum: a determinant of outcome in pulmonary tuberculosis treatment.

Sputum quantitative culture, acid-fast smear, days-to-positive by BACTEC, and Mycobacterium tuberculosis antigen 85 complex were monitored during therapy in 42 patients with pulmonary tuberculosis (TB). By BACTEC, 4 patients were persistently positive on days 90-180, and treatment ultimately failed in 2 of these. Antigen 85 expression increased in subjects in whom disease persisted (persisters) from days 0 to 14 when the difference between persisters and nonpersisters was statistically significant (P = .002). Only antigen 85 complex values at day 14 suggested TB persistence at or after day 90. All subjects with day 14 antigen 85 complex values < 60 pg/mL responded rapidly to treatment and were cured. Of those with values > 60 pg/mL, in 33% TB persisted at or after day 90 and treatment failed in 17%. Biologic factors expressed early in therapy, not related to compliance or resistance, may exert a substantial influence on outcome. The antigen 85 complex is critical in cell wall biosynthesis and is induced by isoniazid in vitro. Its induction may represent an adaptive transition to a persistent state during therapy.

Adult↗
PubMed1997

Are outcome data regarding the survivors of neonatal care available from routine sources?

AIM: To determine whether existing information and surveillance systems can be used to provide follow up data on groups of infants at increased risk of disability--for example, the survivors of neonatal intensive care. METHODS: A survey was made of maternity, neonatal, and community child health information systems and surveillance programmes in the Trent Regional Health Authority. Children known to have received neonatal intensive care in Trent between 1 August 1992 and 31 July 1993, and a random sample of normal children in two health districts (data quality check) were included. A data linkage study was made to determine whether follow up information about a random sample of infants, known to be at increased risk of poor outcome, could be identified on community child health databases. Two widely accepted datasets (birth and 2 years) were used as standards for this exercise. The quality of data was audited. RESULTS: All clinical items of the birth minimum dataset were routinely recorded by at least one agency in each health district in Trent. Of the descriptive items, only the mother's age on leaving full time education was not collected. At 2 years, all clinical items were collected as part of the routine surveillance programme, but data were recorded using a system which severely limited interpretation. Data quality, in terms of the number of errors introduced at data entry, was very good with only 1.1% of the check items (4/368) incorrectly recorded. Only two districts had organised electronic transfer of data between maternity, neonatal, and community child health systems. The mother's NHS number, although available, was not routinely recorded by any system. The NHS number of the infant was routinely collected by six out of 12 community paediatric services. Data linkage was attempted in six districts with appropriate community child health databases. Just over 70% of the intensive care sample was successfully linked with follow up information on child health systems. CONCLUSIONS: The existing programmes for routine child surveillance could provide outcome data for high risk groups of infants, such as the survivors of neonatal intensive care. However, the present coding system used for data entry is inadequate. Furthermore, rates of identification, without the use of a unique identifier (NHS number) for each subject, are currently insufficient for monitoring health status in later life.

Child Health Services↗
PubMed1996

Biphenyl-derivatives of 2-amino-7-phosphono-heptanoic acid, a novel class of potent competitive N-methyl-D-aspartate receptor antagonists--II. Pharmacological characterization in vivo.

A selection of biphenyl-analogues of 2-amino-7-phosphonoheptanoic acid (AP7), N-methyl-D-aspartate (NMDA) receptor antagonists with high affinity in vivo efficacy. The lead compound SDZ EAB 515 was found to inhibit L-phenylalanine uptake by the large neutral amino acid carrier in vitro and in vivo; active transport may thus confer a good bioavailability to this class of compounds. CNS effects were demonstrated by significant changes in 2-deoxyglucose-uptake in various brain regions at doses from 1 to 10 mg/kg i.p. With the most active agent, SDZ 220-581, full protection against maximal electroshock seizures (MES) was obtained at oral doses of 10 mg/kg in rats and in mice. The compound had a fast onset (< or = 1 hr) and a long duration (> or = 24 hr) of action. Motor-debilitating effects (impairment of rotarod performance) occurred at doses about 10 times higher than those required for protection against MES. Neuroprotective activity was demonstrated by the ability of the compounds to reduce the extent of quinolinic acid-induced striatal lesions in rats, in the dose range of 3-15 mg/kg (i.p.) or 10-50 mg/kg (p.o.). In the middle cerebral artery occlusion (MCAO) model of focal cerebral ischemia in rats, the test compounds reduced the infarct size by 40-50% when given i.v. before or by 20-30% when given i.v. 1 hr after MCAO. SDZ 220-581 provided 20-30% protection at > or = 2 x 10 mg/kg p.o. This compound also showed analgesic activity at low oral doses in a model of neuropathic pain, although higher doses were required in model of mechanical inflammatory hyperalgesia. Unexpectedly, SDZ 220-581 at low s.c. doses counteracted the antiparkinsonian effects of L-DOPA in MPTP-treated marmosets. (Sub)chronic administration of SDZ 220-581 did not reduce its ability to protect against quinolinic acid neurotoxicity, and no upregulation of NMDA receptors was detected using a [3H]CGP-39653 binding assay. In conclusion, from a series of biphenyl-AP7-derivatives, SDZ 220-581 is clearly the most active compound in vivo. Its pharmacological profile with a good, long-lasting oral activity might open up novel therapeutic applications for competitive NMDA receptor antagonists.

Amino Acids↗
PubMed1996

Development of hyperthermia and hyperalgesia following intracerebroventricular administration of endotoxin in the rat: effect of kinin B1 and B2 receptor antagonists.

The present study investigated the development of hyperthermia and thermal and mechanical hyperalgesia following i.c.v. injections of E. coli lipopolysaccharide (LPS) in rats. LPS increased core temperature and this was prevented by i.c.v. administration of HOE 140, a kinin B2 receptor antagonist or by indomethacin i.c.v. or i.v. B1 receptor antagonists had no effect. LPS induced thermal and mechanical hyperalgesia which was reversed by i.c.v. HOE 140 and indomethacin i.c.v. and i.v., but not by B1 receptor antagonists. These results indicate that injections of endotoxin to the CNS induces hyperthermia and hyperalgesia and that kinins, acting on centrally located B2 receptors, and prostanoids are involved.

Animals↗
PubMed1996

Development of hyperthermia following intracerebroventricular administration of endotoxin in the rat: effect of kinin B1 and B2 receptor antagonists.

1. E. coli lipopolysaccharide (LPS) produced a dose-dependent (dose range: 0.02-150 micrograms) increase in rat core temperature that was maximal 6 h after intracerebroventricular (i.c.v.) administration. LPS (200 ng) increased core temperature by 1.0 +/- 0.2 degrees C, 6 h following administration, as compared to vehicle-treated controls (-0.2 +/- 0.2 degrees C). 2. LPS-induced (200 ng) hyperthermia was prevented by co-administration of the bradykinin (BK) B2 receptor antagonist, Hoe 140 (10 and 30 pmol, i.c.v.) or by indomethacin (10 nmol, i.c.v.). 3. Systemic administration of Hoe 140 at doses up to 1 mumol kg-1, s.c., did not attenuate LPS-induced (200 ng, i.c.v.) hyperthermia. However, LPS hyperthermia was significantly reduced by systemic administration of indomethacin (1 mumol kg-1, i.v.). 4. Co-administration of the selective B1 receptor antagonists, [des-Arg9, Leu8]BK (0.1 - 1 nmol, i.c.v.) or [des-Arg10] Hoe 140 (0.1 - 1 nmol, i.c.v.), did not prevent LPS-induced hyperthermia. 5. It is concluded that the development of hyperthermia following central administration of endotoxin requires activation of central, but not peripheral bradykinin B2 receptors. The formation of kinins within the CNS may be an important initial component of CNS inflammation following infection.

Animals↗
PubMed1995

Genetic linkage for Darier disease (keratosis follicularis).

Darier disease is an autosomal dominant skin disorder characterized by abnormal keratinocyte adhesion. Recent data have provided evidence for linkage of the Darier disease locus to 12q23-24.1 in British families. We have carried out linkage analysis using the 12q markers D12S58, D12S84, D12S79, D12S86, PLA2, and D12S63 in 6 Canadian families. Pairwise linkage analysis generated positive lod scores at all 6 markers at various recombination fractions, and each family showed positive lod scores with more than one marker. The peak lod score in the multipoint analysis (Zmax) was 5.5 in the interval between markers D12S58 and D12S84. These positive lod scores in North American families of varied European ancestry confirm the location of the Darier disease gene, and suggest genetic homogeneity. The future identification and sequencing of the gene responsible for Darier disease should lead to improved understanding of the disease and of keratinocyte adhesion in general.

Adolescent↗
PubMed1995

Kinins and kinin receptors in the nervous system.

Kinins, including bradykinin and kallidin, are peptides that are produced and act at the site of tissue injury or inflammation. They induce a variety of effects via the activation of specific B1 or B2 receptors that are coupled to a number of biochemical transduction mechanisms. In the periphery the actions of kinins include vasodilatation, increased vascular permeability and the stimulation of immune cells and peptide-containing sensory neurones to induce pain and a number of neuropeptide-induced reflexes. Mechanisms for kinin synthesis are also present in the CNS where kinins are likely to initiate a similar cascade of events, including an increase in blood flow and plasma leakage. Kinins are potent stimulators of neural and neuroglial tissues to induce the synthesis and release of other pro-inflammatory mediators such as prostanoids and cytotoxins (cytokines, free radicals, nitric oxide). These events lead to neural tissue damage as well as long lasting disturbances in blood-brain barrier function. Animal models for CNS trauma and ischaemia show that increases in kinin activity can be reversed either by kinin receptor antagonists or by the inhibition of kinin production. A number of other central actions have been attributed to kinins including an effect on pain signalling, both within the brain (which may be related to vascular headache) and within the spinal dorsal horn where primary afferent nociceptors can be stimulated. Kinins also appear to play a role in cardiovascular regulation especially during chronic spontaneous hypertension. Presently, however, direct evidence is lacking for the release of kinins in pathophysiological conditions of the CNS and it is not known whether spinal or central neurones, other than afferent nerve terminals, are sensitive to kinins. A more detailed examination of the effects of kinins and their central pharmacology is necessary. It is also important to determine whether the inhibition of kinin activity will alleviate CNS inflammation and whether kinin receptor antagonists are useful in pathological conditions of the CNS.

Amino Acid Sequence↗
PubMed1995

The role of platelet-activating factor in lipopolysaccharide-induced myocardial depression in guinea pigs.

PURPOSE: To determine if platelet-activating factor (PAF) is a key mediator of lipopolysaccharide (LPS)-induced myocardial depression in guinea pigs. METHODS: Hartley guinea pigs of either sex received intraperitoneal (IP) injections of either vehicle (n = 45) or one of three chemically dissimilar PAF receptor antagonists (n = 38) followed 30 to 60 minutes later by IP injections of either saline (0.8 mL, n = 33) or LPS (2 to 4 mg/kg, n = 50). Left atria (LA) were harvested 16 hours later, suspended in Krebs-Henseleit buffer and attached to force-displacement transducers. Starling and force-frequency curves, contractile function in the potentiated and resting states, and inotropic response to either isoproterenol or phenylephrine were measured. RESULTS: LPS caused a significant reduction in LA contractile function. Two of the three PAF receptor antagonists failed to ameliorate LPS-induced alterations in cardiac function. The third antagonist, SR27417, was approximately 50% effective in preventing LA contractile dysfunction. However, this beneficial response appeared to be caused by a primary inotropic effect of SR27417 because LA from animals treated with SR27417 and saline showed significantly higher contractile function compared with LA from animals treated with vehicle and saline. In vitro tests confirmed this. Some LA from LPS-treated animals exhibited reduced contractile responses when in the potentiated state, a sign of impaired calcium release from the sarcoplasmic reticulum (SR). The response of LA from endotoxic animals to isoproterenol was unchanged compared with controls whereas it was markedly impaired to phenylephrine. Use of SR27417 failed to improve this abnormal response. CONCLUSIONS: PAF does not appear to be a primary mediator of LPS-induced myocardial depression in guinea pigs. LPS may impair SR calcium release thereby causing cardiac dysfunction.

Animals↗
PubMed1995

The diagnosis of Plasmodium falciparum infection using a new antigen detection system.

With the widespread emergence of drug-resistant Plasmodium falciparum infection, febrile patients in the tropics can no longer be empirically treated with inexpensive yet effective antimalarials. The substitution of newer and more costly drugs brings with it the need for rapid, accurate, and inexpensive diagnostic procedures so that directed therapy can be used. We report a field trial comparing standard microscopic malaria diagnosis and quantitative buffy coat analysis to a new P. falciparum antigen detection system. The ParaSight F test (PFT) was found to be easy to learn, rapid to perform, and highly accurate. If confirmed, the use of the PFT in endemic areas may aid in the identification of patients requiring therapy for drug-resistant malaria.

Adolescent↗
PubMed1994

Evaluation of the genetic stability of the temperature-sensitive PB2 gene mutation of the influenza A/Ann Arbor/6/60 cold-adapted vaccine virus.

A single-gene reassortant bearing the PB2 gene of the A/Ann Arbor/6/60 cold-adapted virus in the background of the A/Korea/82 (H3N2) wild-type virus is a temperature-sensitive (ts) virus with an in vitro shutoff temperature of 38 degrees C. A single mutation at amino acid (aa) at 265 (Asp-Ser) of the PB2 protein is responsible for the ts phenotype. This ts single-gene PB2 reassortant virus was serially passaged at elevated temperatures in Madin-Darby canine kidney cells to generate ts+ phenotypic revertant viruses. Four ts+ phenotypically revertant viruses were derived independently, and each possessed a shutoff temperature for replication in vitro of > 40 degrees C. Each of the four phenotypically revertant viruses replicated efficiently in the upper and lower respiratory tracts of mice and hamsters, unlike the PB2 single-gene reassortant virus, confirming that the ts phenotype was responsible for the attenuation of this virus in rodents. Mating the ts+ revertants with wild-type virus yielded ts progeny in high frequency, indicating that the loss of ts phenotype was due to a suppressor mutation which was mapped to the PA gene in each of the four independently derived ts phenotypic revertants. Nucleotide sequence analysis confirmed the absence of new mutations on the PB2 gene and the presence of predicted amino acid changes in the PA proteins of the revertant viruses. These studies suggest that single amino acid changes at aa 245 (Glu-Lys) or 347 (Asp-Asn) of the PA protein can completely suppress the ts and attenuation phenotypes specified by the Asp-Ser mutation at aa 265 of the PB2 protein of the A/Ann Arbor/6/60 cold-adapted virus.

Amino Acid Sequence↗
PubMed1994

Interdisciplinary team approach in the rehabilitation of hip and knee arthroplasties.

Use of an interdisciplinary case management team approach in the treatment of patients with hip or knee arthroplasty has resulted in a decrease in length of stay and achievement of functional outcomes at the authors' center. Case management was used to standardize patient care and to measure each patient's progress toward independence against established criteria of treatment outcomes. Outcomes established for physical therapy were ambulation distance, performance of a home exercise program, stair climbing, amount of active knee flexion (for knee arthroplasties), and incorporation of hip precautions. Outcomes for occupational therapy were bed mobility, chair transfers, toilet transfers, and activities of daily living with emphasis on lower extremity dressing. The case management team consists of an occupational therapist, an occupational therapy assistant, a physical therapist, and two nurses. The specific role of the occupational therapy personnel in this team approach is to maximize, by discharge, a patient's functional level of independence in activities of daily living. Data from a 6-month period indicated that occupational therapy goals were achieved for 79% of the 33 knee arthroplasty patients and 73% of the 37 hip arthroplasty patients.

Activities of Daily Living↗
PubMed1993

Bradykinin and inflammatory pain.

There is compelling evidence linking bradykinin (BK) with the pathophysiological processes that accompany tissue damage and inflammation, especially the production of pain and hyperalgesia. Several mechanisms have been proposed to account for hyperalgesia including the direct activation of nociceptors as well as sensitization of nociceptors through the production of prostanoids or the release of other mediators. In keeping with this, antagonists of the BK B2 receptor are efficacious analgesic and anti-inflammatory agents in acute inflammatory pain. More recently it has been suggested that when inflammation is prolonged, BK B1 receptors, which are not expressed in healthy tissues to a significant degree, also play an important role in the maintenance of hyperalgesia. This may be one of a number of adaptive mechanisms that occur peripherally and centrally following the prolonged activation of nociceptors during inflammation or injury.

Animals↗
PubMed1993

Effect of zidovudine on human placental trophoblast and Hofbauer cell functions.

We have optimized a procedure to isolate placental trophoblasts and Hofbauer cells simultaneously in a quantity sufficient for short-term cultures and then used these placental cells to investigate the effects of zidovudine (ZDV) on trophoblast and Hofbauer cell functions. Of more than 10 term placentas tested, ZDV inhibits DNA synthesis of trophoblasts in a concentration-dependent manner with half the maximal inhibitory concentration (IC50) of 9.88 +/- 1.35 microM. Of the hormones evaluated, production of progesterone by trophoblasts is most sensitive to ZDV (IC50 = 3.65 +/- 0.29 microM). The inhibitory effect of ZDV on the secretion of placental lactogen and choriogonadotropin by the trophoblasts was detected only at a much higher concentration (> or = 60 microM). ZDV does not affect trophoblast or Hofbauer cell protein synthesis. Collectively, our results indicate that at clinically relevant concentrations (< or = 10 microM), ZDV significantly inhibits both the DNA synthesis of placental trophoblasts and their production of progesterone, while having a minimal effect on protein synthesis of both types of placental cells.

Cells, Cultured↗