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Biomedical subjects

H Phillips

Publications and source records attributed to H Phillips.

At least 55 records · Page 3Linked to original sources
PubMed1996

Complete analysis of the presenilin 1 gene in early onset Alzheimer's disease.

The presenilin 1 gene has recently been identified as the locus on chromosome 14 which is responsible for a large proportion of early onset, autosomal dominantly inherited Alzheimer's disease (AD). We have elucidated the intron/exon structure of the gene and designed intronic primers to enable direct sequencing of the entire coding region (10 exons) of the presenilin gene in a large number of families. This strategy has enabled us to find a further two novel mutations in the gene. We discuss the distribution of mutations and the proportions of autosomal dominant AD with a mean age of onset below 60 years caused by mutations in this gene.

Alzheimer Disease↗
PubMed1996

A further presenilin 1 mutation in the exon 8 cluster in familial Alzheimer's disease.

Recent studies suggest that mutations in the presenilin 1 gene, which encodes a polypeptide predicted to be a multispanning membrane protein, are responsible for the majority of cases of early onset, autosomal dominant Alzheimer's disease. Here we describe a further mutation in the presenilin 1 gene (R269G) in a family with early onset Alzheimer's disease. This mutation is in exon 8 which appears to be a favoured region for pathogenic mutations. In the presenilin protein the region coded for by this exon is likely to comprise a domain located on the membrane surface. We discuss the likely effects of the exon 8 mutations on the structure of the exon and in the pathogenesis of the disease.

Alzheimer Disease↗
PubMed1996

Nicotinamide pharmacokinetics in humans: effect of gastric acid inhibition, comparison of rectal vs oral administration and the use of saliva for drug monitoring.

The effect of inhibiting gastric acid secretion on nicotinamide pharmacokinetics was studied in five volunteers with the intent of reducing the large variations observed previously in the time to and magnitude of peak plasma concentrations. Plasma levels were determined using a standard high-performance liquid chromatography (HPLC) method after an oral dose of 3 g of nicotinamide either alone or preceded by pretreatment with omeprazole. Suppression of gastric acid production had no significant effect on the rate of uptake or on the peak levels achieved. To bypass gastric acidity, the rectal route was also assessed using a suppository in four volunteers and one patient undergoing radiotherapy. Absorption was slow and variable and much lower plasma levels were observed than after oral dosing. Thus, no improvement in the pharmacokinetics of nicotinamide was observed using either of these two approaches. Parallel estimations were made using a novel and non-invasive method for monitoring nicotinamide pharmacokinetics in saliva. A large and variable fraction of the total amount of nicotinamide-related material in saliva was found to be nicotinic acid, a metabolite not normally found in human plasma. This conversion was inhibited by the use of a chlorhexidine mouthwash, indicating that the oral flora was responsible for its production. The time to peak levels of nicotinamide or of nicotinamide plus nicotinic acid in saliva correlated well with that in plasma. However, peak concentrations for nicotinamide alone were significantly lower than in plasma, and very variable, whereas for nicotinamide plus nicotinic acid saliva levels were 20-30% higher, but more consistent. Although there are some practical difficulties in quantitatively handling saliva, the method is very useful for monitoring nicotinamide pharmacokinetics and for assessment of compliance with nicotinamide treatment.

Absorption↗
PubMed1995

The bisindolylmaleimide GF 109203X, a selective inhibitor of protein kinase C, does not inhibit the potentiating effect of phorbol ester on ethanol-induced phospholipase C-mediated hydrolysis of phosphatidylethanolamine.

In fibroblasts, the protein kinase C (PKC) activator phorbol 12-myristate (PMA) either inhibits or stimulates phospholipase C-mediated hydrolysis of phosphatidylethanolamine in the absence or presence of ethanol, respectively. Here, we demonstrate that the specific PKC inhibitor bisindolylmaleimide GF 109203X prevents only the inhibitory, but not the stimulatory, PMA effect.

3T3 Cells↗
PubMed1995

NGF receptor expression in sensory neurons develops normally in embryos lacking NGF.

Numerous in vivo and in vitro studies have shown that NGF increases the expression of its receptors, p75 and TrkA, in NGF-responsive cell lines and in NGF-responsive neurons of the developing and mature nervous system. To determine if endogenous NGF is required for the normal developmental increase in p75 and TrkA expression that occurs in sensory neurons shortly after they innervate their targets, we used quantitative RT/PCR to compare the levels of p75 and trkA mRNAs in the trigeminal ganglia of normal mouse embryos and embryos that are homozygous for a null mutation in the NGF gene. We show that the marked increase in p75 and trkA mRNA expression that occurs between E11 and E13 in normal embryos takes place on time and to the same extent in NGF-/- embryos. We also show that trigeminal neurons from E13 NGF+/+ and NGF-/- embryos have very similar dose responses for survival induced by NGF. These findings clearly show that the expression of both p75 and TrkA and the sensitivity of developing sensory neurons to NGF do not require and are not modulated by target-derived NGF during the early stages of target field innervation.

Animals↗
PubMed1995

Radiological decompression of bowel gas and return of mediastinal shift in congenital diaphragmatic hernia: a signal for surgical repair?

The objective of this study was to document the pattern of bowel gas decompression and mediastinal shift in infants with congenital diaphragmatic hernia (CDH) before delayed surgical correction. The setting was the Neonatal Intensive Care Unit, Royal Alexandra Hospital, Edmonton. The design was a retrospective review of radiographs and charts of all infants with CDH between January 1990 and December 1993. Bowel gas in the upper and middle one third of the hemithorax was classified as grade III and grade II, respectively. Bowel gas in the lower one third of the hemithorax or absent bowel gas was classified as grade I. All the infants showed partial return of the contralateral shift in the mediastinum toward the midline when comparing the admission chest radiographs with the immediate preoperative films. Complete return of the mediastinum to normal (using the first postoperative radiograph as the gold standard) occurred in all but 1 of the 10 infants on extracorporeal membrane oxygenation (ECMO) (90%) and 7 of 13 (54%) of conventionally treated infants (P = .12). At the time of the first radiograph, a similar proportion of non-ECMO and ECMO infants (61% versus 70%, respectively) had either grade II or III bowel gas patterns. By 72 hours none of the non-ECMO-treated infants (who were paralyzed with muscle relaxants) had bowel gas in the middle and upper one third of the hemithorax. In contrast, 66% of infants on ECMO still had a grade II bowel gas pattern at 72 hours (P < .05), with 4 infants showing an actual increase in bowel gas after discontinuation of muscle relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)

Case-Control Studies↗
PubMed1995

Total knee arthroplasty in the management of proximal tibial stress fractures.

Five patients with stress fractures of the proximal tibia adjacent to an arthritic knee joint were treated by resurfacing arthroplasty with intramedullary fixation of the fracture. All five fractures healed and limb realignment was achieved. The literature concerning proximal tibial stress fractures in relation to the arthritic knee and the management of this condition is reviewed.

Aged↗
PubMed1994

Neurotrophin-4/5 is a survival factor for embryonic midbrain dopaminergic neurons in enriched cultures.

Parkinson's disease is a prevalent neurological disease characterized by profound and incapacitating movement disorders. A common pathology in Parkinson's patients is degeneration of substantia nigra dopaminergic neurons that innervate the striatum and a corresponding decrease in striatal dopamine content. We now report that NT-4/5 can prevent the death of rat embryonic substantia nigra dopaminergic neurons in low density, enriched, primary cultures. Furthermore, these neurons express messenger RNA encoding the trkB receptor for NT-4/5 and transcripts for NT-4/5 are present in their environment. In addition, we demonstrate that NT-4/5 protects embryonic dopaminergic neurons from the toxic effects of the neurotoxin MPP+. Thus, NT-4/5 could be a physiological survival factor for midbrain dopaminergic neurons and may be useful as a therapeutic agent for Parkinson's disease.

1-Methyl-4-phenylpyridinium↗
PubMed1993

A cytokine receptor gene cluster in the X-Y pseudoautosomal region?

The receptors for interleukin-3 (IL-3), IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF) are heterodimers comprised of ligand specific alpha chains and a common beta chain. The genes encoding the IL-5 receptor alpha chain and the common beta chain reside on chromosome 3 and 22 respectively, while the GM-CSF receptor alpha chain gene (CSF2RA) has been mapped to the pseudoautosomal region (PAR) of the sex chromosomes, which is a 2.6-Mb stretch of homologous sequence at the tips of the short arms within which a single obligatory recombination occurs during male meiosis. We have mapped the gene encoding the IL-3 receptor alpha chain (IL3RA) to the sex chromosomes by polymerase chain reaction (PCR) analysis of human-mouse or human-chinese hamster cell hybrids, and to Yp13.3 and Xp22.3 using fluorescence in situ hybridization. To explore the possibility that IL3RA is located within the pseudoautosomal region we screened the Centre d'Etude du Polymorphisme Humain (CEPH) pedigrees for an informative-restriction fragment-length polymorphism (RFLP) that showed male meiotic recombination. Two informative CEPH pedigrees were identified that displayed this phenomenon, confirming the psuedoautosomal location of IL3RA. Using long-range restriction mapping we have found that IL3RA maps to the same 190-kb restriction fragment as CSF2RA, suggesting that a cytokine receptor gene cluster may reside in the PAR.

Base Sequence↗
PubMed1993

Antitumor response to recombinant murine interferon gamma correlates with enhanced immune function of organ-associated, but not recirculating cytolytic T lymphocytes and macrophages.

The mechanism of therapeutic activity for recombinant murine interferon-gamma (rMu IFN gamma) in the treatment of metastatic disease was investigated by comparing effector cell augmentation with therapeutic activity in mice bearing experimental lung metastases (B16-BL6 melanoma). Effector cell functions in spleen, peripheral blood, and lung (the tumor-bearing organ) were tested after 1 week and 3 weeks of rMu IFN gamma administration (i.v. three times per week). Natural killer (NK), lymphokine-activated killer (LAK), cytolytic T lymphocyte (CTL) activities against specific and nonspecific targets, and macrophage tumoristatic activity were measured. rMu IFN gamma demonstrated immunomodulatory activity in most assays of immune function. The optimal therapeutic protocol of rMu IFN gamma (2.5 x 10(6) U/kg, three times per week) prolonged survival and decreased the number of pulmonary metastatic foci. This therapeutic activity was correlated with specific CTL activity from pulmonary parenchymal mononuclear cells (PPMC), but not from spleen or blood. Macrophage tumoristatic activity in PPMC also correlated with therapeutic activity, but activity in alveolar macrophages did not. However, therapeutic activity did not correlate with NK or LAK activity at any site. These results demonstrate that the optimal therapeutic protocol is the same as the optimal immunomodulatory dose for pulmonary CTL and macrophage activities. Furthermore, while immunological monitoring may help to optimize treatment protocols, current monitoring procedures that use readily accessible sites, particularly peripheral blood, may not accurately predict the therapeutic efficacy of biological response modifiers in clinical trials.

Animals↗
PubMed1993

A comparison of cefpodoxime proxetil and cefaclor in the treatment of acute exacerbation of COPD in adults.

In this multicenter, observer-blinded study, 301 patients with signs and symptoms of acute bacterial exacerbation of COPD were randomized (2:1) to receive either cefpodoxime proxetil (200 mg, bid) or cefaclor (250 mg, tid) for 10 days. Clinical and microbiologic evaluations were performed before treatment, during therapy (study days 3 to 5), at the end of therapy (3 to 7 days posttreatment), and at long-term follow-up (4 weeks posttreatment). The most common pretreatment isolates were Haemophilus influenzae, Haemophilus parainfluenzae, and Streptococcus pneumoniae. Significantly (p < 0.001) more bacterial isolates were susceptible in vitro to cefpodoxime (233 of 256, 91 percent) than to cefaclor (215 of 255, 84 percent). There were no statistically significant differences between the two drug regimens in eradication of the initial pathogen (cefpodoxime, 116 of 128, 91 percent; cefaclor, 59 of 64, 92 percent) or end-of-therapy clinical response (cure + proved; cefpodoxime, 99 of 100, 99 percent; cefaclor, 45 of 49, 92 percent) rates for evaluable patients. Both drug treatments were well-tolerated, with a similar incidence of drug-related adverse events (cefpodoxime 11 percent, cefaclor 12 percent). Cefpodoxime (bid) was as safe and effective as cefaclor (tid) in the treatment of acute exacerbation of COPD. The less frequent dosing regimen of cefpodoxime may improve patient compliance compared to those antibiotics that require three or four daily doses.

Acute Disease↗
PubMed1992

Effect of tumor burden and route of administration on the immunotherapeutic properties of polyinosinic-polycytidylic acid stabilized with poly-L-lysine in carboxymethyl cellulose [Poly(I,C)-LC].

We examined the immunomodulatory and therapeutic activities of poly(I,C)-LC. Mice received a subcutaneous (s.c.) injection of sufficient numbers of MBL-2 lymphoma cells to produce in 1 week either a high or low tumor burden. A week after tumor cell injection, poly(I,C)-LC treatment was initiated; the agent was administered intraperitoneally (i.p.) at 5 mg/kg twice a week or at 2.5 or 0.5 mg/kg every day or as an intravenous (i.v.) injection at 0.5, 0.05, or 0.005 mg/kg three times a week. Poly(I,C)-LC treatment significantly increased antitumor effector cell functions in a variety of organs (including spleen, lungs, and peritoneum), as shown by increased killing of MBL-2 cells in vitro and increased tumor cell killing by natural killer cells and macrophages. Furthermore, prolongation of survival correlated with peritoneal macrophage tumoricidal activity when poly(I,C)-LC was given i.p. and with pulmonary effector cell function (including natural killer, cytolytic T-lymphocyte and macrophage tumoricidal activity) when the agent was administered i.v.

Animals↗
PubMed1992

Bone grafting in primary uncemented total knee arthroplasty.

Forty-two uncemented ICLH and Freeman Samuelson knee replacements that required bone grafting for tibial defects were studied before and after operation. The pattern of bone loss, the techniques of grafting, and the soft tissue releases required are described. Union of the graft was observed in 98% of cases, confirming the value of bone grafting in the reconstruction of the deformed, arthritic knee.

Aged↗
PubMed1992

Assignment of a gene (NEMI) for autosomal dominant nemaline myopathy to chromosome I.

Nemaline myopathy (NEM) is a neuromuscular disorder characterized by the presence, in skeletal muscle, of nemaline rods composed at least in part of alpha-actinin. A candidate gene and linkage approach was used to localize the gene (NEM1) for an autosomal dominant form (MIM 161800) in one large kindred with 10 living affected family members. Markers on chromosome 19 that were linked to the central core disease gene, a marker at the complement 3 locus, and a marker on chromosome 1 at the alpha-actinin locus exclude these three candidate genes. The family was fully informative for APOA2, which is localized to 1q21-q23. NEM1 was assigned to chromosome 1 by close linkage for APOA2, which is localized to 1q21-q23. NEM1 was assigned to chromosome 1 by close linkage to APOA2, with a lod score of 3.8 at a recombination fraction of 0. Recombinants with NGFB (1p13) and AT3 (1q23-25.1) indicate that NEM1 lies between 1p13 and 1q25.1. In total, 47 loci were investigated on chromosomes 1, 2, 4, 5, 7-11, 14, 16, 17, and 19, with no indications of significant linkage other than to markers on chromosome 1.

Actinin↗
PubMed1991

Determinants of the need for early acute intervention in patients treated conservatively after thrombolytic therapy for acute myocardial infarction. TAMI-5 Study Group.

This study sought to determine whether clinical variables can be used to identify patients at high risk of recurrent spontaneous myocardial ischemia or hemodynamic compromise during the 1st 4 days after intravenous thrombolysis for acute myocardial infarction. Of 288 patients randomly assigned to a conservative postthrombolysis strategy, 54 (19%) required urgent cardiac catheterization within 24 h; 75 (26%) underwent urgent cardiac catheterization within 4 days of admission. Of the clinical variables examined by multiple logistic regression analysis, only patient age and anterior wall myocardial infarction correlated with the need for urgent cardiac catheterization (p = 0.0016 and p = 0.017, respectively). Compared with recombinant tissue-type plasminogen activator or urokinase monotherapy, combination therapy with these agents was associated with a lower need for acute intervention during the 1st 24 h after admission, but the difference did not reach statistical significance (14% for combination therapy vs. 21% for each agent alone, p = 0.30). Of the 75 patients undergoing urgent coronary angiography, only 39% had an occluded infarct-related artery. Emergency coronary angioplasty was performed in 49% of the patients and coronary artery bypass graft surgery was performed urgently in 3%. Despite these interventions, the need for urgent cardiac catheterization was associated with an in-hospital mortality rate of 7% (vs. 3% in the group not requiring urgent angiography, p = 0.36); mean left ventricular ejection fraction was 50.5 +/- 11% (vs. 54.3 +/- 10.8%, p = 0.12) and regional infarct zone wall motion was -2.68 +/- 1.07 SD/chord (vs. -2.46 +/- 1.19 SD/chord; p = 0.44).(ABSTRACT TRUNCATED AT 250 WORDS)

Angioplasty, Balloon, Coronary↗
PubMed1990

The origin of the Public Health Act of 1919.

South Africa's first national public health measure was passed in 1919, just over 70 years ago. Attempts to enact such legislation in the years immediately after Union had been thwarted by vested interests and it was only the effects of World War I and, more particularly, the dire Spanish influenza epidemic of 1918, which forced Parliament to pass this pioneering measure in June 1919. It remained South Africa's basic public health measure until 1977.

History, 20th Century↗
PubMed1990

Serial evaluation of right ventricular dysfunction associated with acute inferior myocardial infarction.

Right ventricular (RV) function was evaluated serially by multigated blood pool imaging in 18 patients with RV dysfunction associated with acute inferior myocardial infarction. Radionuclide ventriculograms were performed on all patients within 18 hours of chest pain and again at 10 days. In addition, 15 of 18 patients had rest and exercise radionuclide ventriculograms at 3 months. The mean resting right ventricular ejection fractions (RVEF) at admission, 10 days, and 3 months in these patients was 31.8 +/- 12.6% (SD), 46.9 +/- 11.2% (p less than 0.05), and 44.5 +/- 10.2% (p less than 0.05), while the left ventricular ejection fractions were 55.9 +/- 10.6%, 57.9 +/- 13.3%, and 53.1 +/- 11.2% (p = ns). The 3-month exercise radionuclide ventriculogram demonstrated an increase in RVEF greater than 5% in 6 of 15 patients. In eight catheterized patients, neither the location nor the severity of coronary artery narrowing nor the presence of collaterals correlated with the RV exercise response. Improvement in RV function over a 10-day interval following acute inferior myocardial infarction suggests the presence of significant reversible right ventricular dysfunction during the acute phase.

Cardiac Catheterization↗