Review article: the functions of the basal ganglia and the paradox of stereotaxic surgery in Parkinson's disease.
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Basal Ganglia↗
Biomedical subjects
J Phillips
Publications and source records attributed to J Phillips.
Glycosylation and biological activity of CAMPATH-1H expressed in different cell lines and grown under different culture conditions.
CAMPATH-1H (where CAMPATH is a trade mark of Wellcome group companies), a humanized IgG antibody used in the therapy of lymphoma, leukaemia and rheumatoid arthritis, has been expressed in Chinese hamster ovary, Y0 myeloma and NS0 myeloma cell lines. These engineered cell lines were grown under different culture conditions, and the antibody isolated and purified. N-Linked oligosaccharides, on the CH2 heavy chain region of the antibody, were isolated and analysed by hydrazinolysis, high-performance anion-exchange chromatography with pulsed amperometric detection, laser-desorption mass spectrometry and sequential exoglycosidase treatment. Both the glycosylation pattern and the biological activity of CAMPATH-1H, as measured by antibody-dependent cell-mediated cytotoxicity, were markedly affected by the cell line used to express the antibody. It is concluded that glycosylation of the antibody may be important in the clinical outcome of therapy.
Alemtuzumab↗
Post dural puncture headache.
We describe the delayed diagnosis and management of a spinal headache following the use of a 24 g Sprotte needle, the results of a survey of spinal needle usage by physicians in the south west of England and a review of the prevention and management of postdural puncture headache.
Aged↗
Low dose aspirin for the treatment of fetal growth restriction: a randomized controlled trial.
The purpose of this study was to investigate the hypothesis that maternal administration of 100mg aspirin each day will improve birth-weight and other measures of neonatal size when given as a treatment to pregnancies complicated by fetal growth restriction and umbilical-placental insufficiency. A randomized, double-blind, placebo controlled study design was employed; 51 pregnant women were enrolled. The entry criteria were a fetal abdominal circumference < 10th per centile together with an umbilical artery Doppler systolic/diastolic ratio > 95th per centile between 28 and 36 weeks' gestation. Compliance was assessed by serial measurement of maternal serum thromboxane B2 levels. The mean gestational age at enrolment was 32 weeks and at delivery was 36 weeks. There were no differences between the 2 groups in gestational age at birth; birth-weight or birth-weight ratio; circumferences of the head, chest or abdomen; skin fold thicknesses; or neonatal morbidity. Low dose aspirin therapy did not alter Doppler systolic/diastolic ratios. After 14 days therapy, mean thromboxane B2 levels fell more than 80% from baseline values; 10.5% of women did not demonstrate biochemical confirmation of aspirin ingestion, despite verbal confirmation of compliance. We conclude that low dose aspirin therapy is not of benefit in the treatment of pregnancies complicated by fetal growth restriction and umbilical-placental insufficiency between 28 and 36 weeks' gestation.
Adult↗
Detection of p24 antigen with and without immune complex dissociation for longitudinal monitoring of human immunodeficiency virus type 1 infection.
Sequential specimens obtained from 87 multicenter AIDS cohort study participants were tested by three p24 antigen tests. They included a polyclonal enzyme immunoassay (EIA), a monoclonal EIA, and a monoclonal EIA after immune complex dissociation (ICD) of specimens. Subjects were grouped into two categories defined by real-time testing with the polyclonal EIA: 39 had become positive for p24 antigen (antigen converters) during follow-up, and 48 had progressed to AIDS without detectable antigenemia. Twenty-four (61%) antigen converters were positive by ICD-monoclonal EIA about 1 year earlier than by monoclonal EIA. In contrast, only 12 (25%) patients who progressed to AIDS without detectable antigenemia became positive by ICD-p24 EIA before developing AIDS. Thus, the main benefit of ICD treatment may be to detect p24 antigenemia approximately 1 year before the regular assay rather than to identify additional antigenemic people. Quantitative plasma RNA levels were also determined in longitudinal samples from 20 antigen converters and 7 men who developed AIDS without antigenemia. Although mean human immunodeficiency virus type 1 RNA levels were higher in antigen-positive than in antigen-negative samples (P = 0.002), more than half (11 of 20) of the antigen converters had no measurable change in human immunodeficiency virus type 1 RNA associated with change to antigen positivity.
Acquired Immunodeficiency Syndrome↗
Encephaloceles of the anterior cranial fossa.
From a total of 114 encephaloceles treated surgically at The Hospital for Sick Children in the 15 years to 1994, the case records of 17 patients with sincipital and 5 patients with basal defects were reviewed retrospectively. The condition was evident at birth in 64% of patients, while the remainder presented with either cerebrospinal fluid (CSF) rhinorrhea, nasal obstruction, or feeding difficulty. Hypertelorism affected 73% of patients. All encephaloceles were repaired transcranially, at a mean age of 2 years, usually by means of an intradural pericranial graft. Five children with gross hypertelorism underwent orbital translocation at the time of encephalocele repair. Of those not corrected, primary and secondary hypertelorism regressed in most instances where the encephalocele was treated before the age of 2 years. There were no deaths. The only case of CSF rhinorrhea occurred in a patient with a basal defect, in whom intradural repair was not possible because of adherence of diencephalic structures to the sac wall. Hypertelorism recurred in 1 patient after orbital translocation, requiring recorrection 2 years later. One patient with untreated secondary hypertelorism failed to regress after the encephalocele was excised at the age of 4 months. Developmental outcome was normal in 59% of children, whilst 18% have mild mental or physical disability, and 23% are severely impaired. A child with a sincipital or basal defect and mild hypertelorism should have the encephalocele treated in early childhood to allow the facial skeleton to remodel with growth. When an encephalocele is accompanied by gross hypertelorism or a facial cleft, one-stage correction can be undertaken safely in early childhood with minimal mortality and acceptable morbidity.
Encephalocele↗
Pseudotumor cerebri responsive to acetazolamide.
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Acetazolamide↗
A recurring dominant negative mutation causes autosomal dominant growth hormone deficiency--a clinical research center study.
Familial isolated GH deficiency type II (IGHD-II) is an autosomal dominant disorder that has been previously shown in some patients to be caused by heterogeneous GH gene defects that affect GH messenger RNA (mRNA) splicing. We report here our finding of multiple G-->A transitions of the first base of the donor splice site of IVS 3 (+ 1G-->A) in IGHD II subjects from three nonrelated kindreds from Sweden, North America, and South Africa. This + 1G-->A substitution creates an NlaIII site that was used to demonstrate that all affected individuals in all three families were heterozygous for the mutation. To determine the effect of this mutation on GH mRNA processing, HeLa cells were transfected with expression plasmids containing normal or mutant + 1G-->A alleles, and complementary DNAs from the resulting GH mRNAs were sequenced. The mutation was found to destroy the GH IVS 3 donor splice site, causing skipping of exon 3 and loss of the codons for amino acids 32-71 of the mature GH peptide from the mutant GH mRNA. Our finding of exon 3 skipping in transcripts of the + 1G-->A mutant allele is identical to our previous report of a different sixth base transition (+6T-->C) mutation of the IVS 3 donor splice site that also causes IGHD II. Microsatellite analysis of an affected subjects' DNA from each of the three nonrelated kindreds indicates that the + 1G-->A mutation arose independently in each family. Finding that neither grandparent has the mutation in the first family suggests that it arose de novo in that family. Our data indicate that 1) + 1G-->A IVS 3 mutations perturb GH mRNA splicing and cause IGHD II; and 2) these mutations can present as de novo GHD cases.
Adult↗
Elevated levels of lipoprotein (a) in association with cerebrovascular saccular aneurysmal disease.
The relationship between cerebrovascular aneurysmal disease and atherosclerosis remains unclear. Elevated serum levels of lipoprotein (a) (Lp[a]), are an independent risk factor for atherosclerosis. We measured serum Lp(a) levels in 50 patients who had angiographically proven saccular aneurysmal disease and who were free of clinically significant atheromatous disease (as judged by their medical histories and the results of physical examination, electrocardiography, and carotid angiography). The Lp(a) serum levels in these patients were compared with the Lp(a) serum levels in a group of 42 normal healthy controls. Serum Lp(a) levels in the patients was 20.1 +/- 0.42 mg/dl (median +/- standard error); however, median serum Lp(a) in the control subjects was 10.8 +/- 0.47 mg/dl (P < 0.01). Among females, the difference in serum Lp(a) levels was significant; the levels were 22.2 +/- 0.6 for female patients (n = 29) and 9.5 +/- 0.53 in female control subjects (n = 26) (P < 0.005). The most significant difference (P < 0.002) was seen in females < 50 years old (14 patients, 10 control subjects). No significant differences were seen in the Lp(a) serum levels between 21 male patients and 16 male control subjects. Lp(a) levels above the threshold level (30 mg/dl) were found in 20 patients and 7 control subjects (chi 2 = 5.99, P < 0.02); 12 female patients and 3 female control subjects (chi 2 = 6.16, P < 0.02; 8 male patients and 4 male control subjects (this difference was not significant). These results indicate either that cerebrovascular aneurysmal disease and subclinical atherosclerosis are related or that Lp(a) is a risk factor for vasculopathies other than atheroma.
Adult↗
Comparison of laser Doppler flowmeter and radioactive microspheres in measuring blood flow in pig skin flaps.
Laser Doppler flowmetry is a noninvasive technique commonly used to monitor skin perfusion after free-tissue transfer or replantation in reconstructive surgery. Several investigators have expressed concern about the reliability of the quantitative value provided by laser Doppler flowmeters (LDF) and the extent to which they reflect nutrient blood flow. This experiment was designed to compare quantitatively the skin blood flow in the pig measured by LDF and by 15-micron radioactive microspheres (RMs). It was observed that the skin blood flow rates measured by LDF and RMs in the normal skin and in acute random-pattern and arterialized skin flaps were highly correlated (r = 0.93, P < .01). However, the skin blood flow rates measured by LDF were consistently higher (P < or = .05) than the corresponding flow rates measured by RMs, and this discrepancy increased considerably at low skin blood flow rates (< 2 mL/min/100 g). We speculated that the LDF most likely measured both nutrient and arteriovenous shunt flow in the skin and that this arteriovenous shunt flow at least in part caused the discrepancy in skin blood flow rates measured by the LDF and RMs because the 15-micron RMs are known to measure nutrient blood flow only. The inherent variations and errors in LDF technique were also discussed.
Animals↗
Prevalence of Canavan disease heterozygotes in the New York metropolitan Ashkenazi Jewish population.
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Base Sequence↗
An audit of medical paediatric out-patient appointments and letters.
All medical out-patient appointments of a firm of three consultants at the Royal Hospital for Sick Children were reviewed over a four week period. Of 758 appointments initially offered, 490 (64%) patients attended; 19% of patients cancelled and 17% did not attend without cancelling. Delay from referral to attendance ranged from 0 to 9 weeks. The characteristics of those patients experiencing prolonged registrar-only follow-up are described. The content of subsequent letters to family practitioners was usually adequate compared to accepted standards. Delays in dictation of letters were usually short in comparison to delays in typing. Such delays and the intervals between consultant review of out-patients may prove costly to providers. Potential improvement strategies are discussed.
Appointments and Schedules↗
Deoxyspergualin: phase I clinical, immunologic and pharmacokinetic study.
Deoxyspergualin (DSG) is an analog of the polyamine spergualin with preclinical evidence of activity in murine and human tumor models. This phase I study examined a 120 h continuous infusion schedule in 56 patients with refractory solid tumors at doses ranging from 80 to 2792 mg/m2/day. Dose-limiting toxicity was reversible hypotension and appeared to be associated with plasma levels of DSG > 4 micrograms/ml. Other dose-dependent effects noted were pruritus and circumoral paresthesias. Myelosuppression and gastrointestinal toxicities were mild and sporadic. Two patients with refractory head and neck cancer had minor responses. The recommended phase II dose on this schedule is 1800 mg/m2. Additional monitoring to identify immunologic properties included immunophenotyping of peripheral lymphocytes and cytotoxic activity by means of standard 51Cr-release assays. These studies revealed a non-dose-dependent increase in the number of cells expressing T cell antigens predominantly the T suppressor (CD8) phenotype posttreatment. In three patients, a mild increase in LAK activity was noted post-treatment without a consistent relationship to dose or change in cell surface antigens. Pharmacokinetic studies were completed on 26 patients ranging from doses of 80 to 2792 mg/m2. The average plasma concentration ranged from 0.07 to 7 micrograms/ml. DSG was rapidly cleared from the plasma with a mean terminal half-life of 1.9 h. Mean total body clearance was 25.24 l/h/m2. Further in vivo immunologic studies should be pursued while the agent is studied in fixed dosage phase II clinical trials.
Adult↗
A manganese superoxide dismutase-encoding cDNA from Drosophila melanogaster.
A cDNA encoding manganese superoxide dismutase (MnSOD) has been cloned and sequenced from Drosophila melanogaster. This 805-bp complete cDNA carries a single open reading frame which specifies a deduced 217-amino-acid (aa) protein with an average identity of 60.8% with deduced MnSOD aa sequences from Caenorabditis elegans and humans.
Amino Acid Sequence↗
Repeated cleaning of protein A affinity column with sodium hydroxide.
Protein A attached to an affinity adsorbent was shown to be remarkably resistant to 0.5 M NaOH. Even repeated treatments gave only a small decrease in functional capacity and no adverse effect on leakage of the protein A into the eluate. This simple cleaning procedure should be useful in applications where antibodies need to be purified free from the risk of contamination with endotoxins or micro-organisms, e.g., for in vivo therapy, either in clinical trials or experimental animals. It can also prevent cross-contamination when the same protein A adsorbent is used for different batches of antibody.
Adsorption↗
Two contiguous residues in human interleukin-3, Asp21 and Glu22, selectively interact with the alpha- and beta-chains of its receptor and participate in function.
We have previously reported that the predicted first helix of human interleukin (IL)-3 contains a hydrophilic region encompassing residues Asp21, Glu22, and Thr25 that is crucial for biological activity and IL-3 receptor binding. Using single amino acid substitution mutagenesis, we have now determined that Asp21 and Glu22, but not Thr25, were crucial for full IL-3 activity. Mutant D21R was 30-fold less potent than wild type IL-3 in the stimulation of biological activity. It also exhibited a similar reduction in its ability to bind to the cloned high affinity IL-3 receptor complex (alpha- and beta-chains) or to the receptor alpha-chain alone, indicating that residue 21 is involved in contacts with the alpha-chain. Mutant E22R was approximately 20,000-fold less potent than wild type IL-3 in the stimulation of biological activity and in binding to the IL-3 receptor high affinity complex. However, the binding of E22R to the IL-3 receptor alpha-chain alone was similar to that of wild type IL-3, suggesting that this mutant was defective in interactions with the receptor beta-chain. These results show that two contiguous residues in the N-terminal region of IL-3 mediate binding to the two different chains of the IL-3 receptor and emphasize the functional significance of the conserved Glu in the first helix of the IL-3, granulocyte-macrophage colony-stimulating factor, and IL-5 cytokine subfamily.
Amino Acid Sequence↗
Alterations in TRH receptors in temporal lobe of schizophrenics: a quantitative autoradiographic study.
We utilized quantitative autoradiography to determine the distribution of receptors for thyrotropin-releasing hormone (TRH) throughout the human temporal lobe and to examine the distribution of these receptors in discrete subregions of the temporal lobe from patients diagnosed premortem with schizophrenia. When compared to non-neurologic controls, schizophrenic patients demonstrated an increase of 51% in the concentration of TRH receptors in the molecular layer of the dentate gyrus. Within nuclei of the schizophrenic amygdala, marked decreases were found in the central (44%), medial (38%), cortical (36%), accessory cortical (52%), lateral (54%), and medial basal (22%) nuclei. We also examined postmortem brain samples from patients with Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's disease for alterations in the distribution of TRH receptors. No significant differences from non-neuropsychiatric controls were noted within the hippocampus in any of these disease states; however, slight alterations were noted in the central and medial basal amygdala in Huntington's disease and in the cortical amygdala in Alzheimer's disease. These disease-specific findings suggest that TRH may play a role in the neurochemical dysfunction of schizophrenia.
Adult↗
Detection of human immunodeficiency virus type 1 p24 antigen and plasma RNA: relevance to indeterminate serologic tests.
BACKGROUND: Most enzyme immunoassay-reactive specimens producing indeterminate Western blot results belong to individuals who are not infected with human immunodeficiency virus type 1 (HIV-1). However, a small percentage may correspond to early seroconversion or advanced disease, at which stage partial reactivity on Western blot may be observed. STUDY DESIGN AND METHODS: To determine the utility of HIV-1 p24 antigen and cell-free RNA detection for the resolution of Western blot-indeterminate serologic results, several types of enzyme immunoassay-positive, sero-indeterminate specimens were analyzed. Samples were obtained from infected individuals at the time of seroconversion (n = 20), from patients with AIDS (n = 2), as specimens from clinical samples obtained for diagnostic testing (n = 57), from blood donors producing persistent indeterminate results (n = 47), and from random blood donors (n = 72). RESULTS: HIV-1 p24 antigen was detected in 10 of 20 specimens collected from 9 of 12 individuals who seroconverted and in 2 of 2 AIDS patients. HIV-1 plasma RNA was positive in 22 of 22 samples from those 14 individuals. All of 57 diagnostic specimens and 47 samples obtained from persistently indeterminate donors were negative for HIV-1 p24 antigen and plasma HIV-1 RNA. One of 72 blood donor specimens was positive for HIV-1 plasma RNA and had borderline reactivity for p24 antigen. CONCLUSION: The detection of plasma RNA appears to be sensitive and specific; negative test results may be used to identify false-positive serologic reactions. The detection of p24 antigen and plasma RNA can also be used to confirm HIV-1 infection in persons with indeterminate serologic results associated with early seroconversion or late-stage disease.
Blotting, Western↗