Search PubMed⌕ Search

Biomedical subjects

A Francis

Publications and source records attributed to A Francis.

At least 37 records · Page 2Linked to original sources
PubMed1999

Amino acid substitutions reveal distinct functions of serine 186 of the ZEBRA protein in activation of early lytic cycle genes and synergy with the Epstein-Barr virus R transactivator.

The ZEBRA protein mediates the switch between the latent and lytic life cycles of Epstein-Barr virus. Z(S186A), a point mutant in ZEBRA's basic domain in which serine 186 is changed to alanine, is unable to induce expression of lytic cycle mRNAs or proteins from the latent EBV genome even though it retains the ability to activate transcription from reporters bearing known ZEBRA-responsive promoters (A. L. Francis et al., J. Virol. 71:3054-3061, 1997). We now describe three distinct phenotypes of ZEBRA mutants bearing different amino acid substitutions at S186. These phenotypes are based on the capacity of the mutants to activate expression of the BRLF1 and BMRF1 genes, which are targets of ZEBRA's action, and to synergize with the BRLF1 gene product Rta (R transactivator) in activating expression of downstream genes. One mutant class, represented by Z(S186T), was similar to the wild type, although reduced in the capacity to activate BRLF1 and BMRF1 early lytic cycle genes from the latent virus. A second class, represented by Z(S186C) and Z(S186G), was impaired in transcriptional activation, unable to activate early lytic cycle products from the latent virus, and not rescued by overexpression of Rta. A third class, Z(S186A), although unable by itself to activate BRLF1 or other lytic cycle genes, synergized with Rta. Rta rescued the capacity of Z(S186A) to activate the BMRF1 early lytic cycle gene from the latent virus. All mutant classes bound to DNA in vitro, although their capacity to bind to different ZEBRA response elements varied. Serine 186 of ZEBRA is a critical residue that is required for the distinct activities of induction of BRLF1 expression and for synergy with Rta. Since only Z(S186T) among the mutants behaved similarly to the wild type, activation of BRLF1 likely requires phosphorylation of S186. However, since Z(S186A) could synergize with Rta, synergy with Rta does not appear to be dependent on phosphorylation of S186. S186 likely mediates DNA recognition on the BRLF1 promoter in the context of the latent virus, protein-protein interactions, or both. The Z(S186) mutants define the amino acid side chains required for these functions.

Antigens, Viral↗
PubMed1999

Respiratory diphtheria in three paediatric patients.

From August till November 1998, the Paediatric and Anaesthetic Units of Hospital Kuala Terengganu managed three patients from Kuala Terengganu District who were ventilated for respiratory diphtheria. Their ages were 5, 4 and 7 years old and their immunisation for diphtheria were not complete. All three patients presented with respiratory distress and were ventilated for upper airway obstruction. Their treatment included intravenous penicillin and diphtheria antitoxin. One patient died of cardiogenic shock with secondary pneumonia. Pharyngeal and tonsillar swabs of all three patients grew toxigenic Corynebacterium diphtheriae biotype mitis. There were 765 throat cultures taken from contacts. The confirmed positive cultures grew 2 toxigenic and 3 non-toxigenic Corynebacterium diphtheriae biotype mitis and surprisingly, 10 non-toxigenic biotype gravis. A prevalence study is needed to document the endemicity of diphtheria in Kuala Terengganu and to determine the carrier rate of both biotypes. Steps have been taken to increase the immunisation coverage in children. The giving of regular booster doses of diphtheria toxoid to the adult population should be considered.

Airway Obstruction↗
PubMed1998

Tissues of MSH2-deficient mice demonstrate hypermutability on exposure to a DNA methylating agent.

The mutational response of mismatch repair-deficient animals to the alkylating agent N-methyl-N-nitrosourea was evaluated by using a transgenic lacI reporter system. Although the mutations detected in MSH2 heterozygotes were similar to those of controls, MSH2-/- animals demonstrated striking increases in mutation frequency in response to this agent. G:C to A:T transitions at GpG sites, as opposed to CpG sites, dominated the mutational spectrum of both MSH2+/+ and MSH2-/- N-methyl-N-nitrosourea -treated animals. Extrapolating to humans with hereditary non-polyposis colorectal cancer, the results suggest that MSH2 heterozygotes are unlikely to be at increased risk of mutation, even when exposed to potent DNA methylating agents. In contrast, mismatch repair-deficient cells spontaneously arising within individuals with hereditary non-polyposis colorectal cancer would likely exhibit hypermutability in response to such mutagens, an outcome predicted to accelerate the pace of tumorigenesis.

Alkylating Agents↗
PubMed1998

Neuregulins in glial cells.

The role of growth factors in controlling the development of glial cells in both the peripheral and central nervous systems has been investigated for a number of years. The recent discovery of a new family of growth factors termed the neuregulins (NRGs) has led to an explosion of information concerning the putative role of these growth factors in the development of Schwann cells (SC), oligodendrocytes (OLG), and astrocytes. Many of these previous studies have focused on the effects of exogenous NRGs on glial cell development and differentiation. We now review the evidence that these glial cells themselves produce NRGs and discuss the major implications of these findings with respect to glial cell development and diseases which affect glial cell function. We also discuss the potential role of endogenous NRGs following neural injury.

Animals↗
PubMed1998

Fetal weight gain in a serially scanned high-risk population.

Physiological as well as pathological variables influence fetal growth. This study was undertaken to assess the influence of physiological variables on fetal weight gain in a high-risk population with normal outcome. A total of 121 pregnancies had 3-13 (median 8) ultrasound scans in the third trimester. Estimated fetal weight was calculated according to standard formulae. The estimated fetal weight at 30, 34 and 38 weeks and growth per day in the last 2 weeks prior to delivery were calculated and compared between subgroups defined on physiological characteristics, such as maternal height, maternal weight, parity and fetal sex. There were differences in growth curves for each of the physiological parameters studied. Maternal height and weight were significantly related to the estimated fetal weight throughout the third trimester but there were no significant differences in growth per day in the last 2 weeks before birth. In contrast, subgroups defined by parity and fetal sex did not show significant fetal weight differences in the third trimester, but the daily growth rate prior to birth was significantly higher for multiparae and male fetuses. Physiological factors affect fetal weight gain and need to be taken into account when fetal growth is monitored in high-risk pregnancies.

Adult↗
PubMed1997

Catatonia and other motor syndromes in a chronically hospitalized psychiatric population.

BACKGROUND: To determine the motor characteristics of chronic catatonia, catatonia and other motor disorders were systematically rated in a long-term hospitalized sample. METHOD: Chronically hospitalized psychiatric inpatients (N = 42) with a clinical diagnosis of catatonic schizophrenia (295.2X) were rated for catatonia with a novel 23-item catatonia rating scale, and for parkinsonism, dyskinesia and akathisia using standard rating scales with scale-based criteria for case definition. RESULTS: Catatonia was the sole motor syndrome in nine cases (21%), co-existed with parkinsonism in five (12%), tardive dyskinesia in four (10%), and both parkinsonism and tardive dyskinesia in 10 (24%). There was no correlation between total scores across the four rating scales. 'Rigidity' was the sole catatonic sign which overlapped with other scales. The symptom profile of catatonia in this chronic sample was similar to previous reports based on acutely ill patients. CONCLUSION: Catatonia is distinguishable from other motor disorders in chronic psychiatric patients using the 23-item catatonia rating scale. The features of chronic catatonia are described, and the distribution of catatonic signs is similar for chronic and acute catatonia.

Adult↗
PubMed1997

Synergism of lorazepam and electroconvulsive therapy in the treatment of catatonia.

Electroconvulsive therapy (ECT) and lorazepam are effective treatments for catatonia. ECT combined with benzodiazepines has been associated with reduced efficacy and efficiency and therefore is not recommended in the routine practice of ECT. We report 5 prospectively identified cases of catatonia treated either sequentially or concurrently with lorazepam and ECT. In each case, the combination of lorazepam with ECT was superior to monotherapy. This apparent synergism, its possible mechanisms, and its implications for treating catatonia are discussed.

Adolescent↗
PubMed1997

Base transitions dominate the mutational spectrum of a transgenic reporter gene in MSH2 deficient mice.

Tumors derived from individuals with hereditary nonpolyposis colorectal cancer syndrome frequently demonstrate mutations in both alleles of hMSH2, a key gene in DNA mismatch repair (MMR). Sporadic tumors also frequently exhibit MMR deficiency. In keeping with the role of MMR in the maintenance of genome integrity, mice deficient in MSH2 via gene targeting demonstrate a high incidence of thymic lymphomas and small intestinal adenocarcinomas. To investigate the effects of MSH2 deficiency in normal tissues, mice containing a retrievable transgenic lacI reporter gene for mutation detection were crossed with MSH2-/- mice. Mice homozygous for MSH2 deficiency revealed 4.8, 11.0 and 15.2-fold elevations in spontaneous mutation frequency in DNA obtained from brain, small intestine, and thymus, respectively, as compared to heterozygous or wild-type mice. Mutations most frequently recovered from MSH2-/- mice were single base substitutions (77%), particularly base transitions (64%). Frameshifts occurred less frequently (19%) and fell within very short (3-5 bp) mononucleotide runs. Thus the number of key growth control genes potentially impacted by MMR deficiency extends beyond those containing repetitive sequences. These results highlight the capacity for MSH2 deficiency to serve as a potent driving force during the multi-step evolution of tumors.

Animals↗
PubMed1997

Comparison of second trimester biometry in singleton and twin pregnancies conceived with assisted reproductive techniques.

The objective of this study was to investigate the size of singleton vs twin pregnancies at the time of a second trimester dating scan. The analysis included 86 infants from 63 pregnancies achieved with assisted reproductive techniques, comprising 40 singletons and 46 twins. Measurements of second trimester biparietal diameter (n = 85) and femur length (n = 74) were plotted against the precisely known gestational age. A common regression line was calculated for each parameter and the residuals for singletons and twins were compared. Gestational age and weight at birth were also analysed for each group. There was no significant difference between singletons and twins in biparietal diameter or femur length in second trimester. In contrast, twins had a lower mean birthweight, gestational age at birth, and weight-for-gestational age centile compared with singletons. Singleton babies from these pregnancies had an average birthweight centile of 49.8% (i.e. close to the median for spontaneously conceived pregnancies in our population). We concluded that the same pregnancy dating charts can be used for singletons and twins. At corresponding gestational age, twins are smaller than singletons at birth because of slower growth in the third trimester.

Anthropometry↗
PubMed1997

Gestational age and induction of labour for prolonged pregnancy.

OBJECTIVE: To examine the length of gestation according to menstrual and ultrasound scan dates, and the rate of induction of labour in a unit with a routine induction policy for prolonged pregnancy. DESIGN: Retrospective analysis of computer files of 24,675 pregnancies delivered in a teaching hospital between 1988 and 1995, which had a record of the last menstrual period and a dating ultrasound scan. Detailed survey of 168 casenotes of consecutive inductions of labour to establish the indications given. SETTING: Teaching hospital with policies of routine mid-trimester ultrasound scan and routine induction for prolonged pregnancy at 290 to 294 days. MAIN OUTCOME MEASURES: Gestational age at delivery by menstrual history and ultrasound biometry in spontaneous and induced labours. RESULTS: The single largest category of reasons given for induction of labour was prolonged pregnancy. 'Post-term pregnancy', from the date of expected delivery as recorded in the notes, together with 'maternal request' and 'social factors', were the reasons given for induction of labour in 71.3% of cases. Menstrual dates systematically overestimated gestational age at term when compared with scan dates. After 41 weeks, this difference exceeded the confidence limits for second trimester scan dating error, suggesting that most pregnancies which are considered 'prolonged' according to menstrual dates are in fact mis-dated. The median gestational age for induced labours was 286 days by last menstrual period but only 280 days by scan, and most (71.5%) inductions done post-term (> 294 days) according to menstrual dates were not post-term if scan dates alone are used to calculate the gestational age. The average induction rate over the seven year study period was 16.6%. It was higher when there was any gestational age error in either direction (16.8%) compared with when menstrual and scan dates were in complete agreement (13.7%, OR 1.27, CI 1.09-1.47, P < 0.001). The induction rate was highest (up to 21.8%) in the cases where menstrual dates overstated gestational age without exceeding the usual limits for adjusting dates according to scan. Such overestimation within tolerance limits of 7, 10 or 14 days occurred in 37.1%, 45.8%, or 52.6% of all pregnancies, respectively. CONCLUSIONS: Most pregnancies undergoing post-term induction are not post-term when assessed by ultrasound dates. Regardless of whether prolonged pregnancy is considered to be a risk factor requiring intervention, the proportion of pregnancies considered 'post-term' can be reduced considerably by a dating policy which ignores menstrual dates and establishes the expected delivery date on the basis of ultrasound dates alone.

Cesarean Section↗
PubMed1996

Genetic variation in immediate and delayed postictal refractory period in rats.

We determined postictal refractoriness in Sprague-Dawley rats by comparing lengths of two suprathreshold ECS seizures given 15 s to 24 h apart. A bimodal (immediate and delayed) decrease in seizure duration was found, suggesting ECS alters mechanisms of seizure termination. Since adenosine is implicated in seizure termination, we determined immediate (30 s) and delayed (24 h) postictal ECS refractoriness in Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats which vary in adenosine properties and initial ECS seizure length. At 30 s, the decrease in seizures did not differ between WKY (-44%) and SHR (-36%) rats. At 24 h, SHR rats showed no change while the WKY rats showed a 20% decrease in seizure length (P < 0.01). These two strains also differed in the ability of the adenosine antagonist caffeine (50 mg/kg, i.p.) to prolong ECS seizures (no change for WKY, +13% for SHR, P < 0.001). The results suggest immediate and delayed postictal refractoriness are subject to genetic variation and may depend on central adenosine mechanisms.

Adenosine↗
PubMed1996

Polymorphisms in the human apolipoprotein-J/clusterin gene: ethnic variation and distribution in Alzheimer's disease.

Apolipoprotein-J/clusterin (APOJ/CLI) shares many biological properties with apolipoprotein-E (APOE) including, but not limited to, avid binding with beta-amyloid peptide. Thus, APOJ/CLI warrants scrutiny as a candidate Alzheimer's disease (AD) susceptibility gene. We identified seven nucleotide sequence polymorphisms in APOJ/ CLI, two of which, in exon 7, after the predicted amino acid sequence. The JVIIB variant is an asparagine-to-histidine substitution, which deletes a glycosylation signal at amino acid 317; the JVIIC variant is an aspartate-to-asparagine substitution, which forms a new glycosylation signal at position 328. Both of these coding variants, as well as two neutral polymorphisms in exon 2, were more frequent in African-Americans than Hispanics and were rare in Caucasians. However, no individual coding or noncoding variant was consistently associated with AD. At the population level, APOJ/CLI polymorphisms are frequent among persons of African descent, but probably do not alter susceptibility to AD.

Black or African American↗
PubMed1996

Trimethaphan (Arfonad) control of hypertension and tachycardia during electroconvulsive therapy: a double-blind study.

STUDY OBJECTIVE: To ascertain the optimal dose of trimethaphan camsylate administered by intravenous (i.v.) bolus injection for the control of hypertension and tachycardia during electroconvulsive therapy (ECT). DESIGN: Prospective, double blind, within-subject study. SETTING: Treating room of the psychiatric unit of the University Hospital at Stony Brook, NY. SUBJECTS: Patients undergoing ECT for major psychiatric illnesses. MEASUREMENTS AND MAIN RESULTS: Fifteen ASA status I or II patients received in a random sequence placebo, or 5, 10, or 15 mg boluses of trimethaphan during their second to fifth treatments. Blood pressure (BP) and heart rate (HR) were recorded every 30 seconds by automated oscillometric recorder. Recordings taken before administration, during seizure, 5, and 20 minutes after seizure were examined. All doses ameliorated BP (systolic, diastolic, and mean), HR, and rate pressure product (RPP) increases during the seizure, compared with placebo. The group that received 15 mg exhibited smaller increases in RPP, i.e., 67.7% increase compared with 155.4%, 110.9%, and 98.7% increases for the placebo, 5, and 10 mg, respectively. The 10 mg and 15 mg doses caused a faster return to baseline than did the 5 mg dose or placebo. No rebound hypertension, prolonged hypotension, arrhythmias, or other side effects were noted. Trimethaphan did not alter seizure duration. CONCLUSIONS: Trimethaphan is safe, practical, and effective in the management of the hyperdynamic response to ECT. An i.v. bolus injection of 15 mg is more effective than 10 mg or 5 mg.

Adult↗
PubMed1996

Catatonia. I. Rating scale and standardized examination.

To facilitate the systematic description of catatonic signs, we developed a catatonia rating examination, rating scale and screening instrument. We constructed a 23-item rating scale and a truncated 14-item screening instrument using operationalized definitions of signs ascribed to catatonia in published sources. Inter-rater reliability was tested in 44 simultaneous ratings of 28 cases defined by the presence of > or = 2 signs on the 14-item screen. Inter-rater reliability for total score on the rating scale was 0.93, and mean agreement of items was 88.2% (SD 9.9). Inter-rater reliability for total score on the screening instrument was 0.95, and mean agreement of items was 92.7% (SD 4.9). Diagnostic agreement was high based on criteria for catatonia put forth by other authors. Seven per cent (15/215) of consecutively admitted patients to an academic psychiatric in-patient facility met criteria for catatonia. It is concluded that catatonia is a distinct, moderately prevalent neuropsychiatric syndrome. The rating scale and screening instrument are reliable and valid. Their use facilitates diagnosis, treatment protocols, and cross-study comparisons.

Catatonia↗