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Biomedical subjects

J S Hall

Publications and source records attributed to J S Hall.

At least 19 recordsLinked to original sources

Three distinct mechanisms facilitate genetic isolation of sympatric wheat streak mosaic virus lineages.

Cross-protection and vector transmission bottlenecks have been proposed as mechanisms facilitating genetic isolation of sympatric viral lineages. Molecular markers were used to monitor establishment and resolution of mixed infections with genetically defined strains of wheat streak mosaic virus (WSMV). Two closely related WSMV strains from the U.S. (Type and Sidney 81) exhibited reciprocal cross-protection in wheat, confirming this classic phenomenon as a mechanism of genetic isolation. In contrast, cross-protection between either U.S. strain and the divergent El Batán 3 strain from Mexico was unilateral, erratic, and only partially effective. Distribution of WSMV strains within individual leaves of plants supporting a mixed infection of Type and Sidney 81 was spatially nonuniform. Strain distribution among individual tillers of coinfected plants also was heterogeneous, with some containing either Type or Sidney 81 alone and some containing both. Transmission by wheat curl mites, acquiring virus from source plants simultaneously infected with both Type and Sidney 81, often resulted in test plants bearing only a single WSMV strain. Spatial subdivision of virus strains within coinfected plants likely contributed to vector transmission bottlenecks during acquisition. Collectively, these three distinct mechanisms enhance genetic isolation of individual viral lineages, and together with stochastic processes, may explain generation and maintenance of genetic diversity in field populations.

Animals↗

Contributions of genetic drift and negative selection on the evolution of three strains of wheat streak mosaic tritimovirus.

Genome sequences of three Wheat streak mosaic virus (WSMV) strains were compared. The Type and Sidney 81 strains of WSMV from the American Great Plains were closely related, with sequence identities of 97.6% (nucleotide) and 98.7% (amino acid). In contrast, the El Batán 3 strain from central Mexico was divergent, and shared only 79.2-79.3% (nucleotide) and 90.3-90.5% (amino acid) sequence identity with Type and Sidney 81. All three WSMV strains were serologically related, however the El Batán 3 capsid protein (CP) had 15 fewer amino acid residues. Phylogenetic analysis of the CP cistron indicated that Type, Sidney 81, and nine other American isolates of WSMV were closely related and distinct from the El Batán 3 sequence. Nucleotide substitutions among the WSMV strains were not randomly distributed across the genome with more variation within P1, HC-Pro, and CP, and less within P3. One 400-nucleotide region of the genome, corresponding to the 3'-end of P3, was strikingly deficient in silent substitutions. Nonetheless, the ratio of synonymous to non-synonymous substitutions throughout the genome was essentially the same for all three WSMV strains. Collectively, our data indicate that both genetic drift and negative selection have contributed to the evolution of WSMV strains.

Amino Acid Substitution↗

Structure and temporal dynamics of populations within wheat streak mosaic virus isolates.

Variation within the Type and Sidney 81 strains of wheat streak mosaic virus was assessed by single-strand conformation polymorphism (SSCP) analysis and confirmed by nucleotide sequencing. Limiting-dilution subisolates (LDSIs) of each strain were evaluated for polymorphism in the P1, P3, NIa, and CP cistrons. Different SSCP patterns among LDSIs of a strain were associated with single-nucleotide substitutions. Sidney 81 LDSI-S10 was used as founding inoculum to establish three lineages each in wheat, corn, and barley. The P1, HC-Pro, P3, CI, NIa, NIb, and CP cistrons of LDSI-S10 and each lineage at passages 1, 3, 6, and 9 were evaluated for polymorphism. By passage 9, each lineage differed in consensus sequence from LDSI-S10. The majority of substitutions occurred within NIa and CP, although at least one change occurred in each cistron except HC-Pro and P3. Most consensus sequence changes among lineages were independent, with substitutions accumulating over time. However, LDSI-S10 bore a variant nucleotide (G(6016)) in NIa that was restored to A(6016) in eight of nine lineages by passage 6. This near-global reversion is most easily explained by selection. Examination of nonconsensus variation revealed a pool of unique substitutions (singletons) that remained constant in frequency during passage, regardless of the host species examined. These results suggest that mutations arising by viral polymerase error are generated at a constant rate but that most newly generated mutants are sequestered in virions and do not serve as replication templates. Thus, a substantial fraction of variation generated is static and has yet to be tested for relative fitness. In contrast, nonsingleton variation increased upon passage, suggesting that some mutants do serve as replication templates and may become established in a population. Replicated mutants may or may not rise to prominence to become the consensus sequence in a lineage, with the fate of any particular mutant subject to selection and stochastic processes such as genetic drift and population growth factors.

Biological Evolution↗

Intracerebral clysis in a rat glioma model.

OBJECTIVE: Intracerebral clysis (ICC) is a new term we use to describe convection-enhanced microinfusion into the brain. This study establishes baseline parameters for preclinical, in vivo, drug investigations using ICC in a rat glioma model. METHODS: Intracranial pressure was measured, with an intraparenchymal fiber-optic catheter, in male Fischer rats 10, 15, 20, and 25 days after implantation of C6 glioma cells in the right frontal lobe (n = 80) and in control rats without tumor (n = 20), before and during ICC. A 25% albumin solution (100 microl) was infused through an intratumoral catheter at 0.5, 1.0, 2.0, 3.0, and 4.0 microl/min. Infusate distribution was assessed by infusion of fluorescein isothiocyanate-dextran (Mr 20,000), using the aforementioned parameters (n = 36). Brains were sectioned and photographed under ultraviolet light, and distribution was calculated by computer analysis (NIH Image for Macintosh). Safe effective drug distribution was demonstrated by measuring tumor sizes and apoptosis in animals treated with N,N'-bis(2-chloroethyl)-N-nitrosourea via ICC, compared with untreated controls. Magnetic resonance imaging noninvasively confirmed tumor growth before treatment. RESULTS: Intracranial pressure increased with tumor progression, from 5.5 mm Hg at baseline to 12.95 mm Hg on Day 25 after tumor cell implantation. Intracranial pressure during ICC ranged from 5 to 21 mm Hg and was correlated with increasing infusion volumes and increasing rates of infusion. No toxicity was observed, except at the higher ends of the tumor size and volume ranges. Fluorescein isothiocyanate-dextran distribution was greater with larger infusion volumes (30 microl versus 10 microl, n = 8, P < 0.05). No significant differences in distribution were observed when different infusion rates were compared while the volume was kept constant. At tolerated flow rates, the volumes of distribution were sufficient to promote adequate drug delivery to tumors. N,N'-Bis(2-chloroethyl)-N-nitrosourea treatment resulted in significant decreases in tumor size, compared with untreated controls. CONCLUSION: The C6 glioma model can be easily modified to study aspects of interstitial delivery via ICC and the application of ICC to the screening of potential antitumor agents for safety and efficacy.

Animals↗

Limitations of the C6/Wistar rat intracerebral glioma model: implications for evaluating immunotherapy.

OBJECTIVE: Intracranial rat glioma models are a useful method for evaluating the efficacy and toxicity of novel therapies for malignant glioma. The C6/Wistar model has been used extensively as a reproducible in vivo model for studying primary brain tumors including anti-glioma immune responses. The objective of the present study is to provide in vivo evidence that the C6 rat glioma model is allogeneic within Wistar rats and is therefore inappropriate for evaluating immune responses. METHODS: Growth patterns and immune responses of C6 cells implanted into the brain and flank of Wistar rats were analyzed and compared to an immunogenic syngeneic model (9L/Fischer). RESULTS: Wistar rats with C6 tumors developed a potent humoral and cellular immune response to the tumor. Wistar rats given simultaneous flank and intracerebral tumors had a survival rate of 100% compared to an 11% survival rate in control animals receiving only intracranial C6 cells. CONCLUSION: The C6 rat glioma induces a vigorous immune reaction that may mimic a specific anti-tumor response in Wistar rats. Efficacy of immunotherapy within this model must be cautiously interpreted.

Animals↗

Tissue distribution and antitumor activity of topotecan delivered by intracerebral clysis in a rat glioma model.

OBJECTIVE: Intracerebral clysis is a drug delivery technique that depends on convection-enhanced microinfusion to achieve therapeutic drug levels within the brain. In this study, brain tumor-bearing rats were treated with topotecan delivered systemically and by the intracerebral clysis method. Our objective was to determine the efficacy and tissue distribution of topotecan delivered by intracerebral clysis. METHODS: The C6/Wistar rat glioma model was used after a thymidine incorporation assay determined topotecan sensitivity of C6 cells in vitro. Long-term survival of animals provided objective measurements of efficacy; records of animal weight during treatment and neurological status served to approximate toxicity. Topotecan tissue penetration was measured in samples of ex vivo tumor and surrounding brain tissue with high-pressure liquid chromatography. RESULTS: Dose escalation demonstrated significant sensitivity of C6 glioma cells to topotecan (median lethal dose, 0.19 micromol/L). Eleven of 12 rats bearing established intracerebral C6 glioma and receiving topotecan by intracerebral clysis survived beyond the end point of 120 days; no untreated control or systemically treated animal survived beyond 26 days (n = 18; P < 0.005). Histopathological assessment of animals demonstrated significant tumor masses in the brains of intraperitoneally treated animals and untreated control animals. In contrast, no residual tumor was found in the brains of intracerebral clysis groups. Animal weights during treatment were markedly reduced by intraperitoneal dosing (n = 6) but not by low-dose intracerebral clysis (32 microg/kg/d for 5 d; n = 6). None of the low-dose intracerebral clysis-treated animals demonstrated neurological toxicity, and one high-dose intracerebral clysis-treated animal (160 microg/kg/d for 2 d; n = 6) died during follow-up. Topotecan was detected well beyond the boundaries of the tumor and even in the contralateral hemisphere in animals treated with intracerebral clysis. CONCLUSION: Topotecan delivered by the intracerebral clysis method is effective for treatment of brain tumors in the rat glioma model. These studies provide compelling justification for further preclinical testing to formally evaluate toxicity and efficacy with variable dosing schedules.

Animals↗

Maternal pre-pregnancy weight and placental weight determine birth weight in normal Jamaican infants.

Birth weight is related to neonatal health and long-term risk of chronic disease. Since animal studies have shown that birth outcome is related to placental function, the present project was designed to explore the relationship between birth weight and placental growth and composition with maternal factors during pregnancy among normal term pregnancies in 51 primiparous and 40 multiparous women delivering at the University Hospital of the West Indies. Both groups were followed from 15 weeks of gestation to term. The primiparous group was generally younger than the multiparous (mean age 22 +/- 4 versus 31 +/- 5 yr). They were significantly lighter (55 +/- 8 versus 61 +/- 9 kg) with a lower body mass index (21 +/- 3 versus 23 +/- 4 kg/m2) during early pregnancy, but gained more weight during pregnancy, 11 kg compared with 8 kg, respectively. The duration of pregnancy was similar for both groups. Although the size of the placenta was not significantly different between the two groups, the mean weight of the multiparous placentae was more than that of the primiparous placentae. Also, for all mothers both placental weight and initial maternal weight related directly to birth weight. Placental non collagen protein (NCP), sodium and potassium contents were significantly higher for multiparous women and were related to birth weight. The primiparous group had babies who were significantly lighter, 3.03 kg compared with 3.36 kg, for the multiparous and this could be attributed to differences in placental function and maternal weight. When account was taken of the difference in maternal weight at the start of pregnancy and the difference in placental weight, parity no longer explained any of the differences in birth weight. It is concluded that maternal body weight at the time of becoming pregnant and the early development of the placenta determine the efficiency with which nutrients might be delivered to the foetus and hence foetal growth. The difference in birth weight between primiparous and multiparous women can be explained by the differences in maternal weight at the time of becoming pregnant.

Adult↗

Molecular cloning, sequencing, and phylogenetic relationships of a new potyvirus: sugarcane streak mosaic virus, and a reevaluation of the classification of the potyviridae.

The nucleic acid of a serologically distinct potyvirus, originally isolated out of sugar cane from Pakistan, was reverse transcribed and the 3' terminal 2000 bp was PCR amplified, cloned, and sequenced. Phylogenetic comparisons of viruses representing each genus of the Potyviridae show that the Pakistani isolate is most closely related to the rymoviruses wheat streak mosaic virus (WSMV) and brome streak mosaic virus. We therefore propose that this new virus species be named sugar cane streak mosaic virus to reflect its similarity to WSMV. The phylogenetic data also show that the genus Rymovirus contains at least two unique evolutionary lineages. Thus the current taxonomy, based on transmission vector, is paraphyletic. We present an analysis of the taxonomic relationships among members of the family and propose a classification that both resolves the paraphyly and more accurately represents the evolutionary history of the Potyviridae.

Amino Acid Sequence↗

Maternal nutritional status in pregnancy and blood pressure in childhood.

OBJECTIVE: To examine the relation between indices of maternal nutrition during pregnancy, including haemoglobin concentration, skinfold thickness and body weight, and the child's blood pressure at 10 to 12 years of age. DESIGN: Follow up study of children whose mothers had haemoglobin estimations, weights and skinfold thicknesses recorded during pregnancy. SETTING: Kingston, Jamaica. SUBJECTS: Seventy-seven children whose mothers took part in a prospective study of nutrition during pregnancy in relation to fetal growth. MAIN OUTCOME MEASURE: Blood pressure at 10 to 12 years of age. RESULTS: The child's mean systolic pressure adjusted for current weight rose by 2.6 mmHg (95% CI 0.5-4.6, P = 0.01) for each 1 g/dl fall in the mother's lowest haemoglobin during pregnancy. Mothers with a lower haemoglobin had thinner skinfold thicknesses, especially over the triceps (P = 0.005). In multiple regression analyses, taking account of the child's sex and current weight, there was a strong association between thin maternal triceps skinfold thickness at 15 weeks of gestation and raised blood pressure in the offspring. Taking account of the mother's triceps skinfold thickness abolished the relation between lower haemoglobin and raised blood pressure in the child. Lower weight gain between 15 and 35 weeks of gestation was independently associated with raised children's blood pressure. Systolic pressure rose by 10.7 mmHg (95% CI 5.7 to 15.6, P = 0.0001) for each log mm decrease in the mother's triceps skinfold thickness, and by 0.6 mmHg (95% CI 0.1 to 1.0, P = 0.02) for each 1 kg decrease in the mother's weight gain during pregnancy. CONCLUSIONS: These results parallel animal experiments suggesting that impaired maternal nutrition may underlie the programming of adult hypertension during fetal life.

Blood Pressure↗

Cellular effects of piezoelectric versus electrohydraulic high energy shock waves.

High energy shock waves produced by a piezoelectric lithotripter, (EDAP LT.01) and an electrohydraulic lithotripter, (Dornier HM3) were examined for their effects on Chinese hamster ovary cells in suspension. The EDAP caused acute lactate dehydrogenase release, consistent with severe membrane disruption in a proportion of cells, with the remaining proportion of cells replicating normally as measured by clonogenic assay. Similarly, the Dornier also caused lactate dehydrogenase release. However, a significant proportion of cells which remained "viable" after Dornier treatment, (intact to lactate dehydrogenase), did not replicate by clonogenic assay. The Dornier HM3 lithotripter has been reported to produce free radicals in aqueous solution. In the current investigation, we could not detect significant free radical formation from the EDAP LT.01. Chinese hamster ovary cell killing by the Dornier HM3 was significantly augmented by radiosensitizers, 5-iodo-2-deoxyuridine or buthionine sulfoximine, while radioprotectors cysteamine and WR-1065 had no protective effect. EDAP cell killing was not influenced by either radioprotectors or radiosensitizers. The mechanism of in vitro cytotoxicity differs between piezoelectric and electrohydraulic high energy shock wave delivery.

Animals↗

Glanzmann's thrombasthenia and pregnancy.

Glanzmann's thrombasthenia is a rare congenital disorder of platelet function manifesting as defective primary haemostasis. Bleeding episodes often require platelet transfusions, and allo-immunization to donor platelets may occur. The problems of ensuring adequate haemostatic potential for delivery of an allo-immunized pregnant female with Glanzmann's thrombasthenia are presented.

Adult↗

Dietary patterns and nutrition in pregnancy in Jamaica.

During a study of nutrition in pregnancy, the diets of 108 Jamaican pregnant women were assessed by single 24-hour recalls. The women were 16-45 years old, of mixed parity (0-9), attended private (23 per cent) and public (77 per cent) antenatal clinics and differed in stage of pregnancy at interview. Mean energy intake (2110 +/- 739 kcal/d) was low, 83 per cent of the average Recommended Dietary Allowance for the Caribbean (CFNI 1976). Most (76 per cent) women had low energy and dietary iron (75 per cent) intakes. Fewer women had low riboflavin (42 per cent) or protein intakes (29 per cent). Maternal age, parity, obstetric performance, and unusual cravings influenced maternal nutrition to some extent. Dietary assessments overestimated the risk of maternal malnutrition.

Adolescent↗

Fluorometric calcium measurement.

Measuring the fluorescence of dyes specific for calcium and other cations allows the elucidation of cellular mechanisms such as neurotransmission, muscle contraction and cardiovascular regulation.

Animals↗

Response of plasma norepinephrine concentration to the vasodepression caused by beta-adrenoceptor antagonists in the conscious spontaneously hypertensive rat.

The subcutaneous administration of a single dose of the beta-adrenoceptor antagonists atenolol, betaxolol, oxprenolol, pindolol, propranolol, or sotalol to conscious spontaneously hypertensive rats (SHR) lowered mean arterial pressure (MAP) by 15-20%, but this vaso-depression was not accompanied by a rise in plasma norepinephrine (NE) concentration. When MAP was decreased at the same rate and to the same extent with the vasodilator minoxidil, plasma NE concentration increased 50-75%. Atenolol, betaxolol, propranolol, and sotalol lowered heart rate, whereas oxprenolol, pindolol, and minoxidil elicited a tachycardia. Atenolol (-48%), betaxolol (-63%), and propranolol (-29%) significantly suppressed plasma renin activity (PRA), and minoxidil elevated PRA by 150-315%. Pindolol (+37%) caused a nonsignificant increase in PRA, and oxprenolol (-23%) and sotalol (-17%) produced nonsignificant decreases in PRA. Because the beta-adrenoceptor antagonists did not increase plasma NE concentration, whereas an equivasodepressor dose of minoxidil did, we conclude that plasma NE concentration is inappropriately low relative to the decrease in MAP caused by beta-adrenoceptor antagonists in the conscious SHR. In addition, the diverse effects of the beta-adrenoceptor antagonists on PRA in SHRs indicate that a suppression of renin release cannot account for either the decrease in MAP caused by these drugs or the failure of plasma NE concentration to increase when MAP is decreased by beta-adrenoceptor antagonists.

Adrenergic beta-Antagonists↗

Pregnancy in chronic active hepatitis with cirrhosis.

Pregnancy in chronic active hepatitis and cirrhosis is rare. There is an appreciable perinatal mortality and the effect of pregnancy on the underlying liver disease remains uncertain. Two patients with autoimmune chronic active hepatitis with cirrhosis who became pregnant during an active stage of their disease while on therapy are described. Both had an uneventful pregnancy with successful deliveries. One of the patients had two other pregnancies but the pregnancy had to be terminated because of clinical deterioration. With close supervision patients with chronic active hepatitis and cirrhosis may have successful pregnancies.

Abortion, Therapeutic↗

The effect of propranolol on blood pressure and central MOPEG concentration in the conscious spontaneously hypertensive rat.

The total concentration of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethyl glycol (MOPEG) and propranolol concentration was measured in the medulla, pons, hypothalamus and thoracic spinal cord of conscious spontaneously hypertensive rats during the development of the antihypertensive effect of a single dose of d,l-propranolol (10 mg/kg s.c.). Propranolol significantly increased MOPEG concentration by 21% in the thoracic spinal cord (2 h) and 16% in the hypothalamus (4 h), but no consistent pattern of change in regional MOPEG concentration was found in relation to the time course of the antihypertensive effect of propranolol.

Animals↗

Iatrogenic neonatal and maternal hyponatraemia following oxytocin and aqueous glucose infusion during labour.

Maternal and umbilical cord serum sodium and osmolality were studied prospectively in 140 deliveries to investigate whether transplacental hyponatraemia, seen following oxytocin infusion during labour, was due to the antidiuretic effect of oxytocin or was secondary to the infusion of aqueous glucose used as a vehicle for oxytocin, or both. Forty-five women received oxytocin in aqueous glucose for induction or augmentation of labour (oxytocin group), 43 received aqueous glucose infusion alone (glucose group) and 52 did not receive any intravenous infusions (control group). Mean cord sodium levels were significantly lower in the oxytocin (131.4, SD 3.6 mmol/l) and glucose groups (132.5, SD 3.2 mmol/l) than in the control group (135.0, SD 3.0 mmol/l). Hyponatraemia (Na less than 130 mmol) was seen in 47% and 30% of the infants in the oxytocin and glucose groups respectively, in contrast to only 5.8% of the infants in the control group. Significant negative linear correlations were seen between serum sodium and the dose of oxytocin (P less than 0.01) and log of the volume of glucose solution infused (P less than 0.001). The hyponatraemic newborn infants had a significantly higher incidence of transient neonatal tachypnea (7/37, 19%) than the normonatraemic infants (2%). Our results strongly suggest that infusion of oxytocin and glucose both cause maternal and transplacental hyponatraemia, even in recommended doses. This should be taken in account while planning a safe dose of oxytocin and glucose for infusion during labour.

Adult↗