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Biomedical subjects

R W Shepherd

Publications and source records attributed to R W Shepherd.

At least 91 records · Page 5Linked to original sources
PubMed1987

Heterogeneity in the responses of clones of Giardia intestinalis to anti-giardial drugs.

Clones of two stocks of Giardia intestinalis have been tested by the [3H]thymidine uptake assay to determine their sensitivity to metronidazole, tinidazole, furazolidone and quinacrine. Each stock was not homogeneous with respect to drug sensitivity but was composed of different populations of organisms. Doubling times of lines derived from clones of a stock did not vary significantly. These findings may, in part, account for treatment failures in human giardiasis patients.

Animals↗
PubMed1987

Gastroesophageal reflux in children. Clinical profile, course and outcome with active therapy in 126 cases.

A clinical profile and the course and outcome with therapy of 126 infants and children with gastroesophageal reflux (GER), diagnosed at a median age of 2.5 months and followed for 1.5 to 3.5 years is presented. Features included repeated regurgitation or rumination (99%), signs suggesting esophageal pain (49%, excessive crying "colic," sleep disturbance, Sutcliffe-Sandifer syndrome, respiratory symptoms 42%), failure to thrive (18%), and minor hematemesis (18%). Feeding problems and maternal distress were common, associated with child abuse in four cases. Therapy was initially conservative (posture, thickening of feeds, antacids, bethanechol), augmented by cimetidine in those with proven esophagitis (n = 34, 0.27%). Most (81%) were symptom-free by 18 months of age (55% by 10 months of age); 17 percent had fundoplication with good results; 2 percent have persisting symptoms beyond 2 years of age (1% failed surgery). No deaths were recorded. Surgery was performed for recurrent apneas/aspiration (6%), refractory esophagitis or stricture (5%), and failed medical management (7%). Esophagitis was a significant determinant to outcome, and the importance of selective early endoscopy is emphasized. GER is a cause of considerable morbidity in infants but, with active therapy, is self-limiting in the majority. Certain distinctive clinical signs indicate those patients who require detailed investigation and to whom more aggressive therapeutic efforts should be directed.

Child↗
PubMed1986

Identification of cystic fibrosis homozygotes and heterozygotes by isoelectric focusing of serum proteins.

Screening of 44 cystic fibrosis homozygotes, 17 heterozygotes and 36 normal controls, by identification of cystic fibrosis protein (CFP), was performed on sera using an improved isoelectric focusing technique. CFP was observed in 91% of homozygotes, 88% of heterozygotes and 8% of normal controls tested. Partial purification of CFP by chromatofocussing indicates that CFP has a molecular weight of about 52,000 u. It is speculated that CFP is a normal serum protein that exhibits a quantitative difference in concentration between CF homozygotes, heterozygotes and normals.

Blood Proteins↗
PubMed1986

Nutritional rehabilitation in cystic fibrosis: controlled studies of effects on nutritional growth retardation, body protein turnover, and course of pulmonary disease.

The effects of a sustained increase in energy and protein intake on weight gain, growth, body protein metabolism, and the course of pulmonary disease were studied in 10 undernourished patients with cystic fibrosis unable to maintain nutrition and growth by the oral route and with declining nutritional and pulmonary status in the year prior to study. A 1-year course of nutrient supplementation using a semielemental high-nitrogen formula was delivered by nocturnal intragastric feeding or as an orally administered supplement; progress was compared with that of 14 height-, sex- and FEV1-matched patients with cystic fibrosis receiving conventional therapy. Supplementation resulted in a catch-up weight gain and sustained improvement in linear growth, with fewer pulmonary infections per year than during the initial observation period. Better weight gain and linear growth than in the comparison group were observed, as well as a significant reversal of the trend for deteriorating lung function. Compared with data from healthy children, 15N-glycine kinetics demonstrated increased protein breakdown and negligible net protein deposition in the treatment group prior to supplementation. After supplementation, synthesis in excess of breakdown, with net protein accretion, occurred by 1 month of supplementation. By 6 to 12 months a significant reduction in the previously high rate of mean synthesis and breakdown was observed, with maintenance of net anabolism. These dynamic changes in whole-body protein turnover reflect a long-term improvement in energy and protein intake, which can favorably affect nutrition, growth, and the course of pulmonary disease in problem cases of cystic fibrosis.

Adolescent↗
PubMed1986

Chemotherapy in giardiasis: clinical responses and in vitro drug sensitivity of human isolates in axenic culture.

To investigate drug sensitivities of human Giardia isolates, we developed a reproducible in vitro 3H-thymidine uptake assay to compare drug potencies. Among 13 Giardia intestinalis stocks obtained from the culture of trophozoites isolated from duodenal juice, considerable variation in susceptibility to a range of currently used drugs was found. The population doubling time of these stocks also varied widely. Clinical features in patients ranged in severity from mild chronic diarrhea to a celiac-like syndrome, with a similar variation in the degree of histologic change in the mucosa. Brush-border enzyme activities were universally reduced in children younger than 5 years of age. The two isolates with the highest ID50 values for furazolidone in vitro were from patients who had persistent symptoms after treatment with this drug; these patients subsequently responded to treatment with a nitroimidazole with greater in vitro potency. These studies suggest that biologic variants of G. intestinalis exist in humans and may in part account for the variable clinical manifestations and for some treatment failures.

Animals↗
PubMed1986

The activity of drugs against Giardia intestinalis in neonatal mice.

The activities of 12 5-nitroimidazoles and ten other compounds have been compared against Giardia intestinalis stock BRIS/83/HEPU/106 in a suckling mouse model. Ronidazole, satranidazole and fexinidazole were the most active compounds being 2.8, 2.0 and 2.0 times more active than tinidazole respectively and warrant further investigation as potential chemotherapeutic agents. The results obtained in mice are consistent with the known activity of nitroimidazoles in man. There was a strong positive correlation between these results and previous in-vitro studies obtained using a 3H-thymidine uptake assay, indicating that in-vitro studies are of value in predicting in-vivo responses.

Animals↗
PubMed1985

Whole body protein turnover in malnourished cystic fibrosis patients and its relationship to pulmonary disease.

To investigate the effect of pulmonary disease in cystic fibrosis (CF), total body protein synthesis and catabolism were determined in eight CF children with acute exacerbations of pulmonary infection at the time of study (CF I), a group of CF children (n = 7) with chronic but stable pulmonary disease (CF II) and a group (n = 8) of healthy children. Protein synthesis was determined by the method of Waterlow et al (1978) using a single oral dose of 15N glycine and protein catabolism derived from nitrogen balance. Protein synthesis was markedly decreased (p less than 0.001) in the CF I group (1.01 +/- 0.10 g kg-1 10 h-1) compared with that of controls (2.02 +/- 0.08) and with CF children with chronic but stable pulmonary disease (CF II) (2.36 +/- 0.17). Protein catabolism was increased (p less than 0.01) in the CF II group compared with both controls and CF I. These findings contrast strongly to studies in normal children and those with mild protein-energy malnutrition (PEM) and infection, where infection increased protein synthesis, but are consistent with the observed decrease in protein turnover where severe PEM is accompanied by infection. We conclude that repeated pulmonary infection can adversely affect protein-energy balance and that adequate nutritional support should be considered in management during and after each episode.

Adolescent↗
PubMed1985

A comparison of the in-vitro activity of some 5-nitroimidazoles and other compounds against Giardia intestinalis.

The activities of 11 5-nitroimidazole compounds have been compared against Giardia intestinalis in vitro using a 3H-thymidine incorporation assay. All the compounds were at least equipotent to, or more active than metronidazole with the exception of panidazole. Satranidazole, ronidazole and S75 0400 A were all about five times more active than metronidazole and warrant further study as potential chemotherapeutic agents for man. No major differences in the response to these compounds was found between two stocks of Giard. intestinalis with the exception of flunidazole. Several other antiprotozoal drugs showed activity against Giard. intestinalis. Berberine sulphate, paromomycin sulphate, erythromycin estolate and sulphasalazine, all of which have been used to treat human patients, showed no activity in vitro.

Giardia↗
PubMed1984

Cryopreservation of viable Giardia intestinalis trophozoites.

A technique is described for the cryopreservation of Giardia intestinalis trophozoites. The most satisfactory results were obtained when organisms were preserved with either 7.5 or 10% dimethyl sulphoxide (Me2SO) and cooled using a liquid nitrogen controlled freezer. Under these conditions more than 70% of organisms were motile after thawing. Lower recovery rates were obtained using glycerol as the cryopreservant or when samples were placed directly into a -70 degrees C refrigerator to cool. Cultures were successfully re-established from material cooled under controlled conditions using either 7.5% Me2SO or glycerol as the cryopreservant. However, the former had an initial generation time of 12.0 hours compared to 24.5 hours for the latter.

Animals↗
PubMed1984

The sensitivity of Giardia intestinalis to drugs in vitro.

Techniques are described for the isolation, microculture and assessment of viability of Giardia intestinalis. The susceptibility of five recent Brisbane isolates and the Portland 1 stock to metronidazole, tinidazole, furazolidone and quinacrine has been determined. All stocks showed little variation in sensitivity to these drugs. The 3H-thymidine incorporation assay proved to be a much more sensitive method of assessing relative drug activity than either motility or dye exclusion methods. Tinidazole proved to be the most effective drug in vitro followed by furazolidone and metronidazole. Quinacrine was the least effective. The generation time of stocks in vitro varied from 12.5 to 44.2 h and the possible significance of this to failures in treatment is discussed.

Antiprotozoal Agents↗
PubMed1983

Changes in body composition and muscle protein degradation during nutritional supplementation in nutritionally growth-retarded children with cystic fibrosis.

Changes in body composition and muscle protein degradation were studied in seven nutritionally growth-retarded children with cystic fibrosis (CF) before and after nutritional supplementation and in eight healthy children who served as controls. Supplemental feedings consisted of a peptide formula that increased dietary protein and energy intakes approximately 20-40% over a 6-month period, delivered either as oral supplement or overnight intragastric feeding. Body composition was assessed by anthropometric data and measurements of whole body potassium (40K) and creatinine excretion. Muscle protein degradation was measured by urinary 3-methylhistidine excretion, an index of myofibrillar protein catabolism. Compared with controls, CF children had significantly reduced body mass, body fat, and muscle mass, and a significantly increased rate of myofibrillar protein degradation. With nutritional supplementation, significant catch-up weight gain and improved linear growth were observed with evidence of accretion of lean body mass and muscle mass, and in all but one severely malnourished patient with progressive disease, there was normalization of the high rate of muscle protein degradation. Thus, this form of nutritional therapy has significant benefits in terms of body protein accretion and myofibrillar protein degradation.

Adolescent↗
PubMed1982

Altered body composition and muscle protein degradation in nutritionally growth-retarded children with cystic fibrosis.

To investigate nutritional growth retardation and the adaptive response to malnutrition in cystic fibrosis (CF), body composition and muscle protein catabolism were studied in nine malnourished CF children and eight healthy controls by anthropometry, measurement of whole body potassium, urinary creatinine excretion, creatinine height index, and urinary 3-methylhistidine excretion, an index of myofibrillar protein catabolism. CF children had a significant deficit of body mass (p less than 0.001), derived from both the body fat and the fat-free compartments, including a deficit in muscle mass (p less than 0.005). A deficit of muscle mass in CF was also reflected by a lower creatinine height index (mean +/- 1 SEM = 0.66 +/- 0.04 in CF, versus 0.85 +/- 0.5 in controls, p less than 0.02). Urinary 3-methylhistidine excretion was elevated in CF children and the mean (+/- 1 SEM) rate of muscle protein catabolism was 0.82 +/- 0.06 versus 0.53 +/- 0.04 kg-1 24 h-1 in CF and controls, respectively (p less than 0.01). 3-Methylhistidine excretion rates did not correlate with severity of disease as assessed by clinical score. We conclude that nutritional growth retardation in CF is characterized by a protein energy deficit resembling that of protein-energy malnutrition, but that in contrast to the normal adaptive response to protein-energy malnutrition, muscle protein catabolism is markedly increased. These data may have important implications regarding the clinical course and prognosis of CF and the design of optimal therapy.

Adipose Tissue↗
PubMed1981

Intestinal glucose transport in acute viral enteritis in piglets.

1. We studied intestinal glucose transport in pigs during the acute and convalescent phases of an invasive viral enteritis, transmissible gastroenteritis. 2. When diarhoea was severe 40 h after experimental infection, net absorption of glucose, Na+ and water, measured by marker perfusion in the jejunum, was reduced; the enhancement of Na+ and water absorption in response to increasing perfusate glucose concentrations up to 120 mmol/l was diminished compared with the response observed in control and convalescent pigs. 3. Measured in vitro, 40 h after infection, unidirectional fluxes of 3-O-methyl-D-glucose across the jejunal epithelium were reduced and net absorption of the sugar was obliterated. Phlorizin (0.05 mmol/l), which completely inhibited net 3-O-methyl-D-glucose absorption in control tissue, had no significant effect on transmissible gastroenteritis jejunum. 4. Our data suggest that in this invasive viral enteritis, which closely resembles human rotavirus enteritis, glucose absorption is impaired as a result of defects in both active and passive glucose flux. 5. Differences between the mechanisms of viral diarrhoea, demonstrated by our study and those of the enterotoxigenic diarrhoeas, should be taken into consideration in formulating active therapeutic measures for children with acute viral diarrhoea.

3-O-Methylglucose↗
PubMed1980

The postnatal development of sodium transport in the proximal small intestine of the rabbit.

To investigate the postnatal development of intestinal Na+ transport, a major determinant of fluid absorption, we measured spontaneous and glucose-coupled Na+ transport across short-circuited epithelium and in isolated villus enterocytes from rabbit jejunum at age intervals after birth. Villus cells from suckling animals actively transported Na+ and responded to glucose, but their capacity to do so was less than that of villus cells from older animals. Net Na+ fluxes across short-circuited epithelium from suckling animals failed to respond to glucose, remaining negligible and less than adult values. This lack of response to glucose in tissue from younger animals was associated with marked paracellular shunting as evidenced by greater unidirectional fluxes and greater tissue conductance. Villus enterocytes from suckling animals compared to those from adults had reduced (Na+-K+)ATPase activity, but were rich in thymidine kinase. We conclude that proximal intestinal epithelium in suckling animals has a limited capacity for active Na+ transport, is incompletely differentiated, and is leaky, with a greater permeability for ions compared with adult intestine.

Age Factors↗