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Biomedical subjects

K L Jones

Publications and source records attributed to K L Jones.

At least 55 records · Page 3Linked to original sources
PubMed2001

Congenital hyperreninemic hypoaldosteronism unlinked to the aldosterone synthase (CYP11B2) gene.

Isolated hyperreninemic hypoaldosteronism presenting in infancy is usually caused by mutations in the CYP11B2 gene encoding aldosterone synthase. We studied five patients in four unrelated kindreds with hyperreninemic hypoaldosteronism, in whom we were unable to find such mutations. All presented in infancy with failure to thrive, hyponatremia, hyperkalemia, markedly elevated plasma renin activity, and low or inappropriately normal aldosterone levels. All had normal cortisol levels and no signs or symptoms of congenital adrenal hyperplasia. All responded to fludrocortisone treatment. There were no mutations detected in exons or splice junctions of CYP11B2. Linkage of the disorder to CYP11B2 was studied in two unrelated consanguineous patients and in an affected sib pair. The consanguineous patients were each heterozygous for at least one of three polymorphic microsatellite markers near CYP11B2, excluding linkage to CYP11B2. However, linkage of the disease to CYP11B2 could not be excluded in the affected sib pair. Genes involved in the regulation of aldosterone biosynthesis, including those encoding angiotensinogen, angiotensin-converting enzyme, and the AT1 angiotensin II receptor were similarly excluded from linkage. These results demonstrate the existence of an inherited form of hyperreninemic hypoaldosteronism distinct from aldosterone synthase deficiency. The affected gene(s) remain to be determined.

Adult↗
PubMed2001

Combination endocrine therapy in the management of breast cancer.

Combination endocrine therapy has long been sought after as a means to better treat breast cancer. Agents that suppress estrogen production are given with agents that suppress estrogenic activity at the cellular level. Historically, these combinations have resulted in initial improvements in response rates, but relapse-free and overall survival were not significantly improved. Also, the increased toxicity seen with these regimens was limiting. New endocrine therapies with more potent activity and less toxicity have led to a resurgence of this idea in the management of breast cancer. Complete estrogen blockade has been compared with single-agent treatments in many different settings. The endocrine effects of this type of therapy are intriguing, but apparently do not readily predict a clinical advantage. The combination of an aromatase inhibitor and an antiestrogen, despite pharmacokinetic interactions, may prove to be beneficial. Results from ongoing trials are eagerly awaited to further address this question in postmenopausal breast cancer patients. For premenopausal breast cancer patients the options are more complex. Clinical outcomes with leutinizing hormone releasing hormone (LHRH) agonists plus aromatase inhibitors are limited to very small phase II studies and are not clearly superior to single-agent therapy. Clinical data in the metastatic setting with premenopausal patients favor the use of an LHRH agonist with tamoxifen over the use of an LHRH agonist alone. However, a similar comparison with tamoxifen alone is lacking with only one trial including this as a treatment arm. Adjuvant therapy with this combined endocrine approach (LHRH agonist plus antiestrogen) has been more extensively studied, but lacks crucial comparisons necessary for making complex treatment decisions. Hopefully, through investigative diligence and ingenuity this issue can be adequately understood. However, many exciting new agents are on the horizon that offer hope to further advance the progress made to date although further confounding the questions already answered.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Relationships of upper gastrointestinal motor and sensory function with glycemic control.

Acute changes in the blood glucose concentration have a major reversible effect on esophageal, gastric, intestinal, gallbladder, and anorectal motility in both healthy subjects and diabetic patients. For example, gastric emptying is slower during hyperglycemia than euglycemia and accelerated during hypoglycemia. Acute hyperglycemia also affects perceptions arising from the gastrointestinal tract and may accordingly, be important in the etiology of gastrointestinal symptoms in diabetes. Elevations in blood glucose that are within the normal postprandial range also affect gastrointestinal motor and sensory function. Upper gastrointestinal motor function is a critical determinant of postprandial blood glucose concentrations by influencing the absorption of ingested nutrients. Interventions that reduce postprandial hyperglycemia, by modulating the rate of gastric emptying, have the potential to become mainstream therapies in the treatment of diabetes.

Blood Glucose↗
PubMed2001

Predictors of delayed gastric emptying in diabetes.

OBJECTIVE: To define the predictors of the rate of gastric emptying in patients with diabetes. RESEARCH DESIGN AND METHODS: A total of 101 outpatients with diabetes (79 type 1 and 22 type 2) underwent measurements of gastric emptying of a solid/liquid meal (scintigraphy), upper gastrointestinal symptoms (questionnaire), glycemic control (blood glucose concentrations during gastric emptying measurement), and autonomic nerve function (cardiovascular reflexes). RESULTS: The gastric emptying of solid and/or liquid was delayed in 66 (65%) patients. Solid (retention at 100 min 64 +/- 3.2 vs. 50.2 +/- 3.6%, P < 0.005) and liquid (retention at 100 min 22.7 +/- 1.7 vs. 16.0 +/- 1.8%, P < 0.001) gastric emptying was slower in women than in men. Of all upper gastrointestinal symptoms (including nausea and vomiting), only abdominal bloating/fullness was associated with slower gastric emptying (P < 0.005). A multiple regression analysis demonstrated that both abdominal bloating/fullness and female sex were predictors of slower gastric emptying of both solids and liquids. CONCLUSIONS: We conclude that the presence of abdominal bloating/fullness but not any other upper gastrointestinal symptom is associated with diabetic gastroparesis and that gastric emptying is slower in diabetic women than in diabetic men.

Animals↗
PubMed2000

Elevation of nitrotyrosine and nitrate concentrations in cystic fibrosis sputum.

Nitric oxide (NO) is increased in the exhaled air of some patients with inflammatory lung disorders, but not in others. NO may combine with superoxide to form peroxynitrite, which lowers NO gas concentrations, increases formation of nitrate, and increases nitration of tyrosine residues on proteins. We hypothesized that superoxide released from neutrophils in the lower respiratory tract of cystic fibrosis (CF) results in increased nitrate and nitrotyrosine levels in sputum. In order to test this hypothesis, exhaled NO was collected from 5 stable adult CF subjects and from 5 nonsmoking normal controls. Consistent with previous reports, exhaled NO concentrations were not increased in CF exhaled air (22.6 +/- 1.5 ppb vs. 28.6 +/- 1.5 ppb in normals, P > 0.05). Sputum was collected from 9 adult CF subjects and the same 5 normal controls and evaluated for nitrite, nitrate, and nitrotyrosine. Nitrate and nitrotyrosine levels, but not nitrite, were significantly elevated in CF. Recently, myeloperoxidase has also been implicated as a mechanism of nitrotyrosine formation. Therefore, myeloperoxidase was measured and found to be elevated in the CF sputum (64.2 +/- 35.9 vs. 0.73 +/- 0.16 U/mL, P < 0.001), and was found to correlate with concentrations of nitrotyrosine (r = 0.87, P < 0.05). However, in vitro studies with myeloperoxidase and murine lung epithelial cells did not demonstrate a reduction of NO gas with nitrotyrosine or an increase in nitrate formation. These data demonstrate that nitrate and nitrotyrosine are elevated in the sputa of CF subjects and suggest increased production of NO in the lower respiratory tract of CF patients, despite the relatively low exhaled NO levels. Pediatr Pulmonol. 2000; 30:79-85. Published 2000 Wiley-Liss, Inc.

Adolescent↗
PubMed2000

Low-copy plasmids can perform as well as or better than high-copy plasmids for metabolic engineering of bacteria.

Multicopy plasmids are often chosen for the expression of recombinant genes in Escherichia coli. The high copy number is generally desired for maximum gene expression; however, the metabolic burden effects that usually result from multiple plasmid copies could prove to be detrimental for maximum productivity in certain metabolic engineering applications. In this study, low-copy mini-F plasmids were compared to high-copy pMB1-based plasmids for production of two metabolites in E. coli: polyphosphate (polyP) and lycopene derived from isopentenyl diphosphate (IPP). The stationary-phase accumulation of polyP on a per cell basis was enhanced approximately 80% when either high- or low-copy plasmids were used, from 120 micromol/g DCW without augmented polyP kinase (PPK) activity to approximately 220 micromol/g DCW. The cell density of the high-copy plasmid-containing culture at stationary phase was approximately 24% lower than the low-copy culture and 30% lower than the control culture. This difference in cell density is likely a metabolic burden effect and resulted in a lower overall product concentration for the high-copy culture (approximately 130 micromol/L culture) relative to the low-copy culture (approximately 160 micromol/L culture). When the gene for DXP (1-deoxy-D-xylulose 5-phosphate) synthase, the first enzyme in the IPP mevalonate-independent biosynthetic pathway, was expressed from the tac promoter on multicopy and low-copy plasmids, lycopene production was enhanced two- to threefold over that found in cells expressing the chromosomal copy only. Cell growth and lycopene production decreased substantially when isopropyl beta-D-thiogalactosidase (IPTG) was added to the high-copy plasmid-containing culture, suggesting that overexpression of DXP synthase was a significant metabolic burden. In the low-copy plasmid-containing culture, no differences in cell growth or lycopene production were observed with any IPTG concentrations. When dxs was placed under the control of the arabinose-inducible promoter (P(BAD)) on the low-copy plasmid, the amount of lycopene produced was proportional to the arabinose concentration and no significant changes in cell growth resulted. These results suggest that low-copy plasmids may be useful in metabolic engineering applications, particularly when one or more of the substrates used in the recombinant pathway are required for normal cellular metabolism.

Acid Anhydride Hydrolases↗
PubMed2000

Opiate withdrawal in the fetal rat: a behavioral profile.

Offspring of women exposed to opiate drugs such as heroin and methadone during pregnancy have a high incidence of morbidity and mortality. Infants also show opiate withdrawal. In this study, we examined the behavioral effects of precipitated withdrawal in morphine-dependent fetal rats at gestational day (GD) 20. The dam was implanted on GD 14 with a pellet containing 75.0 mg of morphine. On GD 20, the dam underwent chemoyelotomy at L1/L2. The uterine horns were externalized and four subject fetuses were selected for behavioral observation, two from each uterine horn. The fetus was then injected subcutaneously with either saline or naltrexone (1.0 mg/kg) and the behaviors of the fetus recorded every 15 sec for 20 min. The results show that naltrexone injected fetuses that had been chronically exposed to morphine demonstrated increased limb and mouth movements, face wiping, and body curls, and spent less time quiet as compared with control fetuses. These results indicate that a morphine withdrawal-like syndrome occurs in the fetal rat.

Animals↗
PubMed2000

Effects of fedotozine on gastric emptying and upper gastrointestinal symptoms in diabetic gastroparesis.

BACKGROUND: Delayed gastric emptying and upper gastrointestinal symptoms occur frequently in patients with diabetes mellitus. AIM: To evaluate the effects of fedotozine on gastric emptying and gastrointestinal symptoms in diabetic gastroparesis. METHODS: Thirty-one diabetic patients (20 type 1, 11 type 2) with gastroparesis were randomized to receive fedotozine (30 mg as the tartrate) or placebo t.d.s. Measurements of gastric emptying (100 g ground beef labelled with 20 MBq 99mTc-sulphur colloid chicken liver and 150 mL 10% dextrose labelled with 10 MBq 113mIn-DTPA) and gastrointestinal symptoms were performed before and after 12-16 days of treatment. Data are the mean +/- s.d. RESULTS: Of the 31 patients enrolled, two were excluded from analysis. Data from the remaining 29 patients (18 type 1, 11 type 2; 22 female, seven male), aged 42.7 +/- 11.1 years (of whom 14 were randomized to fedotozine and 15 to placebo), were analysed. Fedotozine had no effect on either gastric emptying (solid retention at 100 min; fedotozine: baseline, 84 +/- 15%; treatment, 73 +/- 23% vs. placebo: baseline, 83 +/- 10%; treatment, 70 +/- 20%) or liquid 50% emptying time (fedotozine: baseline, 59 +/- 32 min; treatment, 58 +/- 38 min vs. placebo: baseline, 44 +/- 9 min; treatment, 43 +/- 21 min) or gastrointestinal symptoms (fedotozine: baseline, 4.4 +/- 2.9; treatment, 4.1 +/- 3.9 vs. placebo: baseline, 4.9 +/- 4.2; treatment, 4.8 +/- 3.9). CONCLUSIONS: Fedotozine has no effect on gastric emptying in patients with diabetic gastroparesis.

Adult↗
PubMed2000

Long-term effects of pyloromyotomy on pyloric motility and gastric emptying in humans.

OBJECTIVE: The aim of this study was to determine the long term effects of pyloromyotomy for infantile hypertrophic pyloric stenosis (IHPS) on gastric emptying and pyloric motility. METHODS: Concurrent measurements of gastric emptying and antropyloroduodenal pressures were performed in six volunteers (aged 24-26 yr) who had had pyloromyotomy performed in infancy because of IHPS, and in six normal subjects. Subjects were studied on 2 days, once sitting and once in the left lateral position. Gastric emptying of 300 ml 25% dextrose labeled with 20 MBq 99mTc sulfur colloid was measured. Antropyloroduodenal motility was evaluated with a sleeve/multiple sidehole manometric assembly, which was also used to deliver an intraduodenal triglyceride infusion at 1.1 kcal/min for 60 min, starting 30 min after ingestion of the dextrose. RESULTS: In both body positions, gastric emptying and intragastric distribution of the drink did not differ between the two groups. In both groups and postures, the amount emptied was less during intraduodenal lipid infusion. The number (p<0.01) and amplitude (p<0.02) of isolated pyloric pressure waves (IPPWs) was greater in the control subjects, whereas basal pyloric pressure was greater in the pyloromyotomy subjects (p<0.02). In both groups, the rate of gastric emptying in the sitting position was related to the number of IPPWs (r> or =0.40, p<0.05), but not to basal pyloric pressure. CONCLUSIONS: These results indicate that, in adults who have had pyloromyotomy for IHPS in infancy, patterns of pyloric motility are abnormal; pyloric tone is higher, whereas the number and amplitude of phasic pyloric pressure waves are less. In contrast, the overall rate of gastric emptying of a nutrient liquid meal is normal. These observations are consistent with the concept that the stomach has the capacity to compensate for changes in pyloric motility to minimize effects on gastric emptying.

Adult↗
PubMed2000

The stimulation of antral motility by erythromycin is attenuated by hyperglycemia.

OBJECTIVE: Diabetic gastroparesis is usually treated with prokinetic drugs, of which the most potent, when given intravenously during euglycemia, is erythromycin. Recent studies have demonstrated that the gastrokinetic effects of erythromycin are attenuated by hyperglycemia. The aim of this study was to determine whether the effects of erythromycin on antropyloroduodenal motility, including the organization of antral pressure waves, are modified by hyperglycemia. METHODS: A total of eight healthy male volunteers (median age 24 yr) were studied on 2 days each in randomized order. A manometric assembly, incorporating six antral, two pyloric, and seven duodenal sideholes and a pyloric sleeve sensor, was positioned with the sleeve spanning the pylorus. The blood glucose concentration was stabilized at about 5 mmol/L (euglycemia) or 15 mmol/L (hyperglycemia). After 30 min (T = 0), an intraduodenal lipid infusion (1.5 kcal/min) was commenced and continued until the end of the study. At T = 20 minutes, erythromycin (200 mg) as the lactobionate was infused intravenously over 20 min, followed by 100 mg over the next 40 min. RESULTS: Intravenous erythromycin increased the amplitude of antral waves during intraduodenal lipid infusion at both blood glucose concentrations (p < 0.01 for euglycemia and p < 0.05 for hyperglycemia). After erythromycin (T = 20 to T = 80), the frequency (p < 0.05) and amplitude (p < 0.01) of antral waves were less during hyperglycemia than euglycemia. Both propagated (p < 0.0005) and nonpropagated (p < 0.01) antral waves were decreased by hyperglycemia, but the suppression of propagated waves was greater (p < 0.05). Erythromycin reduced the frequency (p = 0.09) but increased the amplitude (p < 0.05) of phasic pyloric pressures, and decreased basal pyloric pressure (p < 0.0005). The frequency (p = 0.06) and amplitude (p < 0.05) of phasic pyloric waves during erythromycin infusion were slightly less during hyperglycemia than euglycemia, whereas there was no effect of the blood glucose concentration on basal pyloric pressure. Erythromycin increased the amplitude (p < 0.001) but not the frequency of duodenal waves; the frequency and amplitude of duodenal waves did not differ between the two blood glucose concentrations. CONCLUSIONS: Hyperglycemia attenuates the stimulation of antral pressures and propagated antral sequences by erythromycin, but not the effects of erythromycin on pyloric or duodenal motility.

Adolescent↗
PubMed2000

Activin A release into the circulation is an early event in systemic inflammation and precedes the release of follistatin.

Recent evidence suggests a role for activin A, and its binding protein, follistatin, in inflammatory pathways. However, whether activin is released systemically during inflammation is not known. In this study, a release of activin A into the circulation occurred in sheep within 1 hour of injection of lipopolysaccharide. This rapid peak in activin A preceded the release of the key inflammatory cytokines, tumor necrosis factor-alpha and interleukin-6. Follistatin release into the circulation occurred some 4 hours after the peak of activin A and continued out to 24 hours from lipopolysaccharide treatment. These data are the first to document a circulatory response of activin A to an inflammatory stimulus, and together with previous findings, suggest that activin A may have both pro- and anti-inflammatory actions in regulating cytokine-driven pathways.

Activins↗
PubMed2000

Release of activin and follistatin during cardiovascular procedures is largely due to heparin administration.

Recent evidence has suggested that activin A complexed to its binding protein, follistatin, may be present on the surface of cells through their interaction with heparan sulfate proteoglycans. As heparin is used routinely in many cardiovascular procedures for its anticoagulation properties, it may also cause the release of heparin-binding growth factors, including activin and follistatin, from the vascular endothelium. We examined the effect of two cardiovascular procedures and the use of heparin directly on the circulating concentrations of activin A and follistatin. A rapid and robust release of activin A and follistatin occurred in the circulation of patients undergoing abdominal aortic aneurysm repair or carotid endarterectomy at the time of vessel clamping and administration of heparin (5000 IU). This release pattern was dissimilar to that of the inflammatory marker, interleukin-1beta. However, administering heparin (2500 IU) to coronary angiography patients produced a similar activin and follistatin response, whereas placebo-treated angiography patients had no response. These findings illustrate that the routine use of heparin in surgical procedures elicits a rapid and robust release of activin and follistatin. This has direct clinical relevance by potentially activating heparin-binding growth factors that are important in injury, hyperplasia, and restenosis of vessels.

Activins↗
PubMed2000

Epidemiology of fetal alcohol syndrome in a South African community in the Western Cape Province.

OBJECTIVES: This study determined the characteristics of fetal alcohol syndrome in a South African community, and methodology was designed for the multidisciplinary study of fetal alcohol syndrome in developing societies. METHODS: An active case ascertainment, 2-tier methodology was used among 992 first-grade pupils. A case-control design, using measures of growth, development, dysmorphology, and maternal risk, delineated characteristics of children with fetal alcohol syndrome. RESULTS: A high rate of fetal alcohol syndrome was found in the schools--40.5 to 46.4 per 1000 children aged 5 to 9 years--and age-specific community rates (ages 6-7) were 39.2 to 42.9. These rates are 18 to 141 times greater than in the United States. Rural residents had significantly more fetal alcohol syndrome. After control for ethnic variation, children with fetal alcohol syndrome had traits similar to those elsewhere: poor growth and development, congruent dysmorphology, and lower intellectual functioning. CONCLUSIONS: This study documented the highest fetal alcohol syndrome rate to date in an overall community population. Fetal alcohol syndrome initiatives that incorporate innovative sampling and active case ascertainment methods can be used to obtain timely and accurate data among developing populations.

Age Distribution↗
PubMed1999

Contribution of clinical teratologists and geneticists to the evaluation of the etiology of congenital malformations alleged to be caused by environmental agents: ionizing radiation, electromagnetic fields, microwaves, radionuclides, and ultrasound.

Analysis of these six clinical problems demonstrates the value of a complete clinical evaluation of a child with congenital malformations by an experienced and well-trained physician who is familiar with the fields of developmental biology, teratology , epidemiology, and genetics. Too often, the entire emphasis is placed on epidemiological data that may be meager or insufficient for a rational conclusion when clinical findings that are readily available can provide definitive answers with regard to the etiology of a child's malformations or the merits of an environmental etiology.

Abnormalities, Radiation-Induced↗
PubMed1999

Developmental delay in fetal aminopterin/methotrexate syndrome.

Maternal exposures to aminopterin and methotrexate have been associated with a pattern of malformation which includes prenatal-onset growth deficiency, severe lack of ossification of the calvarium, hypoplastic supraorbital ridges, small, low-set ears, micrognathia, and limb abnormalities. We report on a patient whose mother received methotrexate during the first trimester of pregnancy and who, in addition to the structural anomalies typical of maternal methotrexate exposure, has significant developmental delay. This is the third patient exposed to folic acid antagonists with mental retardation, providing further evidence that developmental delay is one feature of fetal aminopterin-methotrexate syndrome. Therefore, it is recommended that formal developmental testing be performed in all patients prenatally exposed to methotrexate.

Abnormalities, Drug-Induced↗