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Biomedical subjects

J M Kirk

Publications and source records attributed to J M Kirk.

At least 19 recordsLinked to original sources
PubMed2001

Idiopathic gonadotrophin deficiency: genetic questions addressed through phenotypic characterization.

OBJECTIVE: The association of idiopathic hypogonadotrophic hypogonadism (IHH) with congenital olfactory deficit defines Kallmann's syndrome (KS). Although a small proportion of IHH patients have been found to harbour defined genetic lesions, the genetic basis of most IHH cases remains to be elucidated. Genes currently recognized to be involved comprise KAL (associated with X-linked-KS), the GnRH receptor (associated with resistance to GnRH therapy), DAX 1 (associated with adrenohypoplasia congenita) and three loci also associated with obesity, leptin (OB), leptin receptor (DB) and prohormone convertase (PC1). Because of the rarity of the condition and the observation that patients are almost universally infertile without assistance, familial transmission of IHH is encountered infrequently and pedigrees tend to be small. This has constrained the ability of conventional linkage studies to identify other candidate loci for genetic IHH. We hypothesized that a systematic clinical evaluation of a large patient sample might provide new insights into the genetics of this rare disorder. Specifically, we wished to examine the following propositions. First, whether normosmic (nIHH) and anosmic (KS) forms of IHH were likely to be genetically discrete entities, on the basis of quantitative olfactory testing, analysis of autosomal pedigrees and the prevalence of developmental defects such as cryptorchidism and cleft palate. Second, whether mirror movements and/or unilateral renal agenesis were specific phenotypic markers for X-linked-KS. DESIGN AND PATIENTS: We conducted a clinical study of 170 male and 45 female IHH patients attending the endocrinology departments of three London University teaching hospitals. Approximately 80% of data were obtained from case records and 20% collected prospectively. Parameters assessed included olfaction, testicular volume, family history of hypogonadism, anosmia or pubertal delay, and history or presence of testicular maldescent, neurological, renal or craniofacial anomalies. Where possible, the clinical information was correlated with published data on genetic analysis of the KAL locus. RESULTS: Olfactory acuity was bimodally distributed with no evidence for a spectrum of olfactory deficit. Testicular volume, a marker of integrated gonadotrophin secretion, did not differ significantly between anosmic and normosmic patients, at 2.0 ml and 2.2 ml, respectively. Nevertheless, the prevalence of cryptorchidism was nearly three times greater in anosmic (70.3%, of which 75.0% bilateral) than in normosmic (23.2%, of which 43.8% bilateral) patients. Individuals with nIHH, eugonadal isolated anosmia and/or KS were observed to coexist within 6/13 autosomal IHH pedigrees. On three occasions, fertility treatment given to an IHH patient had resulted in the condition being transmitted to the resulting offspring. Mirror movements and unilateral renal agenesis were observed in 24/98 and 9/87 IHH patients, respectively, all of whom were identifiable as X-KS males on the basis of pedigree analysis and/or defective KAL coding sequence. Abnormalities of eye movement and unilateral sensorineural deafness were observed in 10/21 and 6/111 KS patients, respectively, but not in nIHH patients. DISCUSSION: Patients with IHH are almost invariably either anosmic (KS) or normosmic (nIHH), rather than exhibiting intermediate degrees of olfactory deficit. Moreover, the prevalence of cryptorchidism is nearly three times greater in KS than in nIHH despite comparable testicular volumes, suggesting a primary defect of testicular descent in KS independent of gonadotrophin deficiency. Disorders of eye movement and hearing appear only to occur in association with KS. Taken together, these findings indicate a clear phenotypic separation between KS and nIHH. However, pedigree studies suggest that autosomal KS is an heterogeneous condition, with incomplete phenotypic penetrance within pedigrees, and that some cases of autosomal KS, nIHH and even isolated anosmia are likely to have a common genetic basis. The prevalences of anosmia, mirror movements and unilateral renal agenesis among X-KS men are estimated to be 100, 85 and 31%, respectively. In sporadic IHH, mirror movements and unilateral renal agenesis are 100% specific phenotypic markers of de novo X-KS. By comparison, only 7/10 X-KS families harboured KAL coding defects. Clinical ascertainment, using mirror movements, renal agenesis and ichthyosis as X-KS-specific phenotypic markers, suggested that de novo X-KS was unlikely to comprise more than 11% of sporadic cases. The majority of sporadic KS cases are therefore presumed to have an autosomal basis and, hence, the preponderance of affected KS males over females remains unexplained, though reduced penetrance in women would be a possibility.

Adolescent↗
PubMed2001

Short stature in Noonan syndrome: response to growth hormone therapy.

BACKGROUND: Growth hormone (GH) has been used to promote growth in both the short and long term in a number of dysmorphic syndromes, including Turner syndrome. As this condition shares many clinical features with Noonan syndrome, it would seem logical to treat the latter group with GH. AIMS: To assess the short and long term response to GH therapy in patients with Noonan syndrome. METHODS: Analysis of patients with Noonan syndrome in the Pharmacia & Upjohn International Growth Study (this post-marketing database contains data on the majority of patients currently treated with GH in the UK). A questionnaire was also sent to participating clinicians. RESULTS: Data on 66 patients (54 males) were available for study. At the start of GH therapy children were short, compared with both normal and Noonan children. During the first year of GH therapy height velocity increased from a mean of 4.9 to 7.2 cm per year. For patients treated long term with GH, mean height SDS increased from -2.9 pretreatment to -2.6 after one year and -2.3 after five years. Of the 10 patients at near final height, only one had a height above the 3rd centile for normal adults and above the mean for untreated Noonan patients. The mean increment in final height was 3.1 cm (range -1.1 to 6.5 cm). CONCLUSIONS: GH therapy in patients with Noonan syndrome will improve height velocity in the short term. Longer-term therapy results in a waning of effect; initial indications are that final height is not improved substantially in most patients.

Adolescent↗
PubMed2001

Short report: Hyperammonaemia in critically ill septic infants.

Three infants with subphrenic abscess, pyonephrosis, and obstructive ureterocoele respectively had grossly increased concentrations of plasma ammonia. This was considered to be a result of infections with urea splitting organisms. All died in spite of intensive care support, including specific measures to reduce plasma ammonia.

Ammonia↗
PubMed2001

Diabetic ketoacidosis in Asian children.

Over the 10 year period 1987-1996, 328 children with type 1 diabetes mellitus presented in the city of Birmingham, England, of whom 27% had diabetic ketoacidosis. Asian children under the age of 5 had an eightfold increased risk of presenting in diabetic ketoacidosis compared with non-Asian children of the same age.

Adolescent↗
PubMed2000

Glutamine synthetase and protease enzyme activities and growth response of ruminal bacterium Prevotella ruminicola strain B(1)4 to nitrogen source and concentration.

The objective of this study was to determine the effects of varying nitrogen sources and concentrations upon glutamine synthetase and protease activities in Prevotella ruminicola strain B(1)4. Based on growth response it appears that ammonium chloride or pepticase limited P. ruminicola becomes nitrogen limited when nitrogen concentration is at 0.5 mM. However, when casein was provided as the sole source of nitrogen P. ruminicola becomes nitrogen limited at 2.5 mM. Glutamine synthetase activity was measured from mid-log phase cells grown in either nitrogen-limited or non-limited conditions. No activity was detectable in the non-limited treatments. However, in the N-limited treatments, pepticase had the highest activity (20.76 units), followed by ammonium chloride (18.72 units) and casein (14.42 units). Protease activity assays indicated that nitrogen-limited cultures had higher proteolytic activity than non-limited cultures. Moreover, these activities appeared to follow the same response pattern as the previously observed glutamine synthetase activities. The results of this study indicate that P. ruminicola strain B(1)4 protease activity may be influenced by nitrogen concentration such that activity increases when nitrogen availability decreases.

Animals↗
PubMed2000

Inconsistencies in sweat testing in UK laboratories.

BACKGROUND: Sweat testing procedures are perceived to vary widely. AIM: To evaluate variability in sweat collection, analysis, and interpretation. METHODS: Questionnaire responses from 30 self selected centres: 15 paediatric centres, and 15 district general hospitals. RESULTS: Centres carried out 30-400 tests per year (median 100), with a diagnostic rate of 1:5-152 (median 1:30). Staff performed 5-268 tests per year. Minimum test age varied from 24 hours to four months. All stimulated sweating by pilocarpine iontophoresis using varying currents and times. Twenty six had observed urticaria or skin reddening, and nine blistering or burns. Sweat was collected for 10-60 minutes onto filter paper or into Macroduct coils. Between 2% and 25% of tests were considered insufficient. Twenty eight measured sodium, 24 chloride, and one osmolality and conductivity. Fifteen used literature and five in house reference ranges. Eleven would not test severely eczematous children. CONCLUSIONS: Local audit is required to improve performance, as well as a national guideline to standardise collection, and external quality assessment to provide analytical feedback.

Age Factors↗
PubMed2000

Individual differences in the priming effect of ethanol in social drinkers.

OBJECTIVE: Alcohol-dependent individuals frequently report increased desire for alcohol and exhibit increased alcohol-seeking behaviors following a single drink. The phenomenon, known as priming, has been demonstrated in the laboratory in alcohol-dependent humans and in nonhumans, but the effect is inconsistently observed in nonproblem social drinkers. The current experiment examined this effect in healthy, nonproblem social drinkers across a range of preload doses. METHOD: Using a repeated-measures design, 12 social drinkers were given ethanol (0.2, 0.4 or 0.8 g/kg) or placebo preloads. Various subjective effects measures were obtained at regular intervals. In addition, before and after consuming, the preload subjects performed an operant task on which they made repeated choices for either ethanol or money. RESULTS: Ethanol dose-dependently increased subjective reports of drug liking and desire to take more ethanol. When data from all subjects were examined, ethanol did not affect choices for ethanol on the choice task. However, in subjects who reported the greatest positive mood effects from ethanol (0.8 g/kg), the ethanol preload increased choices for ethanol over money on the choice task. CONCLUSIONS: These findings provide evidence for a priming effect of ethanol in social drinkers as measured by increased subjective desire for drug. The findings also suggest that the priming effects may be strongest in individuals who experience the greatest subjective positive mood effects from ethanol.

Adult↗
PubMed2000

Compound heterozygosity for a Wolman mutation is frequent among patients with cholesteryl ester storage disease.

Cholesteryl ester storage disease and Wolman disease are rare autosomal recessive lipoprotein-processing disorders caused by mutations in the gene encoding human lysosomal acid lipase. Thus far we have elucidated the genetic defects in 15 unrelated CESD patients. Seven were homozygotes for the prevalent hLAL exon 8 splice junction mutation which results in incomplete exon skipping, while eight probands were compound heterozygotes for E8SJM and a rare mutation on the second chromosome. In this report, we describe the molecular basis of CESD in three compound heterozygous subjects of Czech and Irish origin. RFLP and DNA sequence analysis revealed that they were heteroallelic for the common G(934)-->A substitution in exon 8 of the hLAL gene and a mutation which, if inherited on both alleles, would be expected to result in complete loss of enzyme activity and to cause Wolman disease. In patients A. M. and J. J., two nucleotide deletions in exons 7 and 10 were detected, involving a T at position 722, 723, or 724 and a G in a stretch of five guanosines at positions 1064;-1068 of the hLAL cDNA. Both mutations result in premature termination of protein translation at residues 219 and 336, respectively, and in the production of truncated, inactive enzymes. Subject D. H., in contrast, is a compound heterozygote for the Arg(44)-->Stop mutation previously described in a French CESD proband. Combined with data in the literature, our results demonstrate that compound heterozygosity for a mutation causing Wolman disease is common among cholesteryl ester storage disease patients.

Base Sequence↗
PubMed1999

Cushing's syndrome caused by nodular adrenal hyperplasia in children with McCune-Albright syndrome.

McCune-Albright syndrome consists of fibrous dysplasia of bone, café-au-lait skin pigmentation, and endocrine dysfunction (usually precocious puberty). Other endocrine abnormalities occur in a minority of patients, and of these, Cushing's syndrome is the least often recognized. We present 5 children (4 girls) with features of McCune-Albright syndrome who had Cushing's syndrome in the infantile period (<6 months). In 2 children spontaneous resolution occurred, but the remaining 3 required bilateral adrenalectomy. In addition, all 4 girls have experienced precocious puberty, and 3 children demonstrated radiologic evidence of nephrocalcinosis. Understanding of the underlying defect causing McCune-Albright syndrome emphasizes the importance of searching for other endocrine dysfunction in these children.

Adolescent↗
PubMed1999

Responses to oral delta9-tetrahydrocannabinol in frequent and infrequent marijuana users.

It is known that an individual's drug use history affects the quality of subjective effects experienced following administration of several clinically used psychoactive drugs such as barbiturates, diazepam, and morphine. However, it is not known whether drug use history also affects responses to therapeutic cannabinoids such as delta9-THC. The current experiment compared the subjective and behavioral effects of oral delta9-THC in two groups of volunteers: frequent users (FREQ; n = 11), who reported using marijuana at least 100 times, and infrequent users (INF; n = 10) who reported using marijuana 10 or fewer times. Subjects participated in three sessions during which they received delta9-THC (7.5 and 15 mg) and placebo. They completed subjective effects questionnaires for 5 h following administration. In the FREQ group, the lower dose (7.5 mg) increased ratings of "feel drug," relative to placebo, whereas it had no effect in the INF group. In contrast, at the higher dose (15 mg), ratings of "feel drug" were lower in the FREQ group than in the INF group, suggestive of tolerance. In addition, the INF group reported greater sedative effects than the FREQ group following the higher dose of delta9-THC, again suggesting tolerance to delta9-THC's sedative effects. These findings demonstrate that marijuana use history may affect the subjective effects of oral delta9-THC, but that the influence of drug use history depends on the dose of drug administered. These findings may have implications for the clinical use of delta9-THC and other cannabinoids.

Administration, Oral↗
PubMed1999

Quantitative growth hormone secretion and final adult height.

OBJECTIVE: The relationship of quantitative GH secretion to height, growth velocity and puberty is complex and has been the subject of extensive study in children. This study was designed to relate quantitative GH secretion to final height. SUBJECTS: Twenty tall (> 183 cm, 90th centile for adult height) and 20 short (< 166 cm, 10th centile) postpubertal men who had recently completed linear growth (age range 18-27 years). MEASUREMENTS: GH dynamics were studied on four occasions; insulin (0.15 units/kg, iv)-induced hypoglycaemia and GHRH (100 mg, iv) with and without the anticholinesterase, pyridostigmine (120 mg orally). Spontaneous nocturnal GH secretion was assessed by 20 minute sampling from 2100 h until 0600 h. GH was measured by IRMA. Analysis was by comparison of peak GH response and area under the curve (AUC). GH profiles were further analysed using the 'pulsar' programme. RESULTS: The mean height in the tall group was 187.7 cm (range 183-197) compared to 163.5 cm (range 160-166) for the short group. No difference existed between groups in the GH response to hypoglycaemia or GHRH with and without pyridostigmine. Area under the curve, pulse number, length and amplitude for spontaneous nocturnal GH secretion showed no significant difference between the tall and short subjects. Serum IGF-I (mean 230.5 +/- 15. 4 vs. 230.6 +/- 18.9 microg/l) did not differ between the groups. CONCLUSIONS: Quantitative GH secretion does not appear to be an important determinant of final height in healthy individuals.

Adult↗
PubMed1999

Congenital hypothyroidism, seasonality and consanguinity in the West Midlands, England.

Seasonal variation in the incidence of congenital hypothyroidism (CHT) is reported by some centres. Also, the incidence of CHT varies with ethnic origin. We report our experience in the West Midlands, England. The overall incidence of CHT among 1128 632 neonates screened over 16 years in the West Midlands was 1:2924 live births, but was increased (1:2323; p<0.05) between October and December. In the city of Birmingham between 1981 and 1991, the incidence of CHT was 1:781, 1:5540 and 1:2257 in Pakistani, Indian and North-West European children, respectively; no cases were seen in those from other ethnic groups. Consanguinity among those of Pakistani descent could account for the increased incidence within this population. Identification of the cause of seasonal variation may aid development of preventative strategies.

Catchment Area, Health↗
PubMed1998

Novel and recurrent tyrosine aminotransferase gene mutations in tyrosinemia type II.

Tyrosinemia type II (Richner-Hanhart syndrome, RHS) is a disorder of autosomal recessive inheritance characterized by keratitis, palmoplantar hyperkeratosis, mental retardation, and elevated blood tyrosine levels. The disease results from deficiency in hepatic tyrosine aminotransferase (TAT). We have previously described one deletion and six different point mutations in four RHS patients. We have now analyzed the TAT genes in a further seven unrelated RHS families from Italy, France, the United Kingdom, and the United States. We have established PCR conditions for the amplification of all twelve TAT exons and have screened the products for mutations by direct sequence analysis or by first performing single-strand conformation polymorphism analysis. We have thus identified the presumably pathological mutations in eight RHS alleles, including two nonsense mutations (R57X, E411X) and four amino acid substitutions (R119W, L201R, R433Q, R433W). Only the R57X mutation, which was found in one Scottish and two Italian families, has been previously reported in another Italian family. Haplotype analysis indicates that this mutation, which involves a CpG dinucleotide hot spot, has a common origin in the three Italian families but arose independently in the Scottish family. Two polymorphisms have also been detected, viz., a protein polymorphism, P15S, and a silent substitution S103S (TCG-->TCA). Expression of R433Q and R433W demonstrate reduced activity of the mutant proteins. In all, twelve different TAT gene mutations have now been identified in tyrosinemia type II.

Adult↗
PubMed1998

Effects of expectancies on subjective responses to oral delta9-tetrahydrocannabinol.

The effects of expectancies on subjective responses to oral delta9-tetrahydrocannabinol (delta9-THC) were examined. Thirty-five regular marijuana users were assigned to one of two groups: one group was told that they may receive a cannabinoid or placebo and a second group was told that they may receive a drug from one of several classes of drugs (e.g., stimulant, sedative, antiemetic) or placebo. Regardless of the group to which they were assigned, subjects received each of two oral doses of delta9-THC (7.5 and 15 mg) and placebo, one dose per session, for a total of three sessions. Measures of subjective effects, including visual analog scales and the Addiction Research Center Inventory (ARCI), were administered at 0.5-h intervals throughout each session. Consistent with previous research using other drugs, subjects in the current experiment who expected to receive a cannabinoid reported greater pleasurable effects than subjects who did not have this expectancy. The results have implications for understanding the effects of cannabinoids when used in both recreational and clinical settings.

Administration, Oral↗
PubMed1998

P67L: a cystic fibrosis allele with mild effects found at high frequency in the Scottish population.

Only three mutant cystic fibrosis (CF) alleles have to date been established as conferring a dominant mild effect on affected subjects who are compound heterozygotes. We now add a fourth, P67L, which occurs on about 1.4% of Scottish CF chromosomes. Among 13 patients (12 unrelated) with this allele, the average age at diagnosis was 22.5 +/- 11.3 years. None of the cases had consistently raised sweat chloride concentrations, the average value being 57 +/- 9 mmol/l; 77% of the patients were pancreatic sufficient. When compared to three other established mild CF alleles, R117H, A455E, and 3849 + 10kb C-T, a compound heterozygote for P67L has minimal disease and clinical suspicions are unlikely to be confirmed other than by DNA typing.

Adolescent↗
PubMed1997

Behavioral responses to ethanol in light and moderate social drinkers following naltrexone pretreatment.

The opioid antagonist naltrexone has been shown to be effective in the treatment of alcoholism, possibly by dampening the subjective effects of ethanol. However, naltrexone does not consistently attenuate the effects of ethanol in social drinkers in laboratory-based challenge studies. In the present study, 25 healthy volunteers, who were either light drinkers (mean = 3 drinks per week) or moderate drinkers (mean = 16 drinks per week), participated in six evening sessions. At each session, subjects ingested a capsule containing naltrexone (25 or 50 mg) or placebo, and 1 hr later they consumed a beverage containing ethanol (0.25 g/kg, equivalent to about two standard alcoholic drinks) or placebo. Subjects received all combinations of pretreatments and beverages. They completed self-report mood questionnaires and psychomotor tests at regular intervals. This low dose of ethanol produced modest but significant effects on self-report measures such as ratings of feeling a drug effect and of liking the drug effect. However, naltrexone (25 or 50 mg) pretreatment had no dampening effect on subjects' responses to ethanol. These results indicate that acute doses of naltrexone that are effective when administered chronically to alcoholics do not attenuate the acute effects of a low dose of ethanol in non-problem drinkers.

Administration, Oral↗
PubMed1997

Effects of deprivation level on humans' self-control for food reinforcers.

Deprivation level was manipulated in fourteen food- and water-deprived adult human females to examine its effects on self-control for food (choice of larger, more delayed access to apple juice over smaller, less delayed access to apple juice). Each subject was exposed to two treatments: (1) Consumption of a 500 g tomato soup preload just prior to self-control testing and (2) no soup preload. When subjects had consumed soup, they reported significantly less hunger and showed significantly more self-control as compared to when not having consumed soup. Additionally, when subjects had consumed soup, self-control decreased as a function of session time. Subjects who reported that they were currently dieting drank significantly less juice when they had previously consumed soup than when they do not previously consumed soup. Together, the results indicate that when subjects are more deprived they may be less able to wait for food reinforcers (i.e., show less self-control). Such behaviour may be adaptive in situations in which energy is needed to survive periods of food scarcity.

Adolescent↗