bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibin B in boys from birth to adulthood: relationship with age, pubertal stage, FSH and testosterone
Authors: Crofton P. M. , Evans A. E. M. , Groome N. P. , Taylor M. R. H. , Holland C. V. , Kelnar C. J. H. 
Published: March 2003

Summaryobjective Inhibin B in males is produced principally by Sertoli cells under the influence of FSH and is thought to have a role in feedback regulation of FSH. The aims of our study were to investigate how inhibin B changes from birth to late adolescence in boys, to derive reference data and to explore its relation with pubertal stage, FSH and testosterone.design and subjects Blood samples were collected from (i) 366 boys aged 0–18 years to obtain age‐related reference data; (ii) 195 boys who had full pubertal staging; and (iii) a cohort of 15 boys studied longitudinally as they approached and entered early puberty.measurements Dimeric inhibin B was measured by double antibody enzyme‐linked immunosorbent assay (ELISA), FSH by immunoradiometric assay (IRA) and testosterone by an extraction radioimmunoassay.results Inhibin B was high in infant boys, decreased gradually to a nadir at 6–10 years of age, then increased rapidly in early adolescence to reach a new plateau at 12–17 years. It was detectable in all samples. Age‐related reference ranges and data for calculation of SD scores are presented. In prepubertal boys, inhibin B correlated positively with age (P < 0·001), but not with FSH. Inhibin B increased progressively from pubertal stages G1 to G3 but then decreased slightly at stages G4 to G5 (P ≤ 0·01). At stage G2, inhibin B correlated positively with testosterone (P < 0·01) but not with FSH. From stage G3 onwards, inhibin B correlated inversely with FSH (P < 0·01) but lost its relationship with testosterone. In the cohort of boys studied longitudinally, inhibin B increased progressively prior to pubertal onset and further on entry into early clinical puberty (P < 0·05). Testosterone also increased over this period (P < 0·05) but FSH showed no significant change.conclusions The two peaks of inhibin B during infancy and early puberty appear to reflect the two periods of Sertoli cell proliferation in normal human males. During mid‐childhood, a relatively constant amount of inhibin B is secreted constitutively. The early FSH‐independent increase in inhibin B that precedes clinical puberty and continues to stage G2 may be stimulated by testosterone or other factors from Leydig cells. The inverse relationship between inhibin B and FSH that subsequently develops from mid‐puberty onwards is consistent with the establishment of a negative feedback loop at this time.
Hyperkalaemia and selective hypoaldosteronism in myotonic dystrophy*
Authors: Misra Dolly , DeSilva Shari , Fellerman Herbert , Dufour D. Robert , Streeten David H.P. , Nylen Eric S. 
Published: March 2003

SummaryMyotonic dystrophy (MyD) is a common genetic neuromuscular disorder in which chromosome 19 gives rise to an abnormal expansion of CTG‐trinucleotide repeats. MyD is a highly variable multisystem disorder with muscular and nonmuscular abnormalities. Increasingly, endocrine abnormalities, such as gonadal, pancreatic, and adrenal dysfunction are being uncovered. Herein we present three unrelated cases with MyD with abnormally elevated serum potassium; 2 of the 3 cases presented clinically with cardiac dysrhythmias. Hyperkalaemic conditions such as renal failure, cortisol deficiency, pseudohyperkalaemia, and hyperkalaemic periodic paralysis were excluded. Further endocrine evaluation revealed baseline hypoaldosteronism associated with elevated renin activity. Perturbation of the renin‐angiotensin‐aldosterone system resulted in appropriately enhanced renin activity but with a subnormal aldosterone response, which appeared to be due to adrenal hyporesponsivness. The treatment of all cases with fludrocortisone was without effect. Whether the apparent mineralocorticoid abnormality in MyD is due to associated hormonal perturbations (i.e. excessive ACTH responsivness. elevated cytokines, elevated atrial natriuretic hormone, etc.), adrenal atrophy, and/or a manifestation of the underlying kinase dysfunction is uncertain, but merits further evaluation in view of the clinical consequence of hyperkalaemia.
Pharmacokinetics of sildenafil after single oral doses in healthy male subjects: absolute bioavailability, food effects and dose proportionality
Authors: Nichols Donald J. , Muirhead Gary J. , Harness Jane A. 
Published: March 2003

Aims  To determine the absolute bioavailability, dose proportionality and the effects of food on the pharmacokinetics of single oral doses of sildenafil citrate.Methods  Three open‐label, randomized crossover studies were conducted in healthy male subjects. Absolute bioavailability was determined by comparing pharmacokinetic data after administration of single oral and intravenous 50‐mg doses of sildenafil (n=12 subjects). Food effects were examined by comparing pharmacokinetic data for sildenafil and its primary circulating metabolite, UK‐103,320, after administration of a single oral 100‐mg dose in the fasted and fed states (n=34 subjects). Dose proportionality was assessed from pharmacokinetic data obtained after administration of four single oral doses of sildenafil (25, 50, 100 and 200 mg) to 32 subjects. The safety and tolerability of sildenafil were also assessed in all of these studies.Results  The calculated absolute oral bioavailability of sildenafil was 41% (90% CI: 36–47). Food slowed the rate of absorption, delaying mean tmax by approximately 1 h and reducing Cmax by 29% (90% CI: 19–38). Systemic exposure, as assessed by the mean area under the plasma concentration–time curve (AUC), was reduced by 11% (90% CI: 6–16). These food effects were not considered to be of clinical significance. There was statistical evidence of nonproportionality in Cmax and AUC over the dose range 25–200 mg. However the degree of nonproportionality was small, with predicted increases in Cmax and AUC of 2.2‐ and 2.1‐fold, respectively, for a doubling in dose, and was thought to be clinically nonsignificant. Sildenafil was well tolerated in the three studies; the majority of adverse events were mild and transient.Conclusions  Sildenafil had a mean absolute bioavailability of 41%. Food caused small reductions in the rate and extent of systemic exposure; these reductions are unlikely to be of clinical significance. Across the dose range of 25–200 mg, systemic exposure increased in a slightly greater than dose‐proportional manner.
Comparison of clozapine and haloperidol on some autonomic and psychomotor functions, and on serum prolactin concentration, in healthy subjects
Authors: Pretorius J. L. , Phillips M. , Langley R. W. , Szabadi E. , Bradshaw C. M. 
Published: March 2003

Aims
To compare the autonomic, neuroendocrine and psychomotor effects of single doses of the ‘atypical’ antipsychotic clozapine and the ‘classical’ antipsychotic haloperidol, in healthy male volunteers.
Methods
Clozapine (50 mg), haloperidol (3 mg) and placebo were administered to 12 healthy male volunteers at weekly intervals, according to a balanced double‐blind design. Resting pupil diameter, salivary output, heart rate, blood pressure, plasma prolactin concentration, critical flicker fusion frequency and subjective ‘alertness’, ‘contentedness’ and ‘anxiety’ were measured at baseline and 2, 3, 4 and 5 h after drug ingestion. Data were analysed by analysis of variance with individual comparisons (Dunnett's test) with a significance criterion of P < 0.05.
Results
Significant treatment effects (difference from placebo [mean, 95% CI] 5 h after drug ingestion) were as follows: clozapine reduced pupil diameter (mm; −3.02 [−3.56, −2.47]), salivary output (g; −0.34 [−0.60, −0.08]), mean arterial blood pressure (mm Hg; −8.7 [−14.3, −3.1]), critical flicker fusion frequency (Hz; −3.26 [−3.94, −2.58]), and subjectively‐rated ‘alertness’ (mm; −20.94 [−29.21, −12.67]) and ‘contentedness’ (mm; −12.98 [−17.90, −8.06]), whereas haloperidol increased prolactin concentration (mU l−1; 301.3 [196.7, 405.8]) and caused small reductions in pupil diameter (mm; −0.68 [−1.23, −0.14]), mean arterial blood pressure (mm Hg; −7.0 [−12.6, −1.4]) and critical flicker fusion frequency (Hz; −1.15 [−1.83, −0.47]).
Conclusions
The effects of the antipsychotics are in agreement with their receptor binding profiles: α1‐adrenoceptor blockade by clozapine may contribute to reductions in pupil diameter, salivation, mean arterial blood pressure and sedation, and muscarinic cholinoceptor blockade by the drug may underlie the reduction in salivation. Conversely, D2 dopamine receptor blockade by haloperidol is likely to be responsible for the increase in prolactin secretion evoked by the drug.
Effect of local hyperthermia of the bladder on mitomycin C pharmacokinetics during intravesical chemotherapy for the treatment of superficial transitional cell carcinoma
Authors: Paroni Rita , Salonia Andrea , Lev Avigdor , Da Pozzo Luigi Filippo , Cighetti Giuliana , Montorsi Francesco , Rigatti Patrizio , Colombo Renzo 
Published: March 2003

Aims  To assess the effect of local hyperthermia on the systemic absorption of mitomycin C (MMC) during intravesical chemotherapy for the treatment of superficial transitional cell carcinoma of the bladder, and to establish the likely safety of this procedure.Methods  Group 1 (n = 12) received 20 mg intravesical MMC plus local hyperthermia, group 2 (n = 13) 20 mg MMC alone, group 3 (n = 16) 40 mg MMC plus local hyperthermia and group 4 (n = 10) 40 mg MMC alone. Patients in groups 1, 2, and 4 underwent post‐tumour resection adjuvant treatment, whereas those in group 3 still had tumour present and were treated to eradicate it. Intravesical instillation lasted 60 min, with the solution (50 ml) being replaced after the first 30 min. Blood samples were taken before, and every 15 min during instillation. MMC concentrations in plasma and in urine were determined by h.p.l.c.Results  The highest MMC plasma concentration (67.9 ng ml−1) occurred in a patient in group 3. This value was well below the threshold concentration (400 ng ml−1) for myelosuppression. Local hyperthermia associated with the intravesical chemotherapy enhanced plasma MMC concentrations at 30, 45 and 60 min compared with chemotherapy alone (Group 1 vs 2, P ≤ 0.008). Systemic exposure to MMC was not significantly increased by doubling the intravesical dose when intravesical chemotherapy alone was administered. Patients in group 3 displayed the highest degree of MMC absorption and the greatest variability in pharmacokinetics between patients.Conclusions  Local hyperthermia enhances the systemic absorption of MMC during intravesical chemotherapy for bladder cancer. In the doses used, plasma MMC concentrations were always more than six times lower than those shown to cause toxicity.
Saquinavir and ritonavir pharmacokinetics following combined ritonavir and saquinavir (soft gelatin capsules) administration
Authors: Buss Neil , Snell Paul , Bock Jürgen , Hsu Ann , Jorga Karin 
Published: March 2003

Aims  To investigate the influence of combined ritonavir (RTV) and saquinavir (soft‐gelatin capsule formulation; SQV) on systemic exposure to SQV with a view to optimizing the dosing regimen of combined RTV and SQV antiretroviral therapy.Methods  In this open labelled, randomized, parallel group study, SQV and RTV were administered twice daily for 14 days to groups of eight healthy subjects. The two antiretrovirals were either administered alone (800 mg SQV, regimen A, and 400 mg RTV, B) or in combination at various dose levels (RTV : SQV: 400 : 400 mg, C; 300 : 600 mg, D; 200 : 800 mg, E; 300 : 800 mg, F; 400 : 800 mg, G; and 400 : 600 mg, H). Pharmacokinetic parameters of saquinavir and ritonavir were determined and adverse events, vital signs, and clinical laboratory variables recorded.Results  RTV substantially increased the plasma concentration of saquinavir for all dose combinations, compared with SQV alone. Based on the primary statistical analysis there was an overall 17‐, 22‐, and 23‐fold increase in saquinavir AUC(0,24 h) on day 14 with regimens E, F, and G, respectively (with confidence intervals of 10–30, 13–37, and 13–39). The lowest combination dose of RTV (200 : 800 mg; E) significantly increased the saquinavir AUC(0,24 h) from below 5 to 57 µg ml−1 h, which was higher than the exposure obtained with the 400 : 400 mg twice daily regimen (i.e. 36 µg ml−1 h). RTV also reduced intersubject variability in AUC(0,24 h) for saquinavir from 105% to 32–68%, and Cmax(0,24 h) from 124% to 30–49%. In contrast, SQV showed no clinically significant effect on the pharmacokinetics of ritonavir. The combination regimens were well tolerated, with the least number of adverse events recorded for the 200 : 800 mg (RTV : SQV) combination regimen.Conclusions  RTV significantly increases saquinavir exposure as a consequence of inhibiting SQV metabolism and possibly P‐glycoprotein efflux. Pharmacokinetic and safety profiles obtained in the current study indicate that the use of a combination with a lower dose of RTV and a higher dose of SQV than the 400 : 400 mg combination frequently used in clinical practice should be further explored.
Distribution of R‐ and S‐methadone into human milk during multiple, medium to high oral dosing
Authors: Begg Evan J. , Malpas Timothy J. , Hackett L. Peter , Ilett Kenneth F. 
Published: March 2003

Aims  To measure the interdose milk to plasma ratio (M/P) of R‐ and S‐methadone during multiple dosing in lactating mothers taking medium to high doses of methadone (> 40 mg daily), and to assess likely infant exposure.Methods  Eight mother/child pairs were studied, initially during their postpartum hospital stay (immature milk), and where possible again after 15 days (mature milk). The women were on a methadone maintenance programme with daily doses of ≥40 mg day−1. Venous blood was collected at 0, 1, 2, 4, 6, 8, 12, and 24 h and milk was collected from both breasts at 0–4, 4–8, 8–12, 12–16, 16–20, and 20–24 h after dose. R‐ and S‐methadone were quantified by h.p.l.c. The areas under the plasma and milk concentration‐time curves (AUC) were estimated and M/PAUC was calculated. The relative infant dose of both enantiomers was estimated as the product of drug concentration in milk and an average daily milk intake of 0.15 l kg−1.Results  For immature milk (n = 8) the M/PAUC for R‐methadone was 0.68 (95% CI 0.48, 0.89) and for S‐methadone 0.38 (0.26, 0.50). For mature milk (n = 2) the M/PAUCs for R‐methadone were 0.39 and 0.54 and for S‐methadone 0.24 and 0.30, respectively. The estimated doses of R‐ and S‐methadone that would be received by the infant via immature milk were 3.5% (2.05, 5.03%) and 2.1% (1.3, 2.8%), respectively, of the maternal dose (assuming 50% of each enantiomer in the dose). The relative infant dose for R‐ plus S‐methadone together was 2.8% (1.7, 3.9%).Conclusions  Breastfeeding during medium to high dose methadone appears to be ‘safe’ according to conventional criteria because the dosage is < 10%. However because the absolute dose received by the infant is dependent on the maternal dose rate, the risk‐benefit ratio should be considered for each individual case. The doses of methadone received via milk are unlikely to be sufficient to prevent the neonatal abstinence syndrome.
Pharmacokinetics of a contraceptive patch (Evra™/Ortho Evra™) containing norelgestromin and ethinyloestradiol at four application sites
Authors: Abrams Larry S. , Skee Donna M. , Natarajan Jaya , Wong Frankie A. , Anderson Gary D. 
Published: March 2003

Aims  To determine the pharmacokinetic profile of norelgestromin (NGMN) and ethinyloestradiol (EE) following application of the contraceptive patch, Evra™/ Ortho Evra™, at each of four anatomic sites (abdomen, buttock, arm, and torso).Methods  Thirty‐seven healthy, nonpregnant women aged 20–45 years participated in this open‐label, four‐period crossover study. Subjects were randomized to one of four treatment (site of application) sequences. Each patch was worn for 7 days, with a 1 month washout between treatments. Blood samples were collected before and at various times up to 240 h after application of each patch. Serum samples were assayed for NGMN and EE by validated methods.Results  The serum concentration reference ranges for NGMN and EE are 0.6–1.2 ng ml−1 and 25–75 pg ml−1, respectively, based on studies of the mean Cave of oral norgestimate 250 µg and EE 35 µg. For all application sites, mean concentrations of NGMN and EE remained within these ranges during the 7 day wear period. Absorption of NGMN and EE during patch application on the buttock, arm, and torso was equivalent. Absorption of NGMN and EE during patch application on the abdomen was approximately 20% less than observed for the other three sites, although mean serum concentrations were still within reference ranges. A previous study demonstrated therapeutic equivalence of patches worn on the abdomen vs other sites.Conclusions  Serum concentrations of NGMN and EE from the contraceptive patch remain within the reference ranges throughout the 7 day wear period, regardless of the site of application (abdomen, buttock, arm, or torso).
The relationship between male head size and harem size in the sexually dimorphic mountain stone weta Hemideina maori
Authors: Jamieson Ian G. 
Published: March 2003

Abstract 1. Tree weta are a group of large, flightless orthopterans with pronounced sexual dimorphism. Males have enlarged heads that are used in fighting for possession of cavities in trees or under rocks where females shelter during the day.2. The fieldwork reported here examined the relationship between male head size and mating success in Hemideina maori, an alpine tree weta that shelters under rock slabs that have broken off isolated outcrops or tors.3. The relationship between male head size and harem size in H. maori is not as clear‐cut as thought previously. First, overall body size is a better predictor of male mating success than head size per se. Second, both body size and head size explained a relatively low percentage (19.8%) of the overall variation in mating success. Third, despite the intensity of directional selection being estimated to move the frequency distribution of head size and femur size 0.49 and 0.54 standard deviations from the mean, male heads and femurs were ≈ 2 mm smaller at the main study site than at a second site 100 m higher in elevation. A similar pattern was found for adult females. Additional surveys have indicated that body size in H. maori decreases with decreasing altitude, which is correlated with increasing night‐time temperature.4. Although there are reasons why natural selection might favour weta maturing earlier and at smaller body sizes in warmer environments, relatively large males would still have a mating advantage over smaller males under such conditions. This sexually dimorphic alpine insect might be a good example of the trade‐offs and conflicting demands that sexual selection versus natural selection can place on organisms.
CTLA4 gene polymorphism contributes to the mode of onset of diabetes with antiglutamic acid decarboxylase antibody in Japanese patients: genetic analysis of diabetic patients with antiglutamic acid decarboxylase antibody
Authors: Abe T. , Yamaguchi Y. , Takino H. , Fujita N. , Yamauchi‐Degawa M. , Ozaki M. , Yamakawa K. , Sera Y. , Sakamaki H. , Uotani S. , Kawasaki E. , Awata T. , Yamasaki H. , Eguchi K. 
Published: March 2003

AbstractAim  The mode of onset is occasionally similar in Type 1 and Type 2 diabetes mellitus, and some patients with Type 2 diabetes are positive for antiglutamic acid decarboxylase antibody (GAD Ab). We investigated the contribution of Type 1 diabetes susceptibility genes to the progression of the insulin‐deficient state and mode of onset of Type 2 diabetes in GAD Ab‐positive (GAD‐Ab+) patients. We examined the variable number of tandem repeats in the promoter region of the insulin gene (INS‐VNTR, insulin‐dependent diabetes mellitus (IDDM) 2) and cytotoxic T lymphocyte antigen 4 (CTLA4, IDDM12) as representative of Type 1 diabetes susceptibility genes.Methods  Patients with Type 2 diabetes who were GAD‐Ab+ (n = 51) were selected for this study. In INS‐VNTR, the class I allele was classified according to length (1S, 25–38 repeat units; 1M, 39–41 repeat units; 1L, 42–44 repeat units) and the exact class I allele length was analysed by specific polymerase chain reaction (PCR) amplifications. Analyses of classes II and III were performed by Southern blot. CTLA4 gene polymorphism (exon 1 position 49, G/A) was analysed by PCR–restriction fragment length polymorphism.Results  The distribution of INS‐VNTR was no different between Type 1 diabetes and Type 2 diabetes with GAD Ab. The allele frequencies of CTLA4 gene polymorphism G and A in Type 2 diabetes/GAD‐Ab+ were significantly different from those of Type 1 diabetes/GAD‐Ab+ (G: 53%, A: 47% vs. G: 84%, A: 16%; P < 0.0001).Conclusions  Our data showed that GAD‐Ab+ Japanese patients presenting with Type 2 diabetes have shifted A allele while patients with abrupt onset have shifted G allele of CTLA4 gene polymorphism. Our results suggest that immunological function and polymorphism of the CTLA4 gene may contribute to the pathogenesis and progression of Type 1 diabetes.Diabet. Med. 18, 726–731 (2001)
Perinatal ‘programming’ of insulin resistance in childhood: critical impact of neonatal insulin and low birth weight in a risk population
Authors: Harder T. , Kohlhoff R. , Dörner G. , Rohde W. , Plagemann A. 
Published: March 2003

AbstractAim  Low birth weight may predispose to later insulin resistance and hyperinsulinaemia, but the pathophysiological mechanisms are unclear. The perinatal endocrine situation may play an important role, but has been little studied. Children of mothers with diabetes during pregnancy are an important risk population for later insulin resistance and hyperinsulinaemia. We therefore examined relationships between birth weight, insulin and insulin resistance at birth, and insulin secretion and insulin resistance in infancy in these children.Methods  We studied 104 infants of mothers with Type 1 diabetes mellitus during pregnancy. Oral glucose tolerance tests (area under the curve of glucose, AUCG) with determination of insulin (area under the curve of insulin, AUCI) were performed at 1–5 years of age. Using correlation and regression analysis, birth data were related to insulin secretion (AUCI) and stimulated insulin/glucose ratio (AUCI/AUCG) in childhood.Results  Children with an AUCI in the highest tertile of distribution had the lowest birth weights. Birth weight was negatively correlated to AUCI in childhood (P = 0.03). Insulin/glucose ratio at birth was raised in infants with an AUCI in the upper tertile, accompanied by a positive correlation between insulin/glucose ratio at birth and AUCI (P = 0.02). Insulin and insulin/glucose ratio at birth were both positively correlated to AUCI/AUCG (P = 0.04 and P= 0.02 respectively), while the correlation between birth weight and AUCI/AUCG was not significant (P = 0.12). In a stepwise regression analysis, insulin/glucose ratio contributed as much as birth weight to AUCI in childhood. Birth weight, however, was significantly negatively related to AUCI/AUCG only when the insulin/glucose ratio at birth was included in the regression model.Conclusions  Insulin and insulin resistance at birth show a positive relation to insulin secretion and insulin resistance in later life, in addition to the influence of a low birth weight, but independent of it. Perinatal and neonatal insulin, known to be of critical importance for long‐term outcome, should be evaluated in future studies on the ‘small baby syndrome’.Diabet. Med. 18, 634–639 (2001)