bluuebunny/crossref_metadata_2025 huggingface dataset:
Neonatal and Post-Natal Growth
Authors: Gibson Alan T. , Carney Sally , Cavazzoni Elena , Wales Jeremy K.H.
Published: April 2003

Growth velocity is higher in late intra-uterine and early post-natal life than at any time thereafter, and accurate measurements are essential for appropriate monitoring. The accuracy with which such measurements are made and recorded is frequently questionable, however, and short- and medium-term changes in growth may be difficult to interpret in the light of normal variations in the pattern of growth. Infants who are small at birth must be accurately classified because intra-uterine growth retardation and small for gestational age have different implications for both causation and outcome. Prediction of expected growth on the basis of mid-parental height is essential but frequently omitted. Post-natal growth impairment is common in pre-term infants and is often rapid in onset. Poor growth may continue for many months, and catch-up may be incomplete. Early growth failure may have a significant influence on subsequent morbidity and mortality.
Growth Hormone and Neurofibromatosis
Authors: Howell Simon J. , Wilton Patrick , Lindberg Anders , Shalet Stephen M.
Published: April 2003

Data collected from 102 neurofibromatosis (NF) children with growth hormone (GH) deficiency (GHD) who were receiving GH replacement therapy were reviewed to assess the efficacy and safety of GH therapy in this condition. GH was administered at a mean dose of 0.18 mg/kg/week. During the 1st year the median height velocity increased significantly from 4.2 cm/year before treatment to 7.1 cm/year, and the median height standard deviation score increased from –2.4 to –1.9. The response to therapy, however, was not as good as that observed in patients with idiopathic GHD. GH therapy did not influence the progression of any of the features of NF, including intracranial tumours, and was not associated with an excess of other adverse events. We conclude that GH treatment of NF patients with GHD is beneficial in terms of improved growth rate and is well tolerated.
Growth Hormone Therapy in Noonan Syndrome
Authors: Kelnar Christopher J.H.
Published: April 2003

Noonan syndrome (NS) is an autosomal dominant disorder that can be difficult to diagnose. Growth retardation is a consistent feature, however, and although children are not typically growth hormone (GH) deficient, a minority may have suboptimal GH levels. An ongoing multicentre study examining the safety and efficacy of GH therapy in NS showed increases in height standard deviation scores (SDS; p < 0.0001) and height velocity (p < 0.0001) after 12 months of GH at pharmacological doses. There was no increase in mean maximal cardiac left ventricular wall thickness during the 12-month treatment period. Long-term follow-up data covering 3 years of GH therapy showed sustained increases in height SDS and height velocity compared with baseline (p < 0.02). Further large and appropriately controlled studies of high-quality design are essential to further our understanding of NS and to establish the long-term safety and efficacy of GH.
Significance of Basal IGF-I, IGFBP-3 and IGFBP-2 Measurements in the Diagnostics of Short Stature in Children
Authors: Ranke M.B. , Schweizer R. , Elmlinger M.W. , Weber K. , Binder G. , Schwarze C.P. , Wollmann H.A.
Published: April 2003

The role of IGF-I and IGFBP-3 measurements in the diagnostic work-up of short children is established but remains controversial. Little information exists on the value of IGFBP-2 measurements. Based on reference data established in 388 children we have reinvestigated the issue, using data from 392 short children who underwent the same diagnostic procedures between 1987 and 1998 (GHD, n = 187; non-GHD, n = 205, including patients with ISS, n = 76; IUGR, n = 46; and TS, n = 83). In comparing IGF-I, IGFBP-3 and IGFBP-2 serum levels of GHD and ISS children with reference data, we calculated the sensitivity, specificity, efficiency and positive predictive value for the diagnosis of GHD. The overall sensitivity of the parameters was high, the rank order being as follows: IGF-I >IGFBP-3 >IGFBP-2 (75, 67 and 62%, respectively). In contrast, the specificity was relatively low: IGFBP-3 >IGFBP-2 >IGF-I (50, 50 and 32%, respectively). The efficiency and positive predictive value of parameters was in the order of 40, 60 and 70–80%, respectively. In repeated measurements, the recorded basal levels of IGF-I and IGFBP-3 showed an overall narrow range of variation. We conclude that the determination of basal IGF parameters is, together with anthropometry and imaging techniques, an indispensable tool for differentiating between GHD and ISS; and that IGFBP-2 plays an additional role in this process.
Influence of Octreotide and Tamoxifen on Tumor Growth and Liver Metastasis in N-Nitrosobis(2-oxopropyl)amine-Induced Pancreatic Cancer in Syrian Hamsters
Authors: Wenger F.A. , Kilian M. , Mautsch I. , Jacobi C.A. , Schimke I. , Saul G.J. , Guski H. , Müller J.M.
Published: April 2003

In prospective clinical trials single octreotide therapy or combined therapy with tamoxifen has improved the quality of life and survival time in patients with pancreatic cancer. In this study we analyzed the influence of octreotide and tamoxifen on tumor growth and liver metastases in chemically induced pancreatic adenocarcinoma in Syrian hamsters. Octreotide alone and the combined therapy (octreotide/tamoxifen) decreased the incidence of macroscopic pancreatic carcinomas as well as the number and size of liver metastases. The combined therapy showed no superior effect to octreotide alone. Furthermore, there was no difference between the tamoxifen and the control group.
Effect of Excitatory Amino Acids on Serum TSH and Thyroid Hormone Levels in Freely Moving Rats
Authors: Alfonso M. , Durán R. , Arufe M.C.
Published: April 2003

The actions of glutamate (L-Glu), and glutamate receptor agonists on serum thyroid hormones (T4 and T3) and TSH levels have been studied in conscious and freely moving adult male rats. The excitatory amino acids (EAA), L-Glu, N-methyl-D-aspartate (NMDA), kainic acid (KA) and domoic acid (Dom) were administered intraperitoneally. Blood samples were collected through a cannula implanted in the rats jugular 0–60 min after injection. Thyroid hormone concentrations were measured by enzyme immunoassay, and thyrotrophin (TSH) concentrations were determined by radioimmunoassay. The results showed that L-Glu (20 and 25 mg/kg) and NMDA (25 mg/kg) increased serum thyroxine (T4), triiodothyronine (T3) and TSH concentrations. Serum thyroid hormone levels increased 30 min after treatment, while serum TSH levels increased 5 min after i.p. administration, in both cases serum levels remained elevated during one hour. Injection of the non-NMDA glutamatergic agonists KA (30 mg/kg) and Dom (1 mg/kg) produced an increase in serum thyroid hormones and TSH levels. These results suggest the importance of EAAs in the regulation of hormone secretion from the pituitary-thyroid axis, as well as the importance of the NMDA and non-NMDA receptors in this stimulatory effect.
Serum Inhibin A and Inhibin B in Central Precocious Puberty before and during Treatment with GnRH Agonists
Authors: Sehested Astrid , Andersson Anna Maria , Müller Jørn , Skakkebaek Niels E.
Published: April 2003

Serum levels of the gonadal hormones inhibin A and inhibin B are undetectable or low in prepubertal girls, and rise during puberty. In girls with central precocious puberty (CPP) the hypothalamic-pituitary-gonadal axis is prematurely activated, if the girl is thereafter treated with GnRH agonists both gonadotropins and estradiol levels become suppressed. We therefore investigated serum levels of inhibin A and inhibin B in girls with CPP at diagnosis and during treatment in order to test the hypothesis that inhibin secretion would increase and decrease in parallel with the activation and suppression of the hypothalamic-pituitary-gonadal axis. Serum levels of inhibin A and inhibin B were significantly (p < 0.0005) elevated in 42 girls at diagnosis of CPP (inhibin A: 7 pg/ml (<7–139), inhibin B: 80 pg/ml (<20–294) (median, range)) compared to levels in age-matched healthy schoolgirls (inhibin A: all values <7 pg/ml, inhibin B: 21 pg/ml (<20–122) (median, range)), but were appropriate for Tanner stage. During treatment with GnRH agonist (intranasal buserelin and oral cyproterone acetate, treatment group 1, n = 23, or triptorelin depot injections, treatment group 2, n = 19) levels of both hormones fell significantly (p = 0.002). There was a significantly (p = 0.003) greater fall in inhibin B levels during treatment in group 2 compared to group 1, with inhibin B levels now lying below (group 2: <20 pg/ml (<20–68)) rather than within (group 1: 34.5 pg/ml (<20–93)) the age-appropriate range. It is concluded that levels of inhibin A and inhibin B are elevated and suppressed in concert with activation and suppression of the hypothalamo-pituitary-gonadal axis in girls with CPP, supporting the concept that ovarian inhibin secretion is dynamically regulated by gonadotropin stimulation.
Central Diabetes insipidus as the First Manifestation of Neurosarcoidosis in a 10-Year-Old Girl
Authors: Konrad Daniel , Gartenmann Madeleine , Martin Ernst , Schoenle Eugen J.
Published: April 2003

Central diabetes insipidus with thickening of the pituitary stalk has been demonstrated in adults with Langerhans cell histiocytosis (LCH), tuberculosis or sarcoidosis, and in children with LCH. We present a 10.5-year-old girl with central diabetes insipidus. Magnetic resonance imaging (MRI) revealed thickening of the central part of the pituitary stalk and multiple hyperintense lesions in the frontal white matter on T2-weighted images. Laboratory findings were normal except for an elevated serum angiotensin-converting enzyme (ACE) level. The MRI findings together with the elevated serum ACE level highly suggest the diagnosis of sarcoidosis. We conclude that central diabetes insipidus can be the first clinical manifestation of sarcoidosis in children.
Cellular Activities of 20K- and 22K-hGH Do Not Necessarily Correlate with Their Binding Affinities for Rat GH Receptor
Authors: Ikeda M. , Matsumoto K. , Uchida H. , Naito N. , Tsunekawa B. , Wada M. , Honjo M.
Published: April 2003

Even though 20K human growth hormone (20K-hGH) has 3–10% binding affinity for the rat liver and adipose tissue microsomes as compared to 22K-hGH, it was also reported that 20K-hGH has the same potency as 22K-hGH in the hypophysectomized rat weight gain assay. In order to investigate the reason why such controversial data exist, we have studied 20K- and 22K-hGH using the rat GH receptor extracellular domain (rGHR-ECD) and full-length rGHR. When we examined the complex formation of rGHR-ECD with 20K- and 22K-hGH in gel filtration assay, 20K-hGH formed no complex while 22K-hGH formed a 1:1 complex. Next, rGHR cDNA was introduced into Ba/F3 cells and CHO-K1 cells, and stable transfectants (Ba/F3-rGHR and CHO-rGHR) were established. In the proliferation of Ba/F3-rGHR cells, 20K-hGH had 10-fold lower activity than 22K-hGH, which is consistent with their affinities for rGHR. But surprisingly, in the Spi2.1 gene promoter activation in CHO-rGHR cells, 20K- and 22K-hGH had the same activity, which was found not only in stable CHO-rGHR clones but also in CHO-K1 cells transiently expressing rGHR. In conclusion, these results indicate that cellular activities of 20K- and 22K-hGH do not necessarily correlate with their binding affinities for rGHR.
Clomiphene, an Ovulation-Inducing Agent, Mobilizes Intracellular Ca2+ and Causes Extracellular Ca2+ Influx in Bladder Female Transitional Carcinoma Cells
Authors: Jan Chung-Ren , Yu Chia-Cheng , Huang Jong-Khing
Published: April 2003

Background/Methods: The effect of clomiphene, an ovulation-inducing agent, on cytosolic free Ca2+ levels ([Ca2+]i) in populations of BFTC human bladder cancer cells was explored by using fura-2 as a Ca2+ indicator. Results: Clomiphene at concentrations between 10 and 75 µM increased [Ca2+]i in a concentration-dependent manner and the signal saturated at 50 µM. The [Ca2+]i signal was biphasic with an initial rise and a slow decay. Ca2+ removal inhibited the Ca2+ signal by about 40–50% in maximum [Ca2+]i. Adding 3 mM Ca2+ increased [Ca2+]i in cells pretreated with 50 µM clomiphene in Ca2+-free medium, suggesting that clomiphene induced capacitative Ca2+ entry. In Ca2+-free medium, pretreatment with 50 µM brefeldin A (to disrupt the Golgi complex Ca2+ store), 1 µM thapsigargin (to inhibit the endoplasmic reticulum Ca2+ pump), and CCCP (to uncouple mitochondria) inhibited 85% of clomiphene-induced intracellular Ca2+ release. Conversely, pretreatment with 50 µM clomiphene in Ca2+-free medium abolished the [Ca2+]i increase induced by brefeldin, thapsigargin or CCCP. The intracellular Ca2+ release was unaltered by inhibiting formation of inositol-1,4,5-trisphosphate (IP3) with 2 mM 1-(6-((17β-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione (U73122; a phospholipase C inhibitor). Conclusion: The [Ca2+]i increase induced by 50 µM clomiphene was not affected by 10 µM of nifedipine, verapamil or diltiazem. Collectively, the results suggest that clomiphene releases intracellular Ca2+ in an IP3-independent manner and also activates extracellular Ca2+ influx.
Relationship between the Serum Level of Leptin and Life-Style Habits in Japanese Men
Authors: Togo M. , Hashimoto Y. , Futamura A. , Tsukamoto K. , Satoh H. , Hara M. , Watanabe T. , Nakarai H. , Nakahara K. , Kimura S.
Published: April 2003

Aims/Methods: To investigate whether smoking affects the serum level of leptin, 708 male workers aged 25–65 years old were cross-sectionally surveyed. Results: Multiple regression analysis indicated that among the various parameters examined, the level of leptin was positively associated with the body mass index and the levels of insulin, total cholesterol and uric acid, and was inversely associated with physical activity and the level of creatinine. The partial correlation coefficient of leptin was highest against the body mass index (r = 0.40), followed by insulin (0.29) and physical activity (–0.14), after adjustment for other leptin-related variables. However, no association was observed between the level of leptin and smoking (0.05), alcohol consumption (0.09) or age (0.09). Conclusions: The findings suggest that among life-style habits, physical activity, but not smoking or alcohol consumption, significantly affects the serum level of leptin in Japanese men.
Time Relationship between Circadian Variation of Serum Levels of Leptin, Insulin and Cortisol in Healthy Subjects
Authors: Wagner Richard , Oberste-Berghaus Corinna , Herpertz Stephan , Blum Werner F. , Pelz Barbara , Hebebrand Johannes , Senf Wolfgang , Mann Klaus , Albers Norbert
Published: April 2003

Background: Leptin is involved in the regulation of eating behavior. Its serum levels are determined by fat mass but a diurnal rhythm is also described. It is not clear whether leptin levels are also controlled in vivo by hormonal stimuli, like insulin or cortisol. Methods and Results: This possible temporal relation was investigated by serial measurements during 24 h (group A) and 46 h (group B) in 15 healthy volunteers and another 10 subjects (group C) while fasting for 72 h. Maximal leptin levels were observed at 4:00 a.m. and 4:00 p.m. in subjects on a normal diet. During 24 h starvation (group B), there was a 40% decrease of mean leptin concentration when compared to baseline values. In group C, the leptin concentration under starvation dropped to 25% of basal levels after 72 h. Pooled data from group A and the nonfasting data from group B showed an insulin increase preceding leptin increase by 6 h (r = 0.405, p < 0.0001), while cortisol decreased 4 h (r = 0.361, p < 0.001) after leptin decrease. Conclusion: Starvation results in a fall of circulating leptin, ending leptin rhythmicity. Food intake is causally involved in the fluctuation of leptin levels in serum. Presumably this effect is mediated by insulin, while cortisol does not seem to affect leptin release directly in vivo.
Insulin Secretion and Acetylcholinesterase Activity in Monosodium L-Glutamate-Induced Obese Mice
Authors: Lucinei Balbo Sandra , Gravena Clarice , Bonfleur Maria Lucia , de Freitas Mathias Paulo Cezar
Published: April 2003

Objective: Pancreatic islets isolated from mice treated neonatally with monosodium L-glutamate (MSG) were used to study insulin secretion. Material and Methods: Total acetylcholinesterase (AchE) activity of tissue extract was measured as a cholinergic activity marker. Obesity recorded in 90-day-old MSG mice (OM) by Lee index reached 366.40 ± 1.70, compared to control mice (CM) 324.40 ± 1.10 (p < 0.0001). Glucose 5.6 mM induced insulin secretion of 36 ± 5 pg/15 min from islets of CM and 86 ± 13 from OM (p < 0.001). When glucose was raised to 16.7 mM, islets from OM secreted 1,271 ± 215 and 1,017 ± 112 pg/30 min to CM. AchE activity of pancreas from OM was 0.64 ± 0.02 nmol of substrate hydrolyzed/min/mg of tissue and 0.52 ± 0.01 to CM (p < 0.0001). Liver of obese animals also presented increase of AchE activity. Results: These indicate that OM insulin oversecretion in low glucose may be attributed, at least in part, to an enhancement of parasympathetic tonus.
Intracrinology and The Skin
Authors: Labrie Fernand , Luu-The Van , Labrie Claude , Pelletier Georges , El-Alfy Mohamed
Published: April 2003

The skin, the largest organ in the human body, is composed of a series of androgen-sensitive components that all express the steroidogenic enzymes required to transform dehydroepiandrosterone (DHEA) into dihydrotestosterone (DHT). In fact, in post-menopausal women, all sex steroids made in the skin are from adrenal steroid precursors, especially DHEA. Secretion of this precursor steroid by the adrenals decreases progressively from the age of 30 years to less than 50% of its maximal value at the age of 60 years. DHEA applied topically or by the oral route stimulates sebaceous gland activity, the changes observed being completely blocked in the rat by a pure antiandrogen while a pure antiestrogen has no significant effect, thus indicating a predominant or almost exclusive androgenic effect. In human skin, the enzyme that transforms DHEA into androstenedione is type 1 3β-hydroxysteroid dehydrogenase (type 1 3β-HSD) as revealed by RNase protection and immunocytochemistry. The conversion of androstenedione into testosterone is then catalyzed in the human skin by type 5 17β-HSD. All the epidermal cells and cells of the sebaceous glands are labelled by type 5 17β-HSD. This enzyme is also present at a high level in the hair follicles. Type 1 is the 5α-reductase isoform responsible in human skin for the conversion of testosterone into DHT. In the vagina, on the other hand, DHEA exerts mainly an estrogenic effect, this effect having been demonstrated in the rat as well as in post-menopausal women. On the other hand, in experimental animals as well as in post-menopausal women, DHEA, at physiological doses, does not affect the endometrial epithelium, thus indicating the absence of DHEA-converting enzymes in this tissue, and avoiding the need for progestins when DHEA is used as hormone replacement therapy.
The Hair Follicle: A Paradoxical Androgen Target Organ
Authors: Randall Valerie A. , Hibberts Nigel A. , Thornton M. Julie , Hamada Kazuto , Merrick Alison E. , Kato Shoji , Jenner Tracey J. , De Oliveira Isobel , Messenger Andrew G.
Published: April 2003

Androgens are the main regulator of normal human hair growth. After puberty, they promote transformation of vellus follicles, producing tiny, unpigmented hairs, to terminal ones, forming larger pigmented hairs, in many areas, e.g. the axilla. However, they have no apparent effect on the eyelashes, but can cause the opposite transformation on the scalp leading to the replacement of terminal hairs by vellus ones and the gradual onset of androgenetic alopecia. This paradox appears to be an unique hormonal effect. Hair follicles are mainly epithelial tissues, continuous with the epidermis, which project into the dermis. A mesenchyme-derived dermal papilla enclosed within the hair bulb at the base controls many aspects of follicle function. In the current hypothesis for androgen regulation, the dermal papilla is also considered the main site of androgen action with androgens from the blood binding to receptors in dermal papilla cells of androgen-sensitive follicles and causing an alteration of their production of paracrine factors for target cells e.g. keratinocytes. Studies of cultured dermal papilla cells from sites with different responses to androgens in vivo have confirmed the paradoxical responses. All dermal papilla cells from androgen-sensitive sites contain low capacity, high affinity androgen receptors. However, only some cells formed 5α-dihydrotestosterone, e.g. beard but not axillary cells, in line with hair growth in 5α-reductase deficiency. Incubation with androgens also stimulated the mitogenic capacity of beard cell media, but inhibited that produced by scalp cells. This suggests that the paradoxical differences are due to differential gene expression within hair follicles, presumably caused during embryogenesis.
Oestrogen Receptor Beta Is Not Present in the Pilosebaceous Unit of Red Deer Skin during the Non-Breeding Season
Authors: Thornton M. Julie , Taylor Anthony H. , Mulligan Kellie , Al-Azzawi Farook
Published: April 2003

Androgens and oestrogens both have roles in skin physiology. Recently a second oestrogen receptor (ERβ) has been identified in androgen-dependent tissues. The red deer grows a breeding season, androgen-dependent mane when plasma testosterone rises; this is replaced with small neck hairs during the non-breeding season. In non-breeding season deer skin, ERβ was localised to the blood vessels and arrector pili muscle, but in contrast to human skin, not in the pilosebaceous unit or epidermis. The androgen receptor was not expressed. Further studies with breeding season skin may help to elucidate whether serum androgens or androgen receptor expression can modulate the expression of ERβ in skin.
Regulation of Macrophage Gene Expression by the Peroxisome Proliferator-Activated Receptor-γ
Authors: Ricote Mercedes , Welch John S. , Glass Christopher K.
Published: April 2003

The peroxisome proliferator-activated receptor-γ (PPAR-γ), which is a member of the nuclear hormone receptor superfamily and was originally shown to play an important role in adipocyte differentiation and glucose homeostasis, is now known to regulate cellular proliferation and inflammatory responses. A range of synthetic and naturally occurring substances activates PPAR-γ, however the identities of endogenous ligands for PPAR-γ and their means of production in vivo have not been well established. In monocytes and macrophages, interleukin-4 (IL-4) increases the expression of 12/15-lipoxygenase and thus13-HODE and 15-HETE production. We show that IL-4 induces the expression of PPAR-γ and provide evidence that the coordinate induction of PPAR-γ and 12/15-lipoxygenase mediates IL-4 dependent transcription of the CD36 gene and down-regulation of iNOS in macrophages. These findings suggest that PPAR-γ activity may play an important role in mediating macrophage gene expression signaled by IL-4.
Prevalence of Endocrine Dysfunction in HIV-Infected Men
Authors: Brockmeyer Norbert H. , Kreuter Alexander , Bader Arnim , Seemann Ute , Reimann Georg
Published: April 2003

Objective: Endocrine dysfunction is a common problem in patients with human immunodeficiency virus infection (HIV). We therefore evaluated the endocrine function in 31 male homosexual HIV-1-infected men: mean age 37 ± 7.2 years (range 24–52). Methods and Materials: Blood was obtained for baseline T3, T4, TSH, LH, FSH, prolactin, testosterone, ACTH and cortisol values. Endocrine function tests were performed as TRH, CRH, ACTH, LH-RH and HCG tests. Results: Thyroid function: There was a temporarily increased TSH in 3 of 17 patients but normal levels for T3, T4 and fT4 (without thyroid antibodies). One patient showed signs of latent hyperthyroidism (no response in TRH test). Adrenocortical function: Two patients had adrenal insufficiency. They showed a normal baseline cortisol level, an elevated ACTH level and no increase in cortisol levels after stimulation with CRH. All other patients revealed normal responses on the CRH/ACTH tests. Gonadal function: 9 patients had elevated FSH levels (tubular insufficiency), 4 patients additionally had increased LH levels (hypergonadotropic hypogonadism). 5 patients showed signs of tertiary hypogonadism (low LH and testosterone, increase of LH after stimulation with LH-RH). Conclusion: In disorders of thyroid and adrenocortical function of primary or tertiary origin, a substitution of hormones should be taken into consideration.
Interaction of Vitamin D and Retinoid Receptors on Regulation of Gene Expression
Authors: Jimenez-Lara Ana Maria , Aranda Ana
Published: April 2003

Vitamin D and retinoic acid (RA) receptors (VDRs and RARs, respectively), bind as heterodimers with the retinoid X receptor (RXR) to hormone response elements (HREs) in target genes. In some cases RA and vitamin D can cooperate to stimulate transcription through the same HRE. However, VDR/RXR heterodimers bind in a transcriptionally unproductive manner and without a defined polarity on certain RA response elements, and under these circumstances vitamin D inhibits the response to RA. Although competition for binding to DNA may contribute to this inhibitory response, titration of common coactivators by VDR also appears to be involved in transrepression. Therefore, the transcriptional response to RA and vitamin D depends on a complex combinatory pattern of interaction among different receptors wih DNA and coactivators.
A Novel Pathway for Hormonally Active Calcitriol
Authors: Lehmann Bodo , Knuschke Peter , Meurer Michael
Published: April 2003

Calcitriol [1α,25(OH)2D3], the hormonally active form of vitamin D3 (D3) is produced in both renal and extrarenal tissues. Our findings demonstrate that physiological doses of UVB radiation at 300 nm induce the conversion of 7-dehydrocholesterol (7-DHC) via preD3 and D3 into calcitriol in the pmol range in epidermal keratinocytes. The hydroxylation of photosynthesized D3 to calcitriol is strongly suppressed by ketoconazole, a known inhibitor of cytochrome P450 mixed function oxidases. The UVB-induced formation of calcitriol in human skin is demonstrable in vivo by the microdialysis technique. These results suggest that human skin is an autonomous source of hormonally active calcitriol.
Successful Treatment of Non-Segmental Vitiligo: Systemic Therapy with Sex Hormone-Thyroid Powder Mixture
Authors: Nagai Ko , Ichimiya Makoto , Yokoyama Kazuo , Hamamoto Yoshiaki , Muto Masahiko
Published: April 2003

We previously reported a patient with generalized vitiligo improved by oral administration of the drug for menopausal syndrome (sex hormone-thyroid powder mixture). In this study, we reevaluated the efficiency of this drug for vitiligo, and examined its pharmacological action in melanogenesis.
Liposomal Ursolic Acid (Merotaine) Increases Ceramides and Collagen in Human Skin
Authors: Yarosh Daniel B. , Both Dawn , Brown David
Published: April 2003

Skin wrinkling and xerosis associated with aging result from decreases of dermal collagen and stratum corneum ceramide content. This study demonstrates that ursolic acid incorporated into liposomes (MerotaineTM) increases both the ceramide content of cultured normal human epidermal keratinocytes and the collagen content of cultured normal human dermal fibroblasts. In clinical tests, Merotaine increased the ceramide content in human skin over an 11-day period. Merotaine has effects on keratinocyte differentiation and dermal fibroblast collagen synthesis similar to retinoids. However, unlike retinoids, Merotaine increases ceramide content of human keratinocytes. Ursolic acid may bind to members of the glucocorticoid receptor family to initiate changes in keratinocyte gene transcription.
Childhood Diabetes: A Global Perspective
Authors: Silink Martin
Published: April 2003

Diabetes is an evolving disease, with changing patterns seen in both type 1 and type 2 diabetes. A wide (over 400-fold) variation exists in worldwide incidence rates of type 1 diabetes, with the highest occurring in Finland (over 45 per 100,000 under the age of 15 years) and the lowest in parts of China. In many countries (e.g. in Europe, the Middle East, Australia) the incidence of autoimmune-mediated type 1 diabetes in children <15 years of age has risen by 2–5% per annum. Type 2 diabetes is also increasing rapidly globally and is occurring at a younger age, including in adolescence and childhood. In the USA, approximately one third of newly diagnosed in the adolescent age group is type 2, with up to 20% presenting with ketosis and ketoacidosis. The management of type 2 diabetes is especially difficult in the adolescent age group. Obesity is the single most obvious risk factor for type 2 diabetes. Lifestyle modification programmes starting in childhood are urgently needed and society needs to change its attitudes to childhood nutrition, play and exercise.
Natural Course of Preclinical Type 1 Diabetes
Authors: Knip Mikael
Published: April 2003

The clinical presentation of type 1 diabetes is preceded by an asymptomatic latent period characterized by the presence of diabetes-associated autoantibodies in the peripheral circulation, reflecting β-cell damage. This prediabetic period may last for months and years. Several studies observing genetically susceptible subjects from birth have shown that insulin autoantibodies (IAA) are the first or among the first autoantibodies to appear in young children, implying that insulin may be the primary autoantigen in most cases of childhood type 1 diabetes. About 12–16% of siblings of children with type 1 diabetes have been observed to test positive for at least one diabetes-associated autoantibody, whereas the risk of diabetes among siblings has been estimated to be 6–8%. In parallel, close to 4% of Finnish schoolchildren tested positive for at least one diabetes-associated autoantibody; the lifetime risk of type 1 diabetes in the Finnish population has been estimated to be close to 1%. These observations suggest that only 25–50% of those with signs of β-cell autoimmunity eventually progress to clinical type 1 diabetes. Accordingly there is a considerable proportion of children in whom β-cell autoimmunity remains subclinical or is aborted. Positivity for only one diabetes-associated autoantibody may actually represent innocent β-cell autoimmunity, while positivity for two or more autoantibodies seems to mark a point of no return. The autoimmune reponse is very dynamic in the early phase of prediabetes, with spreading from one antigen to another and from one epitope to another within a given antigen. In addition both isotype spreading and switching can be observed in early prediabetes. This indicates that the early prediabetic process may be a suitable target for immunomodulation aimed at delaying or preventing progression to clinical diabetes.
Experience with Insulin Analogues in Children
Authors: Danne Thomas , Deiss Dorothee , Hopfenmüller Werner , von Schütz Wolfgang , Kordonouri Olga
Published: April 2003

Current data on rapid and long-acting insulin analogues in the paediatric age group is limited. While several studies indicate a benefit in reducing hypoglycaemia, particularly at night, with rapid or long-acting insulin analogue treatment, the effect on long-term glycaemic control remains controversial. The continuous glucose monitoring system offers a new option for tailoring treatment with insulin analogues to achieve optimal glycaemia. In 29 adolescents with diabetes this approach confirmed the non-inferiority of postprandial rapid-acting analogue administration compared to preprandial regular insulin, but revealed significant mealtime differences, with increased analogue requirement at breakfast and dinner. Although rapid- and long-acting insulin analogues may offer potential benefits for problems frequently encountered in paediatric diabetology, their value for the individual child still has to be tested in long-term observations in daily clinical practice.
How Do We Organize Smooth, Effective Transfer from Paediatric to Adult Diabetes Care?
Authors: McGill Marg
Published: April 2003

Transition from paediatric to adult care is a major milestone in the life of a young person with diabetes, yet it is commonly poorly done. This finding is supported by the dearth of publications in the literature that particularly relate to transition in diabetes care. Other transitions occur at this time of life, for example: from parental supervision to growing independence and from secondary school to post-school options. Health professionals know, from anecdotal evidence, that this is the period when young people with diabetes ‘drop out’ of the system. They often have no specialist follow-up and attend only the primary care physician for insulin prescriptions. Then, inevitably, a problem occurs that cannot be managed by the family doctor, such as diabetic ketoacidosis or pregnancy, and the patient is finally referred to an adult unit. There are many contributing factors to poor transition but two major reasons are that members of this age group are classic non-attenders and, importantly, they have not been well prepared for the transition. Preparation is the key to success and this must include parents as well as the young person. Components of transition preparation include: self-advocacy, independent health care behaviours, sexual health, psychosocial support, education and vocational planning, and health and lifestyle (drugs, alcohol, etc.). Considerable differences exist between many of the paediatric and adult services, and this cultural shift has significant impact on the success or otherwise of transition. Paediatric care is often multidisciplinary, family focused, prescriptive and requires parental direction and consent. Adult care is often provided by a single doctor, is patient focused, more investigational and requires autonomous, independent skills on the part of the user. Young people and their families, unless well prepared, become confused and disillusioned with the adult system. To avoid this situation, there is a variety of solutions, including adolescent transition clinics attended by both paediatric and adult teams, a transition coordinator who is responsible for making the transfer as smooth as possible, etc. Unfortunately, the very nature of the group in question means that none of these solutions is perfect. In reality, transition is a process that takes place over a number of years and should not be considered an event. The transition process needs to begin in early adolescence, to foster independence and communication skills, and to incorporate health education.
Insulin Treatment at Onset of Diabetes
Authors: Swift Peter G.F.
Published: April 2003

Management strategies and practicalities of insulin therapy in the first days and weeks after the diagnosis of diabetes in children and adolescents depend on the clinical situation and the facilities available. Outpatient or domiciliary management favoured by some centres is only practicable and safe if an experienced team is readily available. There is evidence showing a correlation between the level of glycaemic control achieved in the earliest years of treatment and the metabolic control in subsequent years (the ‘tracking phenomenon’). The major factors influencing metabolic control in the first year after diagnosis certainly include the continuing secretion of endogenous pancreatic insulin. There has been considerable debate as to whether continuing insulin secretion and the induction of the remission phase can be significantly affected by the methods of insulin administration in the first days after clinical diagnosis; whether intravenous insulin has a protective effect; whether psychosocial factors have a more profound influence on metabolic control; and whether there is enough evidence to make valid recommendations on the optimal method(s) for treating children at the onset of diabetes. It seems likely that from the first day after diagnosis benefit is derived from attempting to obtain near normoglycaemia and the rapid induction of a partial remission phase by whatever insulin regimen is found to be most successful. This may occur not only by reducing the threat of glucotoxicity on the β-cells but also by setting a pattern of optimal control for the child and the family. This process is enhanced by frequent contact with the team of experts in childhood diabetes who are able to give advice on insulin adjustments from the onset of diabetes.
The Quality Circle: How to Improve the Outcome of Paediatric Diabetes Care
Authors: Holl Reinhard W. , Grabert Matthias
Published: April 2003

Most multicentre studies demonstrate that the outcome of diabetes therapy falls below the targets set up in recent guidelines. Applying quality control methodology may provide one means better to achieve such targets. Before setting up a quality circle, objective, standardized documentation of relevant quality indicators is necessary. Based on internal (for example longitudinal changes over time) and external quality control (comparison with other institutions), both favourable and unfavourable results achieved by each institution are identified. Such data provide the basis for intensive discussion among the members of diabetes care teams on how to remedy such deficits. In Germany, the working group on paediatric diabetology set up a system for external quality assessment in 1995: For 6 continuous years, quality indicators are compared twice yearly, and regional quality circles for more open discussions have been established, in addition to yearly nationwide meetings among all participants.
Diabetes and the Internet
Authors: Robertson Kenneth J.
Published: April 2003

This paper examines what the World Wide Web has to offer patients, families and professionals in relation to diabetes. The potential pitfalls and dangers are discussed, leading to a wider debate on how the Internet can be expected to impact upon diabetes and other health care provision in the near future, and how health care professionals’ practices will have to change. Themes include: the World Wide Web (finding material, assessing authenticity, pitfalls for patients, personalized pages, chat rooms, security); e-mail consultation (benefits, risks, minimizing risk, what to tell patients, legal constraints, security); telemedicine (telemetry, surveillance, security); search engines (journals, etc.); looking ahead (digital television, web-based medical records).
Screening for Vascular Complications in Children and Adolescents with Type 1 Diabetes mellitus
Authors: Chiarelli F. , Mohn A. , Tumini S. , Trotta D. , Verrotti A.
Published: April 2003

Type 1 diabetes mellitus poses a significant health burden, particularly as a result of its microvascular complications. Clinically evident diabetes-related microvascular complications are extremely rare in childhood and adolescence. However, early functional and structural abnormalities may be present a few years after the onset of the disease. Therefore, regular screening for diabetic microvascular disease, particularly retinopathy and nephropathy, are of foremost importance in paediatric diabetes care. Early detection of diabetic microangiopathy and timely treatment of early signs of these complications have a pivotal role in prevention of blindness and end-stage renal failure in children and adolescents with diabetes.
Effects of Implicit Parameters in Segregation Analysis
Authors: Tai John Jen , Hsiao Chuhsing Kate
Published: April 2003

In human genetic analysis, data are collected through the so-called ‘ascertainment procedure’. Statistically this sampling scheme can be thought of as a multistage sampling method. At the first stage, one or several probands are ascertained. At the subsequent stages, a sequential sampling scheme is applied. Sampling in such a way is virtually a nonrandom procedure, which, in most cases, causes biased estimation which may be intractable. This paper focuses on the underlying causes of the intractability problem of ascertained genetic data. Three types of parameters, i.e. target, design and nuisance parameters, are defined as the essences to formulate the true likelihood of a set of data. These parameters are also classified into explicit or implicit parameters depending on whether they can be expressed explicity in the likelihood function. For ascertained genetic data, a sequential scheme is regarded as an implicit design parameter, and a true pedigree structure as an implicit nuisance parameter. The intractability problem is attributed to loss of information of any implicit parameter in likelihood formulation. Several approaches to build a likelihood for estimation of the segregation ratio when only an observed pedigree structure is available are proposed.
Rapid Multipoint Linkage Analysis via Inheritance Vectors in the Elston-Stewart Algorithm
Authors: O’Connell Jeffrey R.
Published: April 2003

The calculation of multipoint likelihoods of pedigree data is crucial for extracting the full available information needed for both parametric and nonparametric linkage analysis. Recent mathematical advances in both the Elston-Stewart and Lander-Green algorithms for computing exact multipoint likelihoods of pedigree data have enabled researchers to analyze data sets containing more markers and more individuals both faster and more efficiently. This paper presents novel algorithms that further extend the computational boundary of the Elston-Stewart algorithm. They have been implemented into the software package VITESSE v. 2 and are shown to be several orders of magnitude faster than the original implementation of the Elston-Stewart algorithm in VITESSE v. 1 on a variety of real pedigree data. VITESSE v. 2 was faster by a factor ranging from 168 to over 1,700 on these data sets, thus making a qualitative difference in the analysis. The main algorithm is based on the faster computation of the conditional probability of a component nuclear family within the pedigree by summing over the joint genotypes of the children instead of the parents as done in the VITESSE v. 1. This change in summation allows the parent-child transmission part of the calculation to be not only computed for each parent separately, but also for each locus separately by using inheritance vectors as is done in the Lander-Green algorithm. Computing both of these separately can lead to substantial computational savings. The use of inheritance vectors in the nuclear family calculation represents a partial synthesis of the techniques of the Lander-Green algorithm into the Elston-Stewart algorithm. In addition, the technique of local set recoding is introduced to further reduce the complexity of the nuclear family computation. These new algorithms, however, are not universally faster on all types of pedigree data compared to the method implemented in VITESSE v. 1 of summing over the parents. Therefore, a hybrid algorithm is introduced which combines the strength of both summation methods by using a numerical heuristic to decide which of the two to use for a given nuclear family within the pedigree and is shown to be faster than either method on its own. Finally, this paper discusses various complexity issues regarding both the Elston-Stewart and Lander-Green algorithms and possible future directions of further synthesis.
Regulation of CD69 Expression on Eosinophil Precursors by Interferon-γ
Authors: Ochiai Kenichi , Kagami Masaru , Nakazawa Takuya , Sugiyama Takao , Sueishi Makoto , Ito Motohiro , Tomioka Hisao
Published: April 2003

The purpose of this study was to determine whether interferon-γ (IFN-γ) induced CD69 expression by eosinophil precursors. Eosinophil precursors were induced from CD34+ cord blood cells using recombinant human interleukin-3 (IL-3) and interleukin-5 (IL-5). On day 14 of culture, cells constitutively expressed CD69 and the IFN-γ receptor (IFN-γR). Stimulation with IFN-γ for 24 h did not affect IFN-γR expression by the cells. On the other hand, IFN-γ significantly upregulated CD69 expression by the precursors after 24 h of incubation. A specific JAK2 inhibitor (AG-490) caused a concentration-dependent suppression of IFN-γ-induced CD69 expression by the precursors. In conclusion, these results indicate that IFN-γ induces CD69 expression by eosinophil precursors via the activation of JAK2.
Expression of Eotaxin by Normal Airway Epithelial Cells after Influenza Virus A Infection
Authors: Kawaguchi Mio , Kokubu Fumio , Kuga Hideki , Tomita Takeshi , Matsukura Satoshi , Kadokura Mitsutaka , Adachi Mitsuru
Published: April 2003

Background: Viral infection is known to cause lung inflammatory disease, including bronchial asthma. The mechanisms of inflammatory cell accumulation into the airways after viral infection are not well understood. Eotaxin is a CC chemokine which is a potent and specific agonist for CC chemokine receptor 3 (CCR3). CCR3 is expressed on eosinophils, basophils and T lymphocytes. These cells are known to be key cells in the pathogenesis of asthma. Although it has recently been demonstrated that airway epithelial cells express eotaxin in vivo and in vitro, there are few data about its epxression in viral infection. We hypothesized that eotaxin may play an important role in attracting inflammatory cells to the airways after viral infection, and analyzed whether viral infection attracts eotaxin in bronchial epithelial cells in vitro. Methods: Human airway epithelial cells obtained from bronchial tissue at lobectomy for lung cancer were infected with influenza virus A (subtype H3N2). The cells and cultured media were collected 8, 24, and 48 h after infection. Eotaxin mRNA was analyzed with reverse transcriptase-polymerase chain reaction. Eotaxin protein levels in the culture media were analyzed by enzyme-linked immunosorbent assay. We also studied a blocking assay to analyze the intervention of proinflammatory cytokines in its production induced by influenza virus. Results: Eotaxin mRNA appeared to be expressed constitutively in uninfected cells but was expressed more clearly in infected cells. Eotaxin protein release into culture media significantly increased after infection. Anti-TNF-α and anti-IL-1β antibodies did not alter the eotaxin protein levels after viral infection. Conclusions: These results suggest that influenza virus A infection in airway epithelial cells activates the expression of eotaxin and that eotaxin may participate in the pathogenesis of airway inflammatory disease caused by viral infection, such as infectious type asthma.
An Optimal Condition of Bronchial Cell Proliferation Stimulated by Insulin-Like Growth Factor-I
Authors: Oyamada Hajime , Kayaba Hiroyuki , Kamada Yumiko , Kuwasaki Tomoe , Yamada Yoshiyuki , Kobayashi Yoshimi , Cui Chang-hao , Honda Kohei , Saito Norihiro , Chihara Junichi
Published: April 2003

Background: It is known that growth hormones such as insulin-like growth factor-I (IGF-I) and several kinds of cytokines are involved in the regeneration process of injured epithelial cells in chronic respiratory inflammatory diseases such as bronchial asthma. Repetitive degeneration/regeneration processes of the airway epithelial layer is supposed to be responsible for the remodeling and irreversible organic changes of the airway in bronchial asthma. The purpose of this study is to establish a simple and reliable in vitro method for studying airway epithelial cell growth and proliferation using IGF-I. Method: By altering the number of cultured epithelial cells (strain NCI-H292), culture duration before stimulation with IGF-I, concentration of IGF-I, and duration of IGF-I stimulation, the optimum conditions for epithelial cell growth was determined. The epithelial cell growth was evaluated using [methyl-3H]thymidine uptake. Result: Among various culture conditions, the epithelial cells cultured at 1 × 103 cells/well for 24 h followed by 24 h of stimulation by 10–8 M of IGF-I showed the highest growth. Conclusion: The method for the evaluation of epithelial cell growth established in this study requires a small number of cells and has no complicated procedure. This simple model enables us to investigate the effect of various substances on bronchial epithelial cell growth in the presence of IGF-I.