The role of sex steroids in the regulation of insulin sensitivity and serum lipid concentrations during male puberty: a prospective study with a P450-aromatase inhibitor

OBJECTIVE: Our purpose was to study the sex steroid-mediated changes in serum insulin and lipid concentrations in boys during puberty. DESIGN AND METHODS: We treated boys with constitutional delay of puberty either with testosterone plus placebo or with testosterone plus an aromatase inhibitor, letrozole, which inhibits the conversion of androgens to oestrogens. We demonstrated previously that during treatment with testosterone plus letrozole the increase in testosterone concentration was more than 5-fold higher than during treatment with testosterone plus placebo. The concentrations of 17beta-oestradiol, IGF-I and IGF-binding protein-3 increased during testosterone-plus-placebo treatment, but during testosterone-plus-letrozole treatment the concentrations remained unchanged. These divergent changes in the two groups enabled us to study the effects of sex steroids and GH on insulin sensitivity and lipid concentrations. RESULTS: The insulin concentration in the testosterone-plus-placebo-treated group did not change. In contrast, in the testosterone-plus-letrozole-treated group, the concentration decreased during letrozole treatment, indicating improved insulin sensitivity. Changes in insulin and IGF-I concentrations within 12 and 18 months were correlated. In the testosterone-plus-placebo-treated group, the high-density lipoprotein cholesterol concentration did not change but in the testosterone-plus-letrozole-treated group the concentration decreased. The concentrations of low-density lipoprotein cholesterol (LDL-cholesterol) and triglycerides did not change in either of the groups. CONCLUSIONS: The findings indicate that androgens do not directly alter insulin sensitivity in boys during puberty. In contrast, the observations suggest tight regulation of glucose--insulin homeostasis by GH in boys at this stage. Furthermore, our findings indicate that sex steroids do not significantly participate in the regulation of serum concentrations of LDL-cholesterol or triglycerides in boys during early and mid-puberty.     

Central nervous system involvement in severe arterial hypertension of childhood

The case histories of 125 children with hypertension and no apparent primary CNS disease were analyzed for neurological symptoms or complications. Eleven children had neurological symptoms of high blood pressure. In only one of these patients was the diagnosis of arterial hypertension made before the observation of the neurological findings. The symptoms were severe headache in eight children, convulsions and coma in four, hemiplegia in two, and impaired vision and apraxia in one child. Symptomatology was rapidly reversed by antihypertensive treatment in four children, while six had long-term stigmata and one child died in hypertensive crisis. Because elevated arterial pressure can cause severe neurological disease, routine blood pressure measurement in children--especially those with neurological symptomatology--is stressed.     

Epilepsy and associated handicaps in a 1 year birth cohort in Northern Finland

A 1 year birth cohort in the provinces of Oulu and Lapland in the Northern part of Finland consisted of 12058 live-born infants, this being 96% of all children born in 1966 in this area. Information on morbidity up to the age of 14 years was collected prospectively by means of questionnaires, special examinations and from national and regional registers of hospital adminissions and social services contacts.The total number of children with epilepsy, defined as the occurrence of at least one afebrile epileptic seizure, was 208, 113 boys and 95 girls. The cumulative incidences for epilepsy to the age of 14 years was 17.3 per 1000. Primary generalised epilepsy was present in 63% and partial seizures in 37%.At least one additional handicapping condition, such as cerebral palsy, mental retardation, and visual or auditory defect was present in 74 children (35.5%). Mental retardation was the most frequent additional handicap, being present in 28%, whereas 16% of the children had cerebral palsy. A total of 75% of the children were able to attend an ordinary school. The high frequency of epilepsy in this study, as compared to other studies, is explained by the cumulative registration of the cases and a high degree of ascertainment of cases with epilepsy.     

Dixyrazine (Esucos) as premedication for esophagogastroscopy. A controlled double-blind trial.

Dixyrazine (Esucos) as premedication for esophagogastroscopy was studied in a double-blind trial with diazepam and atropine in 321 successive endoscopies. It was established that dixyrazine was fairly well tolerated, regurgitation was significantly reduced. A distinct antiemetic effect was observed compared with diazepam; the difference was statistically significant in the male patients. Dixyrazine may be regarded as a fairly good alternative premedication for esophagogastroscopy.     

Antipyretic Effect and Plasma Concentrations of Rectal Acetaminophen and Diazepam in Children

Plasma levels of acetaminophen (paracetamol) and diazepam were measured in 9 children by gas chromatography after administering these drugs simultaneously in separate suppositories. The antipyretic effects of oral and rectal acetaminophen-diazepam combinations were also studied and compared with that of oral or rectal acetaminophen alone. Diazepam at a dose of 0.2 mg/kg did not increase the antipyretic action of acetaminophen. Acetaminophen and diazepam seemed to be well absorbed from the rectal suppositories, the maximal plasma concentration of diazepam after a rectal dose of 0.5 mg/kg just reaching the assumed anticonvulsant level in about 2 hr. In light of this study, an acetaminophen-diazepam combination in separate suppositories may be suitable for the prevention of recurrent febrile convulsions in susceptible children, but its practical value and efficacy require evaluation in clinical experiments.     

Cell proliferation activities on skin fibroblasts from a short child with absence of one copy of the type 1 insulin-like growth factor receptor (IGF1R) gene and a tall child with three copies of the IGF1R gene

The type 1 IGF receptor (IGF1R) is required for normal embryonic and postnatal growth. The aim of this study was to determine whether we could detect abnormal IGF1R function in skin fibroblasts from children with an abnormal copy number of the IGF1R gene. We report two children with altered copy number of the IGF1R gene who presented with abnormal growth. Case 1 is a girl with intrauterine growth retardation, postnatal growth failure, and recurrent hypoglycemia. Pituitary function tests were normal. Routine karyotype analysis identified a deletion on 15q26.2, and a fluorescence in situ hybridization study using IGF1R probes showed only a single IGF1R gene. Case 2 was large for gestational age, with birth weight and length at or above 97th percentile, and showed rapid early postnatal growth. He was found to have a recombinant chromosome 15 containing a partial duplication at 15q (q25-qter). A fluorescence in situ hybridization study using the same probes showed three copies of the IGF1R gene. In a mitochondrial activity assay, skin fibroblasts from the subject with only one copy of IGF1R showed slower growth, whereas cells from the subject with three copies of IGF1R showed accelerated growth compared with controls. IGF1R phosphorylation, as assessed by Western blot, and IGF1R binding studies were decreased compared with controls in the child with one copy of the IGF1R and increased in the child with three copies of the gene. Our data are consistent with the concept that IGF1R gene copy number is of functional and clinical importance in humans.     

Hemodynamic variables related to outcome in septic shock

Objective To assess the impact of hemodynamic variables on the outcome of critically ill patients in septic shock and to identify the optimal threshold values related to outcome with special reference to continuously monitored mean arterial pressure (MAP) and mixed venous oxygen saturation (SvO₂).Design and setting Retrospective cohort study in a university hospital intensive care unit (ICU).Patients All consecutive 111 patients with septic shock treated in our ICU between 1 Jan. 1999 and 30 Jan. 2002.Measurements and results The data on the hemodynamic and respiratory monitoring and circulation-related laboratory tests over the first 48 h of treatment in the ICU were collected from the clinical data management system. Data from 6 h and 48 h were analyzed separately. The 30-day mortality rate was 33% (36 of 111). Univariate analysis and forward stepwise logistic regression analysis were performed using the 30-day mortality as the primary endpoint. Mean MAP and lactate on arrival during 6 h, while mean MAP, the area of SvO₂ under 70%, and mean CVP during 48 h were independently associated with mortality. MAP level of 65 mmHg and SvO₂ of 70% had the highest areas under receiver characteristics curves.Conclusions MAP, SvO₂, CVP, and initial lactate were independently associated with mortality in septic shock, with threshold values supporting those published in recent guidelines.     

Tissue-specific promoters for cancer gene therapy

Adenoviral cancer gene therapy approaches have resulted in promising recent results. Following only a decade of intense development, some of the crucial obstacles are now being overcome. Insufficient transduction has been the main limitation of earlier approaches. A new approach for increasing transduction of tumour cells is utilisation of replication-competent oncolytic agents, such as conditionally replicating adenoviruses (CRADs). The anti-tumour effect is caused by replication of the virus per se and, thus, replication must be restricted to tumour cells to protect normal tissues from damage. Tissue-specific promoters (TSPs) represent a powerful tool for decreasing the toxicity of cancer gene therapy to normal tissues and have previously been utilised for specific mutation compensation or delivery of prodrug-converting enzymes. However, TSPs can also be used for controlling crucial viral replication regulators and consequent restriction of replication to tumour cells. Initial clinical trials have demonstrated the safety and suggested efficacy for TSP-controlled CRADs as a novel approach for cancer gene therapy.