Test-Retest Reliability and Construct Validity of the German Translation of the Gait Outcome Assessment List (GOAL) Questionnaire for Children with Ambulatory Cerebral Palsy.

The Gait Outcome Assessment List (GOAL) is a patient or caregiver-reported assessment of gait-related function across different domains of the International Classification of Functioning, Disability, and Health (ICF) developed for ambulant children with cerebral palsy (CP). So far, the questionnaire is only available in English. The aim of this study was to translate the GOAL into German and to evaluate its reliability and validity by studying the association between GOAL scores and gross motor function as categorized by the gross motor function classification system (GMFCS) in children with cerebral palsy (CP). The GOAL was administered to primary caregivers of n = 91 children and adolescents with CP (n = 32, GMFCS levels I; n = 27, GMFCS level II; and n = 32, GMFCS level III) and n = 15 patients were capable of independently completing the whole questionnaire (GMFCS level I). For assessing test-retest reliability, the questionnaire was completed for a second time 2 weeks after the first by the caregivers of n = 36 patients. Mean total GOAL scores decreased significantly with increasing GMFCS levels with scores of 71 (95% confidence interval [CI]: 66.90-74.77) for GMFCS level I, 56 (95% CI: 50.98-61.86) for GMFCS level II, and 45 (95% CI: 40.58-48.48) for GMFCS level III, respectively. In three out of seven domains, caregivers rated their children significantly lower than children rated themselves. The test-retest reliability was excellent as was internal consistency given the GOAL total score. The German GOAL may serve as a much needed patient-reported outcome measure of gait-related function in ambulant children and adolescents with CP.

State-Dependent Partial Occlusion of Cortical LTP-Like Plasticity in Major Depression.

The synaptic plasticity hypothesis of major depressive disorder (MDD) posits that alterations in synaptic plasticity represent a final common pathway underlying the clinical symptoms of the disorder. This study tested the hypotheses that patients with MDD show an attenuation of cortical synaptic long-term potentiation (LTP)-like plasticity in comparison with healthy controls, and that this attenuation recovers after remission. Cortical synaptic LTP-like plasticity was measured using a transcranial magnetic stimulation protocol, ie, paired associative stimulation (PAS), in 27 in-patients with MDD according to ICD-10 criteria and 27 sex- and age-matched healthy controls. The amplitude of motor-evoked potentials was measured before and after PAS. Patients were assessed during the acute episode and at follow-up to determine the state- or trait-character of LTP-like changes. LTP-like plasticity, the PAS-induced increase in motor-evoked potential amplitudes, was significantly attenuated in patients with an acute episode of MDD compared with healthy controls. Patients with remission showed a restoration of synaptic plasticity, whereas the deficits persisted in patients without remission, indicative for a state-character of impaired LTP-like plasticity. The results provide first evidence for a state-dependent partial occlusion of cortical LTP-like plasticity in MDD. This further identifies impaired LTP-like plasticity as a potential pathomechanism and treatment target of the disorder.

Stressful life experiences and mental health problems among unaccompanied asylum-seeking children.

Unaccompanied asylum-seeking children aged 10-16 years (N = 93, M = 13.8, SD = 1.4, 81% boys) were assessed 6 months after arrival in Norway (SD = 5 months). Participants originated from 14 countries (63% Asia; 36% Africa). Severe life events (SLE) and psychological symptoms were measured by self-report. Participants reported a mean of 5.5 SLE (SD = 2.4), the most prevalent being death of a close person (68%), witnessing violence (63%), and war (62%). Some 54% scored above clinical cutoff on posttraumatic stress symptoms, 30% on anxiety symptoms, 20% on depressive symptoms, and 7% on externalizing symptoms. Number of SLE was associated with posttraumatic stress disorder symptoms (r =.50, p < .001), depression (r =.27, p = .020), and anxiety symptoms(r =. 34, p = .003), but not externalizing symptoms (r =.02, p = .874). None of the symptom variables were associated with age or gender. Results indicate that many unaccompanied asylum-seeking children have experienced not only war-related traumas but several other severe life adversities as well. It may thus be helpful to conduct early assessments on this group of children to assess their need for treatment or other psychosocial interventions.

A national study on weight classes among children in Greenland at school entry.

OBJECTIVES: To estimate the proportion of gender-specific thinness, overweight and obesity among children born in 2005 at school entry in Greenland and to compare figures between the capital, Nuuk, with the rest of Greenland. STUDY DESIGN: A cross-sectional study based on data from Electronic Medical Records (EMR). METHODS: All children born in 2005 with permanent address in Greenland at the time of data extraction with a registered weight and height in EMR from January 1st 2011 to January 31st 2013 were included in the study. Information about height without shoes and weight in light indoor clothing was obtained. Body Mass Index (BMI) was calculated. Participants were categorized into age and gender-specific weight classes based on the International Obesity Task Force (IOTF) cut-offs for child overweight, obesity and thinness. RESULTS: A total of 842 children born in 2005 were identified. Of those, 72% (N=607, 308 boys and 299 girls) had a recorded weight and height in the study period. In total, 74.6% (71.2-78.1) were categorized as of normal weight. The proportion of children with overweight was 15.8% (12.9-18.7) while 6.8% (4.8-8.8) were obese. In all, 2.9% were categorized as thin. The proportion of overweight among boys (12.7%) was lower (p=0.031) than among girls (19.1%), and boys in Nuuk had a lower median BMI compared to the rest of Greenland. No differences in distribution of age and gender-specific overweight and obesity were observed between the capital and the rest of Greenland. CONCLUSION: Nearly 1 quarter of Greenlandic children are overweight or obese at school entry. No differences were observed between Nuuk and the rest of Greenland. Information about weight and height is available in the EMR for the majority of all children at school entry in Greenland. Continuous monitoring of the proportion of overweight and obesity among children using data from the EMR in Greenland is recommended.

In-vitro comparison of free oscillation rheometry (ReoRox) and rotational thromboelastometry (ROTEM) in trauma patients upon hospital admission.

Plasma-based assays do not provide accurate information on haemostatic resuscitation hence viscoelastic point-of-care haemostatic assays such as rotational thromboelastometry (ROTEM Delta, Pentapharm) are used to monitor coagulopathy in trauma patients. Free oscillation rheometry (FOR) is a new whole blood haemostatic assay that measures not only the clot-forming process but also the initial viscous phase; this could potentially be of value when assessing traumatic coagulopathy. A comparative analysis between FOR and ROTEM was therefore performed. This is a prospective observational study of 40 adult trauma patients admitted to a level 1 trauma centre. Citrated whole blood was analysed with ROTEM EXTEM and FIBTEM assays and FOR Fibscreen1 and Fibscreen2 assays. Predefined variables of ROTEM and FOR were compared using Spearman's ρ. ROTEM maximum clot function (MCF) in both EXTEM and FIBTEM correlated (P < 0.0001 for both) with FOR maximum elasticity Fibscreen1 and Fibscreen2, respectively. Interestingly, ROTEM EXTEM clotting time did not correlate with any of the FOR clot initiation parameters COT1, COT2 or COT2-1 of Fibscreen1. A correlation between ROTEM EXTEM and FIBTEM and FOR Fibscreen1 and Fibscreen2 clot formation and clot strength was found as was a significant correlation between lysis index after 60 min and ClotSR30. ROTEM EXTEM did not correlate with COT1, COT2 or COT2-1 of Fibscreen1 and this warrants further investigation.

Unification of trap-limited electron transport in semiconducting polymers.

Electron transport in semiconducting polymers is usually inferior to hole transport, which is ascribed to charge trapping on isolated defect sites situated within the energy bandgap. However, a general understanding of the origin of these omnipresent charge traps, as well as their energetic position, distribution and concentration, is lacking. Here we investigate electron transport in a wide range of semiconducting polymers by current-voltage measurements of single-carrier devices. We observe for this materials class that electron transport is limited by traps that exhibit a gaussian energy distribution in the bandgap. Remarkably, the electron-trap distribution is identical for all polymers considered: the number of traps amounts to 3 × 10(23) traps per m(3) centred at an energy of ~3.6 eV below the vacuum level, with a typical distribution width of ~0.1 eV. This indicates that the electron traps have a common origin that, we suggest, is most likely related to hydrated oxygen complexes. A consequence of this finding is that the trap-limited electron current can be predicted for any polymer.

Relación entre el diagnóstico clínico preoperatorio y el histopatológico posoperatorio, en pacientes con cáncer prostático localizado / Relationship between clinical preoperative diagnosis and postoperative histology in patients with localized prostate cancer

Introducción: Las variables relevantes preoperatorias con que cuenta el urólogo para una toma de decisión frente a un cáncer prostático localizado son: la edad, el tacto rectal, el antígeno prostático específico (APE) e informe histológico de la biopsia por punción con el Gleason. Además se pueden incluir otras variables como el volumen prostático, número de muestras de biopsias positivas, porcentaje de la muestra comprometida, etc. Nosotros quisimos evaluar el grado de concordancia entre el diagnóstico clínico-patológico preoperatorio con el hallazgo histológico, posoperatorio en pacientes prostatectomizados, debido a la implicancia pronóstica y en la toma de decisión que pudiese tener. Material y Método: Se estudiaron retrospectivamente 119 prostatectomías radicales entre marzo de 2004 y junio de 2009. Se consideraron: edad, tacto, antígeno prostático específico (APE) y score de Gleason. Se excluyeron pacientes con tratamiento antiandrogénico u hormonal neoadjuvante. Resultados: En el preoperatorio la mediana de edad fue de 66 años (61-68), de APE 7,35 ng/ml (5,38-11,8) y de Gleason fue de 6 (5-7). El 87,4 por ciento de los pacientes tenía un APE >4,0 ng/ml. El 54 por ciento (n= 64) tenía un estadio clínico T1c y el 46 por ciento (n= 55) un estadio T2. En el posoperatorio 23,5 por ciento (n= 28) tuvo un estadio pT2 y el 74 por ciento (n= 88) un estadio pT3. En pacientes con estadio pT2 el APE preoperatorio fue de 5,9 ng/ml (4,4-9,4), en el estadio pT3 fue de 7,9 ng/ml (5,7-12,8). El score de Gleason en pT2 fue de 5 (5-6), en el pT3 fue de 6 (5-7). No encontramos diferencia de edad en los estadios pT2 (67 años) y pT3 (68 años). Conclusiones: En el estudio histopatológico posoperatorio de pacientes con estadio clínico T1c y T2, se confirmó un estadio pT2 sólo en 23,5 por ciento, el 74 por ciento tenían un estadio pT3 (a, b). En el cáncer prostático localizado, el tacto rectal no fue útil en su correlación con el estadio histológico...

Introduction: Relevant preoperative variables in patients with localized prostate cancer are: age, digital rectal examination (DRE), prostatic specific antigen (PSA) level and Gleason score in the transrectal biopsy. Other variables include prostate volume, number of positive biopsy samples, percentage of involvement in the biopsy, etc. We evaluated the agreement between the preoperative clinico pathologic diagnosis and the postoperative histology report in patients submitted to prostatectomy. Material and method: This is a retrospective review of 119 radical prostatectomies performed between March 2004 and June 2009. We recorded age, DRE, PSA level, and Gleason score. Patients receiving anti-androgenic treatment or neoadjuvant hormonal treatment were excluded. Results: Preoperative findings: median age was 66 years (61-68), median PSA level was 7.35 ng/ml(5.38-11.8) and median Gleason score was 6 (5-7). PSA level >4 ng/ml was found in 87.4 percent of the patients. Clinical stage T1c was found in 54 percent (n=64) of the cases whereas 46 percent (n=55) were stage T2. Postoperative findings: stage pT2 was found in 23.5 percent (n=28) of the patients whereas 74 percent (n =88)were pT3 stage. In pT2 patients, preoperative PSA was 5,9 ng/ml (4.4-9.4). In pT3 patients, PSA was7.9 ng/ml (5.7-12.8). Gleason score in pT2 was 5 (5-6); in pT3 patients, Gleason score was 6 (5-7). No age difference was found between pT2 stage (67 years) and pT3 stage (68 years).Conclusions: Postoperative histology in patients with T1c and T2 stages confirmed a pT2 stage only in 23.5 percent of the cases; 74 percent of the cases were pT3 (a,b) stage. In localized prostate cancer, DRE was not useful for the correlation with pathologic staging, especially for stage pT3 cases. Preoperative Gleason score was relatively useful; we found understaging 36.2 percent of the cases and overstaging 21.8 percent of the patients. These variables should be considered in the initial evaluation of...

Influence of ghrelin on the gastric accommodation reflex and on meal-induced satiety in man.

Ghrelin increases gastric tone in the fasting state and enhances gastric emptying in gastroparesis. The aims of the study were to evaluate the effect of ghrelin on postprandial gastric tone and on meal-induced satiety in health. Ten healthy volunteers underwent a barostat study on two occasions. After determination of intra-abdominal pressure (minimal distending pressure, MDP), isobaric volume measurement was performed for 90 min at MDP + 2 mmHg. After 20 min, ghrelin (40 microg) or saline was administered i.v. over 30 min in a double-blind-randomized cross-over design, followed 10 min later by a liquid meal (200 mL, 300 kcal). Stepwise isobaric distentions (+2 mmHg per 2 min) were performed 60 min after the meal. Data (mean +/- SEM) were compared using paired Student's t-test and ANOVA. Separately, a satiety drinking test (15 mL min(-1) until satiety score 5) was performed on 10 subjects twice, after treatment with placebo or ghrelin. Ghrelin infusion significantly inhibited gastric accommodation (mean volume increase adjusted means 108.0 +/- 50 vs 23.0 +/- 49 mL, P = 0.03, ANCOVA with the premeal postinfusion volume as covariate) and reduced postprandial gastric volumes (197.2 +/- 24.6 vs 353.5 +/- 50.0 mL, P = 0.01). Pressures inducing perception or discomfort during postprandial gastric distentions were not altered. During satiety testing, ghrelin did not alter nutrient volume ingested till maximal satiety (637.5 +/- 70.9 vs 637.5 +/- 56.2 mL, ns). Ghrelin administered during the meal significantly inhibits gastric accommodation in health, but this is not associated with early satiation.

E10 and a small tension expansion of m theory.

A formal "small tension" expansion of D=11 supergravity near a spacelike singularity is shown to be equivalent, at least up to 30th order in height, to a null geodesic motion in the infinite-dimensional coset space E(10)/K(E10), where K(E10) is the maximal compact subgroup of the hyperbolic Kac-Moody group E10(R). For the proof we make use of a novel decomposition of E10 into irreducible representations of its SL(10,R) subgroup. We explicitly show how to identify the first four rungs of the E10 coset fields with the values of geometric quantities constructed from D=11 supergravity fields and their spatial gradients taken at some comoving spatial point.

Maximal gauged supergravity in three dimensions.

We construct maximally supersymmetric gauged N = 16 supergravity in three dimensions, thereby obtaining an entirely new class of anti--de Sitter supergravities. These models apparently cannot be derived from any known higher-dimensional theory and point to the existence of a new type of supergravity beyond D = 11. One of their noteworthy features is a non-Abelian generalization of the duality between scalar and vector fields in three dimensions. Among the possible gauge groups, SO(8) x SO(8) is distinguished as the maximal compact gauge group, but there are also more exotic possibilities such as F(4(-20)) x G2.

Comparative cardiac toxicity of the i.v. administered benzimidazole pyridazinon derivative Pimobendan and its enantiomers in female Beagle dogs.

The new positive-inotropic and vasodilatating drug Pimobendan (racemate), 4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazole-5-yl]-5-methyl-3 (2-H)-pyridazinone, and its enantiomers were investigated with regard to their cardiotoxicity in young adult female Chbb: Beagle dogs. The racemate and the (-)-isomer (eutomer) were intravenously injected once daily for 4 consecutive weeks at doses of 0.25, 0.75 and 2.25 mg/kg, and the (+)-isomer (distomer) at doses of 0.75, 2.25 and 6.75 mg/kg, respectively. Clinical signs, hematological, clinico-chemical, ophthalmologic and electrophysiological parameters were monitored. Plasma concentration-time profiles of the parent compound and the major metabolite UD-CG 212 were established on day 1 and in week 4 using an HPLC assay. Partial areas under the curves from 0.08 h to 1 h (AUC0.08-1 h) as well as the plasma concentration at time point 0.5 h/C0.5 h) were used for statistical calculations. Necropsy and histopathologic examination were performed after completion of the treatment period. Reduction of the blood pressure occurred already at low dosages of the racemate and the eutomer, but only in high dose distomer-treated animals. A tendency to tachycardia developed only in high dose females receiving the racemate. Consequently, with respect to the pharmacological effects and the adverse events, the racemate is equivalent to the eutomer. Plasma concentrations of parent compound and metabolite were dose-linear for racemate, eutomer and distomer within the dose range 0.25-2.25 mg/kg.d at both time points. There were no significant effects of form or repeated administration. A moderate increase of AUC0.08 1 h and C0.5 h could be seen on day 23 for the distomer indicating a stereoselektive metabolism of the latter. Histologic changes of the valvular and parietal endocardium being termed jet lesion were observed after administration of the racemate (> or = 0.75 mg/kg.d) and the eutomer (> or = 0.25 mg/kg.d) at distinctly lower doses than after the distomer (> or = 2.25 mg/kg.d). Furthermore, extent and severity of the morphologic lesions were found to be higher in dogs exposed to the racemate or the eutomer than in those receiving the distomer. The results gave evidence that the so-called cardiotoxicity by Pimobendan in dogs resulted from the exaggerated pharmacodynamic effect but not from the chemical nature of the compound per se. They corroborate also the previously raised assumption that the exaggerated pharmacodynamic activity of cardiotonic compounds in the broadest sense accounts for their morphologic adverse effects in experimental animals.

Isolation and characterisation of the NBR2 gene which lies head to head with the human BRCA1 gene.

To study the regulation of BRCA1 gene expression and the potential importance of dysregulation of this gene in breast and ovarian cancer, we have examined the 5' region of the human BRCA1 gene in detail. We have identified a new gene, NBR2, which is partially related to the NBR1 gene (formerly known as 1A1-3B and mapping directly adjacent to the pseudo-BRCA1 gene) and which lies head to head with the BRCA1 gene. The physical distance between the transcription start sites of the NBR2 and BRCA1 genes is 218 bp, suggesting that regulation of the expression of both genes may be co-ordinated through a bi-directional promoter. The NBR2 gene contains five exons spanning a genomic region of approximately 30 kb between the BRCA1 and pseudo-BRCA1 genes. Northern analysis showed that the NBR2 gene is expressed in all the tissues examined. The NBR2 cDNA contains an open reading frame of 112 amino acids and is predicted to encode a protein of approximately 12 kDa. Single-strand conformation polymorphism (SSCP) analysis of the NBR2 gene failed to identify any mutations in either breast or ovarian cancer, suggesting that if the NBR2 gene is involved in the development of these cancers, other mechanisms for tumorigenesis may exist. Hybridisation of NBR2 probes to zoo blots showed that the NBR2 gene is present in human and other primates. No hybridisation to DNA from other species was observed, suggesting that genomic elements controlling BRCA1 expression may differ between species.

Duration of action and pharmacokinetics of the oral antidiabetic drug gliquidone in patients with non-insulin-dependent (type 2) diabetes mellitus.

The duration of action and the pharmacokinetics of gliquidone (1-cyclohexyl-3-[[4-[2-(3,4-dihydro-7-methoxy-4,4-dimethyl-1, 3-dioxo-2(1H)-isochinolyl)ethyl]phenyl]-sulfonyl]-urea, AR-DF 26 SE, CAS 33342-05-1, Glurenorm, Beglynor) were investigated in 32 patients with non-insulin-dependent (type 2) diabetes mellitus over 16 h. In a single-blinded cross-over design vs. placebo, one 30 mg tablet gliquidone was administered 15 min before breakfast. Concomitant to the measurement of glucose and insulin, the gliquidone plasma levels of 20 subjects were determined by a new specific liquid chromatographic (HPLC) assay method with fluorescence detection, and the pharmacokinetic parameters calculated. Following the gliquidone administration, the mean plasma glucose profiles of the responders were up to 15% lower than with placebo (p < 0.005) between 8 a.m. and 6 p.m., representing a duration of the blood sugar-lowering effect of 8 to 10 h. Insulin values were raised, with peaks over 40% higher, during or shortly after meals. Subsequently, the insulin levels returned to approximately the same levels obtained with placebo during the postprandial phase. Plasma concentrations of gliquidone showed pronounced interindividual variability. The mean maximum concentration in plasma Cmax was 0.65 microgram/ml, (range: 0.12-2.14 micrograms/ml, coefficient of variation (CV): 82%). The median time to reach maximum plasma concentrations tmax was 2.25 h (range: 1.25-4.75 h). The areas under the plasma concentration-time curve from zero time to infinity (AUC0-infinity) and the mean terminal elimination half-lives (t1/2 beta) were computed from those patients (N = 8) who exhibited at least five plasma levels above the limit of quantitation in the terminal log-linear phase using a two-compartment model: the mean AUC0-infinity was 5.1 micrograms.h/ml (range: 1.5-10.1 micrograms.h/ml, CV 56%). The dominant half-life t1/2 alpha derived from therapeutically relevant plasma levels of gliquidone (> 80 ng/ml) was approximately 1.2 h (range: 0.4-3.0 h. CV: 71%) and the mean terminal half-life t1/2 beta was approximately 8 h (range: 5.7-9.4 h, CV: 17%). From the pharmacodynamic behavior as well as from the pharmacokinetic parameters it can be deduced that gliquidone belongs to the class of short-acting sulfonylureas used in antidiabetic therapy.

Mutations and alternative splicing of the BRCA1 gene in UK breast/ovarian cancer families.

BRCA1 is a tumour suppressor gene located on chromosome band 17q21. It is estimated that mutations in the BRCA1 gene account for approximately 45% of the breast cancer families and almost all of the breast/ovarian cancer families. We have used single strand conformation polymorphism analysis, direct sequencing, allele specific oligonucleotide hybridisation, and reverse transcription polymerase chain reaction (RT-PCR) to look for mutations in the BRCA1 gene in 49 breast or breast/ovarian cancer families. Five distinct mutations, three novel and two previously observed, were detected in seven families. Each novel mutation was identified in one family: 3896delT in exon 11, a splicing mutation in the intron 9-exon 10 junction, and an inferred regulatory mutation. The 185delAG in exon 2 was found in three families sharing the same haplotype, but this haplotype is different from that shared by the Ashkenazi Jewish families, suggesting that the 185delAG in our families may have arisen independently. Another previously reported mutation, the 3875del4 in exon 11, was identified in one family. Of the 49 families examined, linkage analyses for both the BRCA1 and the BRCA2 regions were performed on 33 families, and mutations in the BRCA1 gene were identified in all but one family that have a lod score above 0.8 for BRCA1. All of the mutations cause either a truncated BRCA1, or loss of a BRCA1 transcript, thus are likely to be functionally disruptive. In addition, we found that alternative splicing is a common phenomenon in the processing of the BRCA1 gene. Seven variant BRCA1 transcripts were identified by RT-PCR; all but one maintained the BRCA1 open reading frame. We believe that alternative splicing may play a significant role in modulating the physiological function of BRCA1.

Ambroxol improves the broncho-spasmolytic activity of clenbuterol in the guinea-pig.

The effects of ambroxol on the spasmolytic action of clenbuterol were investigated on acetylcholine-induced bronchospasm in guinea-pigs. Ambroxol (50 mg kg-1 day-1) or vehicle was administered orally for 14 days. Approximately 45 min after the final dose on day 14, the animals were anaesthetized and the spasmolytic effects of clenbuterol (3, 6 or 12 micrograms kg-1 injected intravenously) were determined by use of acetylcholine (40 micrograms kg-1, i.v.)-induced bronchoconstriction. For both vehicle- and ambroxol-treated animals, a positive linear relationship was observed between the log-dose of clenbuterol and the percent inhibition of bronchospasm. The calculated ED25 of clenbuterol (i.e., the dose producing 25% inhibition of the acetylcholine-induced bronchospasm) was 3.98 micrograms kg-1 (3.29 to 4.82 micrograms kg-1, 95% confidence interval) in the presence of ambroxol and 5.81 micrograms kg-1 (4.98 to 6.79 micrograms kg-1) in the absence of ambroxol. The linear regressions with or without ambroxol differed from each other (P < 0.001) but ran parallel (covariance analysis), enabling us to calculate a relative potency, the value of which was 1.46 (1.16 to 1.84). These results demonstrate that the spasmolytic activity of clenbuterol is significantly improved in animals pretreated with ambroxol.

Skeletal immaturity, IGF-I and IGFBP-3 serum concentrations in Legg-Calvé-Perthes disease (skeletal immaturity, IGF-I and IGFBP-3 in LCPD).

BACKGROUND: Skeletal immaturity is a major feature in Legg-Calvé-Perthes disease (LCPD). Evaluation of growth hormone concentration, somatomedin activity, or insulin-like growth factor I (IGF-I) concentration revealed inconsistent results. Recently, IGF-binding protein 3 (IGFBP-3) was found normal in relation to chronological age in LCPD patients. PATIENTS: In this study IGF-I and IGFBP-3 were measured in the serum of 23 children with unilateral LCPD and in 23 sex and age matched controls. METHODS: IGF-I and IGFBP-3 were measured with radioimmunoassays, using an IGF binding site-blocked assay for IGF-I. The results were related to the chronological age in all and to the bone age in 19 of the patients. RESULTS: Bone age was retarded in 16 of 19 patients with a delay of one year or more in twelve children (mean 14.75, range 2-35 months). Chronological age and bone age related IGF-I and IGFBP-3 serum concentrations were predominantly within the normal ranges and did not differ significantly from the matched controls. IGF-I and IGFBP-3 serum levels showed a high correlation, which was similar in LCPD (r = 0.7; p < 0.0001) and in the control group (r = 0.8; p < 0.0001). CONCLUSIONS: Our data confirm that most children with LCPD are skeletally immature. However, IGF-I measured with IGF-II-blocked IGFBP binding sites, and IGFBP-3 serum concentrations analysed with respect to bone age show no evidence for a disturbance of the hypothalamo-pituitary-somatomedin axis in these children.

The frequency and mechanism of loss of heterozygosity on chromosome 11q in breast cancer.

Loss of heterozygosity (LOH, allele loss) occurs frequently on the long arm of chromosome 11 in breast cancer. Seventy-one paired tumour/normal DNA samples from breast cancer patients under 50 years old were studied for allele loss at four microsatellite loci on 11q: D11S29 (11q23.3), NCAM (11q22-q23), D11S968 (11qtel), and D11S1313 (11qcen). The maximum frequency of LOH (approximately 35 per cent) was found at the D11S29 and NCAM loci. This result is consistent with previous studies and the frequency of allele loss is moderate to high compared with the usual baseline of 0-20 per cent. In most of the cases studied, LOH on chromosome 11q could be accounted for by one of two mechanisms. Either chromosomal non-disjunction had occurred, or sequences stretching from the telomere at least as far as NCAM had undergone deletion or mitotic recombination. These results suggest that a putative tumour suppressor gene is most likely to exist near 11q22-q23. There was a very low frequency of microsatellite instability in the tumours. An association was found between lack of progesterone receptor (PgR) expression and LOH at NCAM, suggesting that deletion of sequences on 11q may prevent high levels of PgR expression in some cases.

The 5' end of the BRCA1 gene lies within a duplicated region of human chromosome 17q21.

To begin to address the hypothesis that abnormal regulation of the breast/ovarian cancer susceptibility gene BRCA1 is a critical step in sporadic breast/ovarian tumorigenesis, we have determined the detailed structure of the BRCA1 genomic region. We show that this region of the genome contains a tandem duplication of approximately 30 kilobases, which results in two copies of BRCA1 exons 1 and 2, of exons 1 and 3 of the adjacent 1A1-3B gene and of the previously reported 295 base pair intergenic region. Sequence analysis of the duplicated exons of BRCA1 and 1A1-3B and flanking genomic DNA reveals maintenance of the intron-exon structure and a high degree of nucleotide sequence identity, suggesting that these are non-processed pseudogenes and that the duplication is a recent event in evolutionary terms. We also show that a processed pseudogene of the acidic ribosomal phosphoprotein P1 (ARPP1) is inserted directly upstream of pseudo-BRCA1 exon 1A. We believe that these findings could not only confound BRCA1 mutation analysis, but could have implications for the normal and abnormal regulation of BRCA1 transcription, translation and function.

Ordering of 66 STSs along the entire short arm of human chromosome 17 and chromosome assignment of a transcribed sequence (FMR1L2) homologous to FMR1.

Sixty-four PCR-markers previously assigned to the short arm of chromosome 17 and two newly established STSs were localized on a hybrid cell-YAC clone panel. The 66 STSs fell into 23 unique retention patterns, providing a map converting the entire short arm of human chromosome 17 with an average resolution of approximately 1.2 Mb. The combination of radiation-reduced hybrids, somatic cell hybrids and selected YAC clones enabled the precise localization of break-points in two cell hybrids. Since polymorphic STSs from the CEPH as well as the UTAH genetic map were used in this study, a physical link has been generated between these two high resolution genetic maps. FMR1L2, a second FMR1 autosomal homologue has been identified and assigned to a genomic interval between D17S796 and D17S799.