ACTH resistance: genes and mechanisms.

ACTH resistance is a rare disorder typified by familial glucocorticoid deficiency (FGD), a genetically heterogeneous disease. Previously, genetic defects in FGD have been identified in the ACTH receptor gene (MC2R), its accessory protein (MRAP) and the steroidogenic acute regulatory protein gene (STAR). The defective mechanisms here are failures in ACTH ligand binding and/or receptor trafficking for MC2R and MRAP and, in the case of STAR mutations, inefficient cholesterol transport to allow steroidogenesis to proceed. Novel gene defects in FGD have recently been recognised in mini-chromosome maintenance-deficient 4 homologue (MCM4) and nicotinamide nucleotide transhydrogenase (NNT). MCM4 is one part of a DNA repair complex essential for DNA replication and genome stability, whilst NNT is involved in the glutathione redox system that protects cells against reactive oxygen species. The finding of mutations in these two genes implicates new pathogenetic mechanisms at play in FGD, and implies that the adrenal cortex is exquisitely sensitive to replicative and oxidative stresses.

Sustained benefits of continuous subcutaneous insulin infusion.

AIM: To evaluate the efficacy and safety of continuous subcutaneous insulin infusion (CSII), and its impact on glycaemic control, insulin doses and auxological parameters in children with diabetes over a 4-year period. METHOD: A retrospective analysis of all patients treated with CSII. Data on HbA1c, height, weight, insulin doses, hypoglycaemia and diabetic ketoacidosis (DKA) were analysed. RESULTS: 67 patients, aged 1-16 years showed a mean (±SD) HbA1c pre-CSII of 8.2%, decreasing to 7.3% (±0.8%) at 6 months (p<0.01), 7.7% (±0.99) at 2 years (p<0.05), 7.4% (±0.94) at 3 years (n=9, p=0.15) and 7.6% (±0.97) at 4 years (n=4, p=1.0). Insulin doses reduced significantly with a trend towards reduced BMI SDS. Nine preschool children showed HbA1c reduction from 8.4% (±0.94) to 7.4% (±0.32, p<0.01) over 20 months with no episodes of severe hypoglycaemia or DKA. CONCLUSION: The authors demonstrate that CSII is associated with significantly improved sustained glycaemic control, especially in preschool children with diabetes in motivated families.

Missense mutations in the melanocortin 2 receptor accessory protein that lead to late onset familial glucocorticoid deficiency type 2.

BACKGROUND: Familial glucocorticoid deficiency (FGD) is an autosomal recessive disorder characterized by isolated glucocorticoid deficiency. Mutations in the ACTH receptor [melanocortin 2 receptor (MC2R)] or the MC2R accessory protein (MRAP) cause FGD types 1 and 2, respectively. Typically, type 2 patients present early (median age, 0.1 yr), and no patient reported to date has presented after 1.6 yr. AIM: The aim of this study was to investigate the cause of disease in two families with late-onset FGD. PATIENTS: The proband in family 1 was diagnosed at age 4 yr. Family review revealed two older siblings with undiagnosed FGD. One sibling was well, whereas the second had cerebral palsy secondary to hypoglycemic seizures. The proband in family 2 was diagnosed at age 18 yr with symptoms of fatigue, weight loss, and depression. METHODS: The coding exons of MC2R and MRAP were sequenced. ACTH dose-response curves were generated for MC2R when transfected with wild-type or mutant MRAP constructs using HEK293 cells. MC2R trafficking with both mutant MRAPs was investigated using immunocytochemistry. RESULTS: MRAP gene analysis identified two novel homozygous missense mutations, c.175T>G (pY59D) in family 1 and c.76T>C (p.V26A) in family 2. In vitro analysis showed that the Y59D mutant had significant impairment of cAMP generation, and both mutants caused a shift in the dose-response curve to the right when compared to wild type. Immunocytochemistry showed normal trafficking of MC2R when transfected with both mutant MRAPs, indicating a probable signaling defect. CONCLUSION: These results indicate that missense MRAP mutations present with a variable phenotype of ACTH resistance and can present late in life.

Evidence for strain-induced local conductance modulations in single-layer graphene on SiO2.

Graphene has emerged as an electronic material that is promising for device applications and for studying two-dimensional electron gases with relativistic dispersion near two Dirac points. Nonetheless, deviations from Dirac-like spectroscopy have been widely reported with varying interpretations. Here we show evidence for strain-induced spatial modulations in the local conductance of single-layer graphene on SiO(2) substrates from scanning tunneling microscopic (STM) studies. We find that strained graphene exhibits parabolic, U-shaped conductance vs bias voltage spectra rather than the V-shaped spectra expected for Dirac fermions, whereas V-shaped spectra are recovered in regions of relaxed graphene. Strain maps derived from the STM studies further reveal direct correlation with the local tunneling conductance. These results are attributed to a strain-induced frequency increase in the out-of-plane phonon mode that mediates the low-energy inelastic charge tunneling into graphene.

Population structure in a common Caribbean coral-reef fish: implications for larval dispersal and early life-history traits.

Genetic population structure throughout the Caribbean Basin for one of the most common and widespread reef fish species, the bicolour damselfish Stegastes partitus was examined using microsatellite DNA markers. Spatial autocorrelation analysis showed a significant positive correlation between genetic and geographic distance (isolation by distance) over distances <1000 km, suggesting that populations are connected genetically but probably not demographically, i.e. over shorter time scales. A difference in spatial patterns of populations in the eastern v. the western Caribbean also raises the probability of an important role for meso-scale oceanographic features and landscape complexity within the same species. A comparison of S. partitus population structure and life-history traits with those of two other species of Caribbean reef fish studied earlier showed the findings to be concordant with a common hypothesis that shorter pelagic larval dispersal periods are associated with smaller larval dispersal scales.

Mild phenotype due to tandem duplication of l7p11.2.

We present a mildly affected girl with de novo dup(17)(p11.2p11.2). The patient was evaluated because of minor anomalies noted during a hospitalization for nonrecurrent tonic-clonic seizures associated with transient hypoglycemia. She also had unilateral renal hypoplasia and relative short stature, but at 2 years of age, she scored within the low normal range on neurodevelopmental examinations. Compared with other similar duplications, this patient represents the milder range of the spectrum for this karyotypic abnormality. Am. J. Med. Genet. 94:296-299, 2000.

Early house moves, indoor air, heating methods and asthma.

OBJECTIVES: To assess whether house moves or certain housing conditions are a risk factor for the development of childhood asthma. DESIGN: A case-control study of asthmatic and non-atopic children aged 4-16 years. SUBJECTS: One hundred children with confirmed asthma in a group general practice of 11000 patients in Plymouth, U.K. Each was matched by age and gender with a child with no history of wheeze, eczema or hay fever. MAIN OUTCOME MEASURES: House moves and main heating methods, prior to the age of onset of asthma in cases and controls. RESULTS: There was a non-significant association between early house moves and the subsequent development of asthma. No association was found with heating methods, except for ducted-air heating which, because of the small numbers involved could have occurred by chance. None of the other factors studied affecting indoor air showed an association. CONCLUSION: Moving house at an early age may increase the risk of developing asthma, or may be associated with other more important risk factors, such as increased general mobility and hence, exposure to viral infections. Heating methods or other factors likely to affect the indoor air quality in early life were not useful predictors of subsequent asthma in children.

Using chronotherapy to treat severe sleep problems: a case study.

Chronotherapy was used to treat severe sleep problems (irregular sleep onset times, frequent night and early wakings, and short total sleep times) in a girl with mental retardation. Chronotherapy involved systematically delaying the child's bedtime each night while maintaining a regular schedule during waking hours until an age-appropriate bedtime was achieved. Immediate improvements in the child's sleep pattern were observed with the introduction of treatment, and an age-appropriate bedtime was achieved in 11 days. Four months of follow-up data indicated that improvements maintained in the home. Although chronotherapy was developed specifically for adults with delayed sleep phase insomnia, the current results suggest that the treatment may be useful for other populations and problems.

Developing microsatellites when they are rare: trinucleotide repeat loci in the northern mockingbird Mimus polyglottos.

The great value of microsatellite loci to population studies spurs their development. However, finding loci is difficult when microsatellites are uncommon in the genome. Because trinucleotide-repeat loci are rare in northern mockingbirds Mimus polyglottos, we sought a new method for developing a suite of loci. Here we show that a bacterio-phage cloning vector, Lambda Zap Express (Stratagene, La Jolla, CA, USA) has several features which make it suitable for this purpose. Using this vector, we made a library of 150,000 size-selected clones and screened with an AAT10 probe; 97 positives were identified. From these, 12 pairs of PCR primers were developed, nine of which amplify polymorphic loci. Certain combinations of these primer pairs enable simultaneous amplification of up to three loci.

Trinucleotide microsatellite loci and increased heterozygosity in cross-species applications in the social wasp, Polistes.

Though microsatellite loci are usually found to be most polymorphic in the species in which they are first identified, we have found significant increases in polymorphisms in some cross-species applications. We present eight new trinucleotide microsatellite loci derived from two species of social wasps, Polistes annularis and Polistes bellicosus. We assessed the primers designed from these species and the degree of polymorphism in two additional species, P. dorsalis, which is very closely related to P. bellicosus, and P. dominulus, which is an Old World congener, thought to have diverged from New World Polistes over 80 million years ago. Cross-species applications for these microsatellite loci indicate that the priming sites from P. bellicosus loci are conserved in P. dorsalis and amplified similarly sized products with higher heterozygosities than the original species in two of three cases. A locus that was monomorphic in P. annularis had a heterozygosity of 1.0 in the distantly related P. dominulus. Cross-species applications of these loci indicated that alleles were generally of similar lengths in the new and original species when they retained their heterozygosity.

Renal cyst rupture following blunt abdominal trauma: case report.

We report a case of simple renal cyst rupture resulting from blunt trauma. The injury was detected on computed tomographic scanning. The patient was treated conservatively and CT scan one month later demonstrated resolution of the cystic rupture.

Laparoscopic repositioning of a continuous ambulatory peritoneal dialysis (CAPD) catheter.

We describe a laparoscopic technique for relieving obstruction of a continuous ambulatory peritoneal dialysis (CAPD) catheter. Laparoscopic repositioning of the catheter and omentectomy obviated the need for laparotomy in a patient with end-stage renal disease.