Dominant and recessive COL6A1 mutations in Ullrich scleroatonic muscular dystrophy

In this study, we characterized five Ullrich scleroatonic muscular dystrophy patients (two Italians, one Belgian, and two Turks) with a clinical phenotype showing different degrees of severity, all carrying mutations localized in COL6A1. We sequenced the three entire COL6 complementary DNA. Three of five patients have recessive mutations: two patients (P1and P3) have homozygous single-nucleotide deletions, one in exon 9 and one in exon 22; one patient (P2) has a homozygous single-nucleotide substitution leading to a premature termination codon in exon 31. The nonsense mutation of P2 also causes a partial skipping of exon 31 with the formation of a premature termination codon in exon 32 in 15% of the total COL6A1 messenger RNA. The remaining two patients carry a heterozygous glycine substitution in exons 9 and 10 inside the triple-helix region; both are dominant mutations because the missense mutations are absent in the DNA of their respective parents. As for the three homozygous recessive mutations, the apparently healthy consanguineous parents all carry a heterozygous mutated allele. Here, for the first time, we report a genotype-phenotype correlation demonstrating that heterozygous glycine substitutions in the triple-helix domain of COL6A1 are dominant and responsible for a milder Ullrich scleroatonic muscular dystrophy phenotype, and that recessive mutations in COL6A1 correlate with more severe clinical and biochemical Ullrich scleroatonic muscular dystrophy phenotypes.     

Melanoma of the glans penis

The authors describe the case of a 64-year old man who presented with an asymptomatic brown macula on his glans penis that had appeared about 18 months earlier. Dermoscopy analysis demonstrated a prominent, wide and irregular pigment network, which stopped abruptly at the periphery of the lesion. A diagnostic biopsy showed the characteristics of a melanoma in situ .The patient was referred for partial surgical excision of the glans. No recurrence or metastasis occurred during the two years after the operation. Melanoma in situ of the penis is very rare in dermatologic literature. Early diagnosis is of paramount importance because its prognosis is very poor. Early systematic use of dermoscopy may be useful for the differential diagnosis of pigmented mucosal lesions, which include mucosal melanosis and other benign melanoses of genitalia.     

Absence of NK1 receptors in human blood lymphocytes and granulocytes

Substance P is a peptide that exerts its activity through the interaction with specific receptors that are distributed in different brain areas. Given the potential of NK1 receptor antagonists as antidepressants, the availability of a peripheral model of NK1 receptors would be particularly relevant for the possibility to perform studies in samples of patients. Therefore, with the present study we aimed to explore the possible existence of NK1 receptors by means of [3H]SR140333 and [125I]BHSP that behave as, respectively, antagonist and agonist, at this level, in human blood lymphocytes and granulocytes of healthy donors. The results of the present study failed to detect the presence of a high-affinity and saturable binding of [3H]SR140333 and [125I]BHSP in human blood cells, whereas a specific binding for both compounds was found in rat cerebral cortex that was used as the control tissue. These findings would question the presence of NK1 receptors in human circulating cells.     

New devices for imaging in nuclear medicine

Pinhole gamma camera imaging offers the ability to obtain high resolution images from single gamma ray emitting radiotracers playing a reasonable tradeoff between very small field of view (FoV) and sensitivity. On the other hand the total spatial resolution of a pinhole imaging device is predominantly affected by the detector intrinsic spatial resolution for reduced magnification factors. To design very compact pinhole SPET scanners with very high intrinsic spatial resolution, authors investigated a miniature gamma camera based on the newly developed Hamamatsu H8500 flat panel photomultiplier. The PSPMT was coupled to the following scintillation arrays: CsI(Tl) array with 0.2-mm, 1-mm, 1.4-mm pixel size and NaI (Tl) with 1-mm pixel size. The imaging performances were evaluated by 57Co spot and flood irradiations. NaI(Tl) array shows a better pixel identification for 1 mm pixel size, proving to be a good candidate to make a large area photodetector based on multi PSPMTs closely packed. Although CsI(Tl) array had the smallest pixel size, the low light output limited the best intrinsic spatial resolution to about 0.5 mm.     

Partial glucocorticoid resistance in obese children detected by very low dose dexamethasone suppression test

The effects of glucocorticoids (GC) are mediated by the activation of specific receptors that can be quantified in vitro by several laboratory tests. In vivo, other tests to determine GC sensitivity have been described, but only employing pharmacological doses. In this study, we used a very low dose of dexamethasone, an in vivo model to assess individual GC sensitivity. Fifty-five obese children and adolescents and 17 controls were studied. The patients were submitted to four 12-h urine collections, starting at 22:00 h; dexamethasone was administered orally at the end of the second urine sample. Patients were divided in the following groups: group Ob75 (n = 29) and the control group (n = 17) received dexamethasone 75 microg/m2, and group Ob150 (n = 26) received dexamethasone 150 microg/m2. Urinary cortisol was determined by RIA and expressed as microg/m2/12 h. All patients and controls showed a circadian rhythm before GC, which was maintained after dexamethasone only in controls. In the obese patients the circadian rhythm was abolished following both doses of dexamethasone, but more prominently with the dose of 150 microg/m2. In the obese group given 75 microg/m2, urinary cortisol inhibition was only observed in the first 12 h after dexamethasone, suggesting a partial and shorter suppression of the hypothalamic-pituitary axis. In both control and obese patients, the very low dose of dexamethasone was able to create a gradient of cortisol suppression that could be useful to identify an individual's sensitivity to glucocorticoids.     

Molecular characterization of 22q11 deletion in a three-generation family with maternal transmission

Haploinsufficiency of chromosome 22q11.2 is a well-established cause of both the DiGeorge anomaly and the velocardiofacial syndrome. This condition shows a continuous spectrum of phenotypic manifestations with a considerable inter- and intrafamilial variability. We report on a three-generation family with four members sharing the same 3 Mb long deletion but showing different phenotypic expression. In the first generation, the deleted patient has hypernasal speech and suffers from recurrent psychotic episodes. Two of her offspring inherited the deletion. One of these, a male, has hypernasal speech, low-set ears, hypocalcemia, severe development delay, and tetralogy of Fallot. The other, a female, has hypernasal speech, minor facial anomalies, and very mild mental retardation. Her daughter has tetralogy of Fallot, velopharyngeal insufficiency, and mild facial anomalies. This family is an example of the widely variable phenotypic expressivity of the 22q11.2 deletion. There is no correlation between the size of the deletion and the phenotypic manifestations. Genetic background and/or environmental factors could explain the different phenotypes observed in the affected members of the family.     

Urinary diversion in infants with primary high-grade vesicoureteric reflux, urinary sepsis and renal function impairment

INTRODUCTION: General consensus on the optimal treatment of septic infants with primary high-grade vesicoureteric reflux (VUR) and renal function impairment has not been reached. Our study aims at evaluating the role of temporary urinary diversion. MATERIALS AND METHODS: Twenty male infants, affected by sepsis and primary high-grade VUR, underwent urinary diversion in 1996-2001 because of estimated risk of renal function deterioration, due to non-compliance with the antibiotic treatment. Plasmatic creatinine clearance, ultrasonography, micturition cystography and scintigraphy were evaluated. RESULTS: Creatinine clearance was abnormal in 13 infants on admission, in 10 after urinary diversion and in 6 after second surgery. Renal damage (focal or diffuse) was evident in 16 patients, without modifications after surgery. No patient developed urinary tract infections (UTI). Vesicostomy was done in 12 cases, ureterostomy in 8. Nephrectomy was performed in 3 cases with poor renal function, and ureteroneocystostomy in 17. CONCLUSIONS: Urinary diversion in septic infants with high-grade VUR can represent an alternative approach to the conservative or surgical treatment in selected patients presenting risk of renal function impairment. This procedure allowed an easy management of UTI without worsening of renal function while waiting for a better anatomical status to perform reconstructive surgery.     

Adipose tissue is a major source of interleukin-1 receptor antagonist: upregulation in obesity and inflammation

The secreted form of the interleukin-1 receptor antagonist (IL-1Ra) is an acute-phase protein intervening in the counterregulation of inflammatory processes. We previously showed that this cytokine antagonist is upregulated in the serum of obese patients, correlating with BMI and insulin resistance. In this study, we examined the expression pattern of IL-1Ra and showed that it is highly expressed not only in liver and spleen, but also in white adipose tissue (WAT), where it is upregulated in obesity. In WAT of obese humans, IL-1Ra was also markedly increased. Moreover, human WAT explants secreted IL-1Ra into the medium, a process that could be stimulated fivefold by interferon-beta. Finally, lipopolysaccharide administration induced a long-lasting expression of IL-1Ra in mouse WAT, suggesting that adipose tissue is an important source of IL-1Ra in both obesity and inflammation. In summary, we demonstrated that WAT is one of the most important sources of IL-1Ra quantitatively, suggesting that this tissue could represent a novel target for anti-inflammatory treatment. Moreover, it can be speculated that IL-1Ra, whose production is markedly increased in WAT in obese individuals, contributes further to weight gain because of its endocrine and paracrine effects on the hypothalamus and adipocytes, respectively.