Compound heterozygous deletion of the PROP-1 gene in children with combined pituitary hormone deficiency

Mutations in the prophet of Pit-1 gene (PROP1) have been shown to be responsible for combined pituitary hormone deficiency (CPHD) with deficiencies of growth hormone (GH), Prolactin (Prl), thyroid-stimulating hormone (TSH) and gonadotropins. We previously reported that homozygosity for a 2bp deletion in exon 2 (296delGA) accounted for CPHD in three patients from two Russian families. Here we report a second mutational hot spot in exon 2. This 2bp 149delGA deletion results in a frame shift that leads to the same serine to stop codon change at codon 109 (S109X). The predicted proteins are each truncated at residue 108 but diverge from the wild type sequence at different points in the homeodomain. Compound heterozygosity for the two mutations (149delGA/296delGA) was detected in 5 of 14 CPHD children from 4 families (36%). This provides the first evidence of heterozygosity for two common deletions as a cause of CPHD in Russian children.     

A 4-base pair deletion mutation of Gs alpha gene in a Japanese patient with pseudohypoparathyroidism

Mutations in the guanine nucleotide binding protein alpha subunit (Gs alpha) have been found in patients with pseudohypoparathyroidism (PHP). We have screened the Gs alpha gene for mutations in a Japanese patient with this disorder and identified a novel 4-base pair deletion in exon 7 in codons 189-190. This deletion causes a frameshift and if synthesis of a truncated form of Gs alpha occurred, it would likely be biologically inactive. The patient was heterozygous for this deletion. The patient's mother and an unaffected brother were tested for the presence of this mutation. His mother had the same mutation, and although her serum calcium and parathyroid hormone levels were within the normal range, she had subcutaneous calcifications. Thus, this mutation appears to be necessary but not sufficient to cause the complete pseudohypoparathyroidism phenotype and thus, other unknown factors, either genetic or acquired, may be necessary for the full syndrome to occur.     

Detection of a homozygous four base pair deletion in the protein X gene in a case of pyruvate dehydrogenase complex deficiency

While the presence of a lipoyl-containing protein (protein X) separate from lipoyl transacetylase in the pyruvate dehydrogenase complex (PDC) has been known for some time, until recently only the cDNA for the yeast enzyme has been cloned. We have cloned, sequenced and characterized the cDNA encoding the human protein X and localized the protein X gene to chromosome 11p13. We also report here a new case of protein X deficiency identified immunologically, with decreased activity of PDC and without mutations in the E1alpha subunit or E1beta subunit. We report that the cDNA and gene of this patient for protein X has a homozygous 4 bp deletion, specifically in the putative mitochondrial targeting signal sequence which results in a premature stop codon. This is the first documented case of a molecular defect in pyruvate dehydrogenase protein X.     

Homologous recombination of a flanking repeat gene cluster is a mechanism for a common contiguous gene deletion syndrome

Smith-Magenis syndrome (SMS), caused by del(17)p11.2, represents one of the most frequently observed human microdeletion syndromes. We have identified three copies of a low-copy-number repeat (SMS-REPs) located within and flanking the SMS common deletion region and show that SMS-REP represents a repeated gene cluster. We have isolated a corresponding cDNA clone that identifies a novel junction fragment from 29 unrelated SMS patients and a different-sized junction fragment from a patient with dup(17)p11.2. Our results suggest that homologous recombination of a flanking repeat gene cluster is a mechanism for this common microdeletion syndrome.     

The most common cause of cascade stomach

In a random sample of 396 patients with stomach complaints, 54 were found to have cascade stomach (overall frequency 13.6%). The analysis of the results showed the leading cause of this condition to be adhesion of the front costal diaphragm sinus.     

Allelic deletion in 11p15 is a common occurrence in esophageal and gastric adenocarcinoma

The pressure broadening, pressure shift coefficients, and absolute intensities have been obtained for the J = 6 <-- 5 and the J = 5 <-- 4 absorption lines of acetonitrile CH3CN at 110 and 92 GHz, respectively. The absorption line shapes have been directly recorded modulating the radiation beam by an optical chopper. In addition to the self-effects, the foreign-broadening coefficients have also been measured for N2, O2, and Ar. Copyright 1998 Academic Press.     

The MEN-1 gene is rarely down-regulated in pituitary adenomas

The gene for multiple endocrine neoplasia type 1 (MEN-1) has recently been cloned and encodes a putative tumor suppressor protein named menin. We have previously reported inactivating MEN-1 gene mutations associated with loss of heterozygosity (LOH) of the normal allele in tumors of patients with MEN-1 and in some sporadic pituitary tumors. These genetic alterations, however, are noted in no more than 10% of sporadic adenomas. To investigate whether other mechanisms may result in down-regulation of menin gene expression in pituitary adenomas, we examined menin gene expression by semiquantitative RT-PCR in 60 sporadic pituitary adenomas. Ribonucleic acid (RNA) was extracted from surgically resected, morphologically characterized tumors. Primers were designed to amplify a 257-bp fragment spanning exons 4-6 of the MEN-1 gene. A product of the predicted size was amplified from normal pituitary samples as well as from adenomas. Competitive PCR was performed with the housekeeping gene PGK-1 to quantitate menin gene expression. A comparable ratio of menin/PGK-1 messenger RNA was identified in all but three samples; in two tumors with LOH, menin expression was weak, and in one tumor, menin messenger RNA was undetectable, associated with LOH and mutation of the other allele. Reduced expression of menin in some sporadic adenomas is consistent with a putative tumor suppressor role for this gene product. However, lack of menin down-regulation in the majority of these tumors, which exhibit LOH at 11q13 in up to 20% of cases, provides compelling evidence for an additional tumor suppressor gene at this locus, which is more commonly involved in the pathogenesis of pituitary neoplasms.     

Interleukin-1 beta: a common cause of Alzheimer's disease and diabetes mellitus

Alzheimer disease is characterized by the presence of beta-amyloid protein deposits, neurofibrillary tangles and cholinergic dysfunction throughout the hippocampal region. In addition, the hippocampus, hypothalamus and olfactory bulb--the three areas where the insulin receptors are most dense--are also subject to neurodegeneration. The exact cause of the beta-amyloid deposits and NFTs is unknown. However, it is our intention to explicate the various pathogenic pathways through which Alzheimer disease arises. Fundamentally, the structural and metabolic damage found in Alzheimer disease is due to sustained elevation of interleukin-1 beta, a feature which is also found in insulin-dependent diabetes mellitus. Similarly, the beta-AP deposits found in the Alzheimer brain share the same molecular structure as the amylin deposits found in the pancreatic beta-cells in non-insulin-dependent diabetes mellitus (NIDDM), and are equally neurotoxic. These, and other pathophysiological parallels, afford some insight into the probably cause of Alzheimer disease and, as such, forms the basis of the causal hypothesis advanced in this paper.     

De novo mutations of the growth hormone gene: an important cause of congenital isolated growth hormone deficiency?

OBJECTIVES: To determine the epidemiological features of injuries associated with fireworks. DESIGN: A retrospective study of reported cases. SUBJECTS: Subjects were those who attended selected Victorian hospital emergency departments (n = 17) and those admitted for firework related injuries (n = 16). RESULTS: The mean (SD) age of attenders at emergency department between January 1988 and June 1996, was 8.9 (6.2) years and most (88%) were under 18 years of age. Males accounted for 71% of the cases. The most common anatomical sites and types of injury were head (47%) and burns (88%), respectively. About 53% of the injuries were caused by firecrackers, the remainder by sparklers and penny bangers. Among those admitted to hospital between July 1987 and June 1996, the mean (SD) age was 22.9 (14.8) years and 50% were under 18 years of age. Males accounted for 87% of the cases. There was a significant difference in mean age between those admitted and not admitted to hospital, the former being significantly older. CONCLUSIONS: Although relatively rare, injuries from fireworks still occur in Victoria after legislative restrictions on their sale in 1985. Consequently, there is a potential risk for injuries among children, particularly from firecrackers. More enforcement of the regulations, education, and parental supervision are needed to prevent injuries from fireworks.     

Diurnal variations in twenty-four-hour energy expenditure during growth hormone treatment of adults with pituitary deficiency

The effects of growth hormone (GH) treatment on 24-h energy expenditure (EE) were studied in a open trial over a period of 4 weeks. Five subjects, four men and one woman, with a history of complete GH deficiency were included. All the subjects were examined on 2 consecutive days on baseline and, thereafter, at six occasions during a period of 1 month (days 1, 2, 5, 8, 15, and 30). The dose of GH was 0.25 U/kg.week, administered sc once a day in the evening. EE was determined in a chamber for indirect calorimetry. Body composition was determined with dual-energy x-ray absorptiometry and computed tomography using a four-scan technique. Blood samples were examined using well-established RIAs. During the first 2 weeks, 24-h EE increased by 6 +/- 3% (range 1-8%) from 40.9 +/- 4.8 to 42.9 +/- 4.8 kcal/24 h.kg (P < 0.05), sleeping metabolic rate by 14 +/- 3% (range 10-18%) from 28.4 +/- 1.9 to 32.9 +/- 2.2 kcal/24h.kg (P < 0.001), and basal metabolic rate by 11 +/- 7% (range 0-18%) from 29.6 +/- 2.4 to 33.3 +/- 2.6 kcal/24h.kg (P < 0.05). No change was found in daytime EE. The increase in EE covaried with changes in insulin-like growth factor 1, the free T3/free T4 ratio, insulin-like growth factor-binding protein-3, and the aminoterminal procollagen III peptide but not with changes in body composition. It is suggested that the stimulating effect of GH on EE occurs gradually during a 2-week period and is only detectable during night and morning hours, when significant levels of GH occur.     

Elevated nocturnal melatonin is a consequence of gonadotropin-releasing hormone deficiency in women with hypothalamic amenorrhea

Elevated nocturnal melatonin is found in women with idiopathic hypogonadotropic hypogonadism (IHH), but it is not known whether this is implicated in the etiology of their GnRH deficiency. It is unlikely that nocturnal melatonin can be implicated in the etiology of the GnRH deficiency of Kallmann's syndrome (KS), because this condition is caused by defective neuronal migration in embryonic life. We therefore measured nocturnal melatonin in women with IHH and KS to determine whether it was elevated in one or both conditions and thereby to determine whether it was implicated as cause or consequence of GnRH deficiency. Four women with IHH, 3 women with KS, and 7 individually matched (age and body size) controls were recruited. Frequent day- and nighttime samples were taken for LH pulsatility studies. All patients showed absent or diminished LH pulsatility, compared with their respective controls. Samples were also taken over 24 h for melatonin and 6-sulphatoxymelatonin (the principle metabolite of melatonin and an independent marker of its secretion). Melatonin and 6-sulphatoxymelatonin levels were elevated in 6 of 7 patients (compared with their matched controls) and were significantly elevated in the KS group (compared with their controls). The finding of elevated nocturnal melatonin (and its metabolite) in GnRH-deficient women with KS (as well as IHH) suggests that nocturnal melatonin is elevated as a consequence of GnRH deficiency, irrespective of its etiology.     

The etiology of isolated thyroid stimulating hormone deficiency

Umbilical hernia (UH) is a common condition in infants and young children, especially in those of Afro-Caribbean origin. Spontaneous closure occurs in a majority of cases before the age of 4 years unless the neck of the sac is greater than 2 cm in diameter. Complications are rare, and conservative management is therefore advised during this time. We present three cases of incarcerated UH in boys under 4 years old, all of whom presented with small-bowel obstruction. Interestingly, in two of them undigested vegetable matter in the small bowel appeared to have precipitated the obstruction. A survey of the literature suggests that the incidence of this complication is approximately 1:1,500 UHs. We conclude that the present policy of expectant management is safe for the vast majority of children, but parents and general practitioners should be aware of the small risk and early symptoms of incarceration.     

The time course of attentional and oculomotor capture reveals a common cause.

Eye movements are often misdirected toward a distractor when it appears abruptly, an effect known as oculomotor capture. Fundamental differences between eye movements and attention have led to questions about the relationship of oculomotor capture to the more general effect of sudden onsets on performance, known as attentional capture. This study explores that issue by examining the time course of eye movements and manual localization responses to targets in the presence of sudden-onset distractors. The results demonstrate that for both response types, the proportion of trials on which responses are erroneously directed to sudden onsets reflects the quality of information about the visual display at a given point in time. Oculomotor capture appears to be a specific instance of a more general attentional capture effect. Differences and similarities between the two types of capture can be explained by the critical idea that the quality of information about a visual display changes over time and that different response systems tend to access this information at different moments in time. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Mutational spectra of a 100-base pair mitochondrial DNA target sequence in bronchial epithelial cells: a comparison of smoking and nonsmoking twins

Seventeen separate mitochondrial hot spot mutations in a 100-bp target sequence (mitochondrial bp 10,030-10,130) were detected and measured in bronchial epithelial cell samples isolated from smokers and nonsmokers. Among the individuals sampled were three pairs of monozygotic twins in which one twin had never smoked and had a nonsmoking spouse, and the other had a smoking history of >10 pack-years. Individual point mutations present at frequencies as low as 10(-6) were detected. Partially denaturing electrophoresis was used to separate mutant from nonmutant sequences on the basis of their melting temperatures, and the target sequence was subsequently amplified via high-fidelity PCR with Pfu DNA polymerase. Tests were performed to determine whether mismatch intermediates or DNA adducts present in the cellular DNA were converted to mutants during PCR. Hot spot mutations were clearly observed in bronchial epithelial cells, and the same hot spots were observed consistently in different samples. Significant numerical variability in the mutant fractions for individual mutants was observed among samples and are ascribed to unequal mitochondrial segregation in stem and transition cells. The mutational spectra in smokers' samples did not differ significantly from the mutational spectra in nonsmokers' samples for this 100 bp of mitochondrial DNA. No smoking-specific hot spots were detected. The overall mutant fractions in smokers' samples were not elevated compared to those of nonsmokers. As much variability was observed between two samples from the same individual's lung as between a sample from a smoker and a sample from a nonsmoker. These findings demonstrate that inhaled tobacco smoke does not induce prominent point mutations in this 100-bp target mitochondrial sequence in smokers' bronchial epithelial cells. Endogenous factors (e.g., DNA replication errors or DNA damage by endogenous reactive chemicals) are suggested to be more likely to represent the most important contributors to mitochondrial mutagenesis.     

Thy-1 is a component common to multiple populations of synaptic vesicles

To understand the influence of the ascending path linking area 17 to area 18 of visual cortices, experiments were carried out in which a small neuronal population of area 17 was inactivated with GABA, while unitary responses were recorded in area 18. In the latter, cells are identified as belonging to the simple or complex family according to their firing pattern evoked in response to sine-wave gratings scrolling through the receptive fields. Anesthetized cats were prepared for single-cell recordings. In area 17, a GABA-containing pipette was placed in superficial layers in order to inactivate reversibly a small neuronal population. Prior to blockade, the orientation tuning curves were obtained in both areas and the difference in optimal orientation between areas 17 and 18 was recorded. In area 18, cells were classified as simple or complex. The strategy was to study the reaction of neurons in area 18 prior to, during and after area 17 depression. In most simple cells, whenever the difference in orientation was in the iso-range, that is when the difference in optimal orientations of the injected site (in area 17) and of the neuron in area 18 was less than 30 degrees, the GABA application produced a decline of the evoked discharges, whereas GABA injection augmented the evoked firing rate when the difference was in the cross-range (>60 degrees). In contrast to simple cells, GABA depression enhanced the responses in the majority of complex cells with like orientations in both areas. When the difference between recording sites was in the cross-range, then area 17 depression produced weaker evoked firing. A tangential penetration of the injecting pipette, allowing injection of different orientation sites while testing the same unit in area 18, revealed that the latter could react with an enhancement or a decline of the responses as the injecting pipette shifted from iso (or cross) to cross (or iso) disparity in optimal orientations between areas 17 and 18. These results suggest that the path connecting area 17 to area 18 may be functionally discriminated on the basis of the orientation domain and cell types. In addition, our data suggest that the ascending visual streams are required to generate orientation specificity in area 18.     

A thyrotropin-secreting pituitary adenoma as a cause of thyrotoxic periodic paralysis

We describe a patient with thyrotoxic periodic paralysis (TPP) caused by a thyrotropin-secreting pituitary adenoma. The diagnosis TPP was based on the combination of episodes of reversible hypokalaemic paralysis, hyperthyroidism and electrophysiological findings. A thyrotropin-secreting pituitary adenoma was diagnosed on the basis of endocrinological function tests and MRI of the pituitary gland. Before transsphenoidal resection of the adenoma, treatment with octreotide restored euthyroidism both clinically and biochemically. Immunocytochemistry of the pituitary adenoma was positive for TSH exclusively. Incubation with octreotide or quinagolide induced decreased TSH and alpha-subunit production by the cultured adenoma cells, in agreement with the pre-operative in vivo data. This paper is the first to describe in vivo and in vitro characteristics of a thyrotropin-secreting pituitary adenoma in a patient presenting with periodic paralysis.