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PubMed2005

Boosting alternating decision trees modeling of disease trait information.

We applied the alternating decision trees (ADTrees) method to the last 3 replicates from the Aipotu, Danacca, Karangar, and NYC populations in the Problem 2 simulated Genetic Analysis Workshop dataset. Using information from the 12 binary phenotypes and sex as input and Kofendrerd Personality Disorder disease status as the outcome of ADTrees-based classifiers, we obtained a new quantitative trait based on average prediction scores, which was then used for genome-wide quantitative trait linkage (QTL) analysis. ADTrees are machine learning methods that combine boosting and decision trees algorithms to generate smaller and easier-to-interpret classification rules. In this application, we compared four modeling strategies from the combinations of two boosting iterations (log or exponential loss functions) coupled with two choices of tree generation types (a full alternating decision tree or a classic boosting decision tree). These four different strategies were applied to the founders in each population to construct four classifiers, which were then applied to each study participant. To compute average prediction score for each subject with a specific trait profile, such a process was repeated with 10 runs of 10-fold cross validation, and standardized prediction scores obtained from the 10 runs were averaged and used in subsequent expectation-maximization Haseman-Elston QTL analyses (implemented in GENEHUNTER) with the approximate 900 SNPs in Hardy-Weinberg equilibrium provided for each population. Our QTL analyses on the basis of four models (a full alternating decision tree and a classic boosting decision tree paired with either log or exponential loss function) detected evidence for linkage (Z >or= 1.96, p < 0.01) on chromosomes 1, 3, 5, and 9. Moreover, using average iteration and abundance scores for the 12 phenotypes and sex as their relevancy measurements, we found all relevant phenotypes for all four populations except phenotype b for the Karangar population, with suggested subgroup structure consistent with latent traits used in the model. In conclusion, our findings suggest that the ADTrees method may offer a more accurate representation of the disease status that allows for better detection of linkage evidence.

Algorithms↗

PubMed1999

Neuronal loss in functional zones of the cerebellum of chronic alcoholics with and without Wernicke's encephalopathy.

This study examines the effect of chronic alcohol consumption on the human cerebellum using operational criteria for case selection [Caine D. et al. (1997) J. Neurol. Neurosurg. Psychiat. 62, 51-60] and unbiased stereological techniques. We describe, for the first time, structural changes in different functional zones of the cerebellum of chronic alcoholics and correlate these changes with specific clinical symptoms. No consistent changes in the number of neurons or the structural volume for any cerebellar region were observed in the chronic alcoholics without the clinical signs of Wernicke's encephalopathy. In all cerebellar measures, these chronic alcoholics did not differ significantly from the non-alcoholic controls, suggesting that chronic alcohol consumption per se does not necessarily damage human cerebellar tissue. However, several cerebellar changes were noted in the thiamine-deficient alcoholics studied. There was a significant decrease in Purkinje cell density (reduced on average by 43%) and molecular layer volume (reduced by 32%) in the cerebellar vermis in all thiamine-deficient chronic alcoholics. A decrease in cell density and atrophy of the molecular layer, where the dendritic trees of the Purkinje cells are found, without significant cell loss suggests loss of cellular dendritic structure and volume. These thiamine-deficient alcoholics also had a significant decrease (36% loss) in the estimated Purkinje cell number of the flocculi, disrupting vestibulocerebellar pathways. These results indicate that cerebellar Purkinje cells are selectively vulnerable to thiamine deficiency. There is evidence that this damage contributes significantly to the clinical signs of Wernicke's encephalopathy. There was a 36% loss of Purkinje cells in the lateral lobe in alcoholics with mental state signs and 42% atrophy of vermal white matter in ataxic alcoholics. The finding of a 57% loss of Purkinje cells and a 43% atrophy of the molecular layer of the vermis in alcoholics with cerebellar dysfunction supports previous findings highlighting the importance of spinocerebellar pathways to these symptoms.

Adult↗

PubMed2005

Complete loss-of-function of the heart/muscle-specific adenine nucleotide translocator is associated with mitochondrial myopathy and cardiomyopathy.

Multiple mitochondrial DNA deletions are associated with clinically heterogeneous disorders transmitted as mendelian traits. Dominant missense mutations were found in the gene encoding the heart and skeletal muscle-specific isoform of the adenine nucleotide translocator (ANT1) in families with autosomal dominant progressive external opthalmoplegia and in a sporadic patient. We herein report on a sporadic patient who presented with hypertrophic cardiomyopathy, mild myopathy with exercise intolerance and lactic acidosis but no ophthalmoplegia. A muscle biopsy showed the presence of numerous ragged-red fibers, and Southern blot analysis disclosed multiple deletions of muscle mitochondrial DNA. Molecular analysis revealed a C to A homozygous mutation at nucleotide 368 of the ANT1 gene. The mutation converted a highly conserved alanine into an aspartic acid at codon 123 and was absent in 500 control individuals. This is the first report of a recessive mutation in the ANT1 gene. The clinical and biochemical features are different from those found in dominant ANT1 mutations, resembling those described in ANT1 knockout mice. No ATP uptake was measured in proteoliposomes reconstituted with protein extracts from the patient's muscle. The equivalent mutation in AAC2, the yeast ortholog of human ANT1, resulted in a complete loss of transport activity and in the inability to rescue the severe Oxidative Phosphorylation phenotype displayed by WB-12, an AAC1/AAC2 defective strain. Interestingly, exposure to reactive oxygen species (ROS) scavengers dramatically increased the viability of the WB-12 transformant, suggesting that increased redox stress is involved in the pathogenesis of the disease and that anti-ROS therapy may be beneficial to patients.

Adenine Nucleotide Translocator 1↗

PubMed2006

Functional outcomes and life satisfaction in long-term survivors of pediatric sarcomas.

OBJECTIVES: To describe the inter-relationships among impairments, performance, and disabilities in survivors of pediatric sarcoma and to identify measurements that profile survivors at risk for functional loss. DESIGN: Prospective, cross-sectional. SETTING: Research facility. PARTICIPANTS: Thirty-two participants in National Cancer Institute clinical trials. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Range of motion (ROM), strength, limb volume, grip strength, walk velocity, Assessment of Motor and Process Skills (AMPS); Human Activity Profile (HAP), Sickness Impact Profile (SIP), standard form of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36); and vocational attitudes and leisure satisfaction. RESULTS: Twenty of 30 survivors tested had moderate or severe loss of ROM; 13 of 31 tested had 90% or less of predicted walk velocity; all of whom had trunk or lower-extremity lesions. Women with decreased ROM (r=.50, P=.06) or strength (r=.74, P=.002) had slow gait velocity. Sixteen of 31 tested were more than 1 standard deviation below normal grip strength. Eighteen had increased limb volume. These 18 had low physical competence (SF-36) (r=-.70, P=.001) and high SIP scores (r=.73, P=.005). AMPS scores were lower than those of the matched normed sample (P<.001). HAP identified 15 of 30 who had moderately or severely reduced activity. Leisure satisfaction was higher in the subjects (P<.001). Eight reported cancer had negatively impacted work and 17 reported that it negatively impacted vocational plans. CONCLUSIONS: Survivors with lower-extremity or truncal lesions and women with decreased ROM and strength likely have slow walk velocity, low exercise tolerance, and high risk for functional loss. They should be identified using ROM, strength, limb volume, and walk time measures.

Adolescent↗

PubMed2000

Loss of function of the Prx1 and Prx2 homeobox genes alters architecture of the great elastic arteries and ductus arteriosus.

Prx1 (MHox) and Prx2 (S8) are non-clustered homeobox genes that are expressed in a complex, mostly mesenchyme-specific pattern throughout embryogenesis. The expression pattern and gene-targeted mice previously revealed a major role for Prx1 in skeletogenesis. In addition, specific and high expression of both Prx genes was reported in the developing cardiovascular system, predominantly in prospective connective tissues of the heart and in the great arteries and veins. We examined embryos of previously generated gene-targeted mice. Prx2-/- mutants were viable and did not show cardiovascular malformations. Intracardiac morphology of Prxl-/- and Prx1/Prx2-combined null mutants also appeared normal throughout development. However, the Prx1-/- and Prx1/Prx2 double-null mutants showed a vascular abnormality with an abnormal positioning and awkward curvature of the aortic arch in addition to a misdirected and elongated ductus arteriosus, and in two of seven combined mutants, an anomalous retro-oesophageal right subclavian artery. Generally, all great arteries appeared to run somewhat tortuously through the surrounding mesenchyme. The vascular histology and vessel wall thickness were normal in all mutants. Prx1-/- and Prx double-gene-targeted mice revealed similar spectra of vascular anomalies, but double mutants appeared to be more seriously affected. The current findings suggest that other genes may compensate for the loss of Prx in the heart, but, in contrast, our data support a role for Prx in the development of vascular and perivascular matrix.

Animals↗

PubMed1998

Intertester reliability of manual muscle strength testing in leprosy patients.

This study reports the results of a study on the intertester reliability of manual muscle strength testing in leprosy patients with confirmed motor function loss of at least one nerve. Three testers graded the muscle strength of 72 patients in random order. Both hands and feet were graded. Strength was graded on a modified Medical Research Council Scale (9 points, 5, 4+, 4, 3+, 3, 2+, 2, 1, 0). The following movements were tested for strength: little finger and index finger abduction, intrinsic position of all four fingers, thumb abduction and opposition, foot dorsiflexion and eversion and extension of the big toe. The weighted kappa statistic was used to calculate the chance-corrected percentage of agreement between observers. Overall agreement for each of the 11 tests appeared to be good or very good (0.61-1.00). However, when data for hands or feet with normal strength or complete paralysis were excluded from the analysis, the reliability of the remaining mid-range scale was not acceptable (kappa 0.55-0.88, direct agreement range 11-41%). While the reliability of this scale could possibly be improved by special training, we feel that, for the evaluation of nerve function for leprosy patients with (suspected) nerve function loss, the extended 9-point VMT scale should only be used when direct intra- or intertester agreement is more than 80%.

Female↗

PubMed1997

Loss of functional cell surface transforming growth factor beta (TGF-beta) type 1 receptor correlates with insensitivity to TGF-beta in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in Western countries, and there is significant variability in survival within CLL clinical stages. Earlier studies showed that CLL cells produce and are usually growth inhibited by transforming growth factor beta type 1 (TGF-beta1), suggesting a mechanism for the clinically indolent course of most CLL. Here we studied the mechanism by which CLL cells from about one-third of the patients are insensitive to TGF-beta1. Of the 13 patients studied, CLL cells isolated from the peripheral blood of 8 patients were sensitive to growth inhibition by TGF-beta1, as determined by incorporation of tritiated thymidine, whereas those from 5 patients were completely resistant to TGF-beta1. As judged by binding of radiolabeled TGF-beta1 followed by cross-linking and immunoprecipitation with anti-receptor antisera, CLL cells sensitive to TGF-beta1 exhibited normal cell surface expression of both types 1 and 2 TGF-beta receptors. In contrast, all CLL cells resistant to TGF-beta1 exhibited no detectable surface type I receptors able to bind TGF-beta1, but normal expression of type II receptors. Both TGF-beta1-sensitive and TGF-beta1-resistant CLL cells contained normal amounts of both type 1 and type 2 receptor mRNAs. Specific loss of type 1 receptor expression represents a new mechanism by which cells acquire resistance to TGF-beta1-mediated growth inhibition in the development and progression of human lymphoproliferative malignancies.

Activin Receptors, Type I↗

PubMed1994

Effects of silica on the outcome from experimental spinal cord injury: implication of macrophages in secondary tissue damage.

A model of spinal cord trauma in guinea-pigs, using lateral compression to a set thickness, produces a delayed functional loss at one to two days, followed by a partial recovery over several weeks, as measured using hindlimb motor behavior, vestibulospinal reflex testing, and mapping the receptive field of the cutaneous trunci muscle reflex. The role of inflammatory events in these secondary changes, was investigated with intraperitoneal injections of the macrophage toxin, silica. In one experiment, 11 matched pairs of animals were injured. One of each pair was selected randomly and injected with a suspension of 1.2 g of silica dust in sterile saline, immediately after injury and surgical closure. In a second experiment, involving 10 pairs of guinea-pigs, a similar dose of silica was administered to one of each pair at either one or two days before the injury. The animals survived up to three months, then were fixed by perfusion with glutaraldehyde. Histopathology of the lesion was quantified by line sampling of myelinated axons, and by measurement of blood vessels, in plastic sections through the center of the lesion. Surgery, injury, analysis of behavior and histology were all performed without knowledge of the experimental status of the animal. The secondary onset of functional loss below the lesion appeared to be delayed by one to two days in silica-treated animals with respect to controls. The number of myelinated axons at the center of the lesion, examined at two weeks to three months after injury was higher in the animals injected with silica immediately after surgery, most significantly in the dorsal quadrant of the cord. Myelin sheath thickness and axon caliber distribution were not different. Hypervascularity of the lesion was significantly reduced in animals injected with silica within one day of injury. These findings support the hypothesis that inflammatory activity plays an important role in secondary tissue damage, and that it may be responsible for some proportion of long-term neurological deficits, but do not suggest a prominent role for early macrophage activity in the mechanisms of demyelination.

Animals↗

PubMed1999

Intra-renal and subcellular distribution of the human chloride channel, CLC-5, reveals a pathophysiological basis for Dent's disease.

Dent's disease, which is a renal tubular disorder characterized by low molecular weight proteinuria, hypercalciuria and nephrolithiasis, is associated with inactivating mutations of the X-linked chloride channel, CLC-5. However, the manner in which a functional loss of CLC-5 leads to such diverse renal abnormalities remains to be defined. In order to elucidate this, we performed studies to determine the segmental expression of CLC-5 in the human kidney and to define its intracellular distribution. We raised and characterized antisera against human CLC-5, and identified by immunoblotting an 83 kDa band corresponding to CLC-5 in human kidney cortex and medulla. Immunohistochemistry revealed CLC-5 expression in the epithelial cells lining the proximal tubules and the thick ascending limbs of Henle's loop, and in intercalated cells of the collecting ducts. Studies of subcellular human kidney fractions established that CLC-5 distribution was associated best with that of Rab4, which is a marker of recycling early endosomes. In addition, confocal microscopy studies using the proximal tubular cell model of opossum kidney cells, which endogenously expressed CLC-5, revealed that CLC-5 co-localized with the albumin-containing endocytic vesicles that form part of the receptor-mediated endocytic pathway. Thus, CLC-5 is expressed at multiple sites in the human nephron and is likely to have a role in the receptor-mediated endocytic pathway. Furthermore, the functional loss of CLC-5 in the proximal tubules and the thick ascending limbs provides an explanation for the occurrences of low molecular weight proteinuria and hypercalciuria, respectively. These results help to elucidate further the patho-physiological basis of the renal tubular defects of Dent's disease.

Adolescent↗

PubMed2002

Renoprotection: a matter of blood pressure reduction or agent-characteristics?

Data from recent clinical trials show that lowering of BP reduces the rate of renal function loss in chronic renal disease. There is evidence supporting the assertion that BP lowering obtained by intervention in the renin-angiotensin-aldosterone system (RAAS) has an additive renoprotective effect in both diabetic and nondiabetic renal diseases. However, to dissociate BP-dependent and non-BP-dependent action of RAAS blockade, the relevant trials are in many cases flawed by design, resulting in BP differences between the comparative antihypertensive strategies. This review discusses whether the relevant literature allows for the conclusion that RAAS intervention has renoprotective effects in addition to its effects on BP. In particular, the main evidence for a specific renoprotective action of RAAS blockade is provided by its consistent antiproteinuric action, which cannot completely be attributed to the reduction in BP. Indeed, other strategies that lower proteinuria without having an antihypertensive effect, such as lowering dietary protein intake or the use of non-steroidal antiinflammatory drugs, appear to have a renoprotective effect as well. Interestingly, a consistent finding across different intervention studies is that the more proteinuria is reduced the better the kidney appears to be protected. Therefore, it is concluded that agent-characteristics of RAAS intervention (i.e., antiproteinuric properties) independently influence renal function loss in addition to its BP-lowering effect. Future studies should further explore the renoprotective benefit of non-antihypertensive intervention measures, alone and in combination with antihypertensive strategies.

Antihypertensive Agents↗

PubMed1999

Loss of function of Trp53, but not Apc, leads to the development of esophageal adenocarcinoma in mice with jejunoesophageal reflux.

INTRODUCTION: APC and TP53 are tumor suppressor genes known to be altered frequently in human esophageal adenocarcinoma (EAC), which arises as a complication of reflux disease. To determine the functional role of these genes in the development of EAC, we have created reflux in mice gene-targeted for either Trp53 or Apc. METHODS: Wild-type (WT), p53-knockout (Trp53-/-), or Apc-mutated (ApcMin/+) mice were generated in our breeding colony. Total gastrectomy with esophagojejunostomy was performed at 6 weeks of age, creating jejunoesophageal reflux. Unoperated control mice were maintained under identical conditions. Mice were sacrificed at 30 weeks of age. Histology of the esophagus and jejunal anastamosis or gastroesophageal junction was reviewed by a single pathologist blinded to the genotype of the animal. RESULTS: The esophagus was normal in all of the unoperated mice (6 ApcMin/+, 6 WT, and 6 Trp53-/-). All operated mice (6 ApcMin/+, 12 WT, and 4 Trp53-/-) had esophagitis, with squamous hyperplasia and early focal ulceration. Barrett's metaplasia was identified in 33% of the operated ApcMin/+ (2/6) and 25% of the Trp53-/- (1/4) mice, but not in the WT mice. Of 4 operated Trp53-/- mice, all developed severe dysplasia of the squamous epithelium and 2 (50%) had EAC on histology, although no gross tumors were seen. No severe dysplasia or carcinoma was identified in any of the ApcMin/+ or WT mice. CONCLUSIONS: Loss of either Trp53 or Apc leads to the development of columnar metaplasia, whereas loss of Trp53, but not Apc, leads to development of cancer in mice with jejunoesophageal reflux.

Adenocarcinoma↗

PubMed2000

Src family kinase activity is required for Kit-mediated mitogen-activated protein (MAP) kinase activation, however loss of functional retinoblastoma protein makes MAP kinase activation unnecessary for growth of small cell lung cancer cells.

Small cell lung cancer (SCLC) is characterized by multiple genetic alterations that include inactivation of the retinoblastoma protein (Rb), the establishment of several autocrine loops including that induced by coexpression of stem cell factor (SCF) and Kit, and the ectopic expression and activation of Src family kinases. Previous studies have shown that Lck associates with, and becomes activated by, Kit after SCF stimulation of SCLC cells. In the present study, we have demonstrated that PP1, a pharmacological inhibitor of Src kinases, blocked SCF-mediated activation of mitogen-activated protein (MAP) kinase, but it also inhibited Kit activation. However, MAP kinase activation was more sensitive than Kit activation to the effects of PP1. Overexpression of Lck reduced the sensitivity of MAP kinase activation to PP1 without altering the sensitivity of Kit activation, which suggested a role for Lck in SCF-mediated MAP kinase activation. Inducible expression of a dominant negative Lck inhibited MAP kinase activation in a dose-dependent manner, which confirmed that Src family kinase activity is required for SCF-induced MAP kinase activation. The growth of cells that expressed dominant negative Lck was unaffected, however, despite the inhibition of MAP kinase. Growth was also unaffected by the inhibition of the MAP kinase pathway using PD 98059, but sensitivity to the MAP/extracellular signal-regulated kinase kinase inhibitor could be partially restored by expression of wild-type Rb. Therefore, MAP kinase activation seems to be dispensable for the growth of SCLC only in the absence of Rb expression. These data suggest that the SCF/Kit autocrine loop, through activation of Lck and subsequently MAP kinase, and the mutational inactivation of Rb contribute to the loss of G1-S phase checkpoint regulation during the pathogenesis of SCLC. Furthermore, the data demonstrate that, in established SCLC cell lines, proliferative signal transduction initiated by Kit is mediated by pathways other than the classic MAP kinase pathway.

Blotting, Western↗

PubMed2024

Adaptation for Staphylococcus aureus to hosts via insertion mutation in the accessory gene regulator agrC gene: decreased virulence and enhanced persistence capacity.

UNLABELLED: Staphylococcus aureus is an important human pathogen due to its vast array of virulence factors regulated by multiple regulatory mechanisms, including the accessory gene regulator. In this study, two S. aureus strains were simultaneously isolated from the blood of a febrile patient, belonging to the same clone, designated as 23H with a complete hemolytic phenotype, and 23B, exhibiting an incomplete hemolytic phenotype. The genomic comparison between strains 23B and 23H revealed that 23B had a single adenine base insertion at position 923 in the agrC gene, leading to a functional loss of the encoded AgrC. Experimental findings showed that strain 23B had decreased hemolytic activity, lower cytotoxicity against human alveolar epithelial A549 cells and in the Galleria mellonella model, and a reduced ability to survive intracellularly after infecting macrophages, in comparison to 23H. Conversely, 23B exhibited enhanced biofilm formation, greater adherence to A549 cells, and increased persistence in the face of vancomycin and daptomycin treatment. Transcriptomic analysis revealed that 23B upregulated surface protein-encoding genes while simultaneously reducing the expression levels of virulence factors, highlighting the intricate regulatory adjustments facilitating its persistence and reducing pathogenic potential. ATP assay results indicated that 23B maintained elevated ATP levels during the exponential phase yet exhibited reduced levels in the stationary phase when compared with 23H. Our findings suggested that the mutation in the agrC gene of S. aureus results in diminished virulence but markedly enhances persistence. This mutated strain warrants clinical attention because it may lead to treatment failures and persist in patients. IMPORTANCE: In clinical antimicrobial therapy, bacterial strains often develop resistance to antimicrobial agents. Additionally, mutations in their gene regulatory networks can increase their persistence, especially in immunocompromised patients. This study identified an insertion mutation in the accessory gene regulator, agrC gene, carried by a Staphylococcus aureus strain isolated from the blood of a febrile patient, leading to the functional loss of AgrC. Further research revealed that despite the reduced virulence of the mutated strain, it significantly bolstered the capacity to adapt and endure within the host during prolonged infections. This was evidenced by increased adhesion and biofilm formation capabilities, development of antimicrobial tolerance, and decreased ATP levels linked to persistence. Therefore, monitoring these mutations in S. aureus is crucial clinically, as they can complicate treatment strategies.

Staphylococcus aureus↗

PubMed2002

Clinical variations in assessment of bull's-eye maculopathy.

OBJECTIVES: To evaluate the phenotypic variation in bull's-eye maculopathy and seek possible correlations between functional loss and clinical appearance. METHODS: From January 1, 1999, to September 30, 2000, we prospectively examined patients with bull's-eye lesions. Age of onset, duration of symptoms, visual acuity, clinical appearance, and autofluorescence images were recorded, the area of atrophy measured, and electrophysiologic investigations performed. RESULTS: Forty-seven patients, including 6 sibling pairs, met the study entry criteria. On the basis of autofluorescence imaging, 3 distinct groups were identified. Group 1 showed a distinct ring of increased autofluorescence surrounding an area of decreased autofluorescence. In group 2, the ring of increased autofluorescence was not present. Group 3 displayed a speckled appearance within the affected area. All patients had evidence of central sparing in an area of centrally increased autofluorescence. There was significant correlation with the age of onset, visual acuity, and duration of disease. Electrophysiologic tests revealed that 28 patients had macular dysfunction only, 14 had cone-rod dystrophy, 3 had rod-cone dystrophy, and only 2 (monozygotic twins) had cone dystrophy. The correlation between electrophysiologic and autofluorescence data was poor. The sibling pairs had concordant autofluorescence appearance, but electrophysiologic grouping differed in 2 pairs. CONCLUSIONS: Bull's-eye maculopathy represents a heterogeneous group of disorders. The clinical appearance was not helpful in assessing the degree of retinal dysfunction. The difference in qualitative characteristics of functional loss between siblings implies that these attributes do not necessarily reflect the influence of the primary mutation.

Adolescent↗

PubMed2005

Loss of function mutations of the GJB2 gene detected in patients with DFNB1-associated hearing impairment.

Mutations in GJB2, which encodes the gap junction protein connexin 26 (Cx26), are one of the major causes for inherited and sporadic nonsyndromic hearing impairment. This study aimed to functionally characterize more frequent GJB2 mutations identified in patients showing nonsyndromic hearing impairment. Following injection of wild type and mutated cRNA in Xenopus oocytes, Cx26 hemichannel activity was measured by depolarization activated conductance in noncoupled oocytes. All mutants showed a partially or completely defective phenotype, except (V27I)Cx26, a polymorphism tested as positive control. Coexpression of wild type and mutant Cx26 injected at equimolar levels revealed that p.M34T, p.V37I and p.I82M, but not p.G59V, p.L90P, p.R127H and p.R143W exert a dominant inhibitory effect. When coexpressed with Cx30, a connexin partially colocalized with Cx26 in the cochlea, all mutants had a dominant behavior. This study provides data that might be important for the improvement of genetic diagnosis and counseling for patients with hearing impairment.

Animals↗

PubMedDate not supplied

Vestibular investigations in acoustic neuroma.

Forty-eight patients with surgically proven acoustic neuroma were examined preoperatively with a comprehensive battery of vestibular tests. In 87% of the patients, reduced caloric responses were measured on the side of the lesion. In 60% of the patients a non-responsive labyrinth was found. Spontaneous nystagmus was observed in 29% of the patients. A significant correlation with the size of the tumour was found in the occurrence of abnormal saccades in the calibration test, pathological smooth pursuit movements and the occurrence of gaze nystagmus, respectively. There was no correlation between the magnitude of the caloric response reduction and the mean hearing loss, which suggests that the hearing loss and the vestibular function loss do not occur synchronously. This study shows that in most cases of acoustic neuroma, the peripheral part of the vestibular system is severely disturbed. Abnormalities in the central and peripheral part of the vestibular system are more easily recognized with increasing tumour size. We conclude that a complete battery of vestibular tests is essential in combination with audiometric, neurologic and radiologic analysis for the early clinical diagnosis of acoustic neuroma.

Caloric Tests↗

PubMed1997

Male accessory sex organ morphogenesis is altered by loss of function of Hoxd-13.

The role of the Hox gene Hoxd-13 in postnatal morphogenesis of the male accessory sex organs was examined by correlating the distribution and temporal regulation of expression in the accessory sex organs of postnatal mice with morphologic abnormalities of Hoxd-13-deficient transgenic mice. Previous studies of Hoxd-13 expression in the perinatal period have shown a broad domain of expression in the lower genitourinary tract, with expression in both mesenchyme and epithelium; focal expression was also noted in the epithelium of the nascent ducts of the developing prostate. Quantitative RT-PCR studies of Hoxd-13 expression in the 5 day mouse confirm widespread expression in the accessory sex organs developing from both the Wolffian duct and the urogenital sinus. Expression is down-regulated with age, and a detailed time course of expression in the developing prostate shows that the level of Hoxd-13 expression correlates with morphogenetic activity in the development of the prostate ductal system. Transgenic Hoxd-13-deficient mice display multiple abnormalities in the male accessory sex organs. The most severe abnormalities were observed in organs exhibiting ductal branching during postnatal development and included diminished mesenchymal folding in the seminal vesicles, decreased size and diminished ductal branching in the ventral and dorsal prostate, and agenesis of the bulbourethral gland. We conclude that Hoxd-13 expression in the postnatal period correlates with a period of intense morphogenetic activity in accessory sex organ development and that the function of Hoxd-13 is evidenced by morphologic abnormalities in accessory sex organs of the Hoxd-13-deficient mutant.

Animals↗

PubMed1999

Co-segregation of MEN2 and Hirschsprung's disease: the same mutation of RET with both gain and loss-of-function?

Multiple endocrine neoplasia type 2 (MEN2) and Hirschsprung's disease (HSCR) are two dominantly inherited neurocristopathies ascribed to mutations in the RET gene [Chakravarti, 1996; Pasini et al., 1996; Eng and Mulligan, 1997]. MEN2 is a cancer syndrome comprising three related clinical subtypes: (1) MEN type 2A (MEN2A; MIM# 171400) characterized by the association of medullary thyroid carcinoma (MTC), pheochromocytoma (Pheo), and hyperparathyroidism; (2) MEN type 2B (MEN2B; MIM# 162300), which includes MTC, Pheo, mucosal neuromas, ganglioneuromatosis of the digestive tract, and skeletal abnormalities; and (3) familial MTC (FMTC; MIM# 155240), defined by the sole occurrence of MTC. HSCR (MIM# 142623) is a congenital malformation caused by the absence of enteric plexuses in the hindgut, leading to bowel obstruction in neonates. The RET gene (MIM# 164761) codes for a transmembrane tyrosine kinase, a component of a multimeric complex that also comprises one of four members of a novel family of glycosylphosphatidylinositol (GPI)-anchored receptor, GFRalpha((1-4) (e.g., GFRA1, MIM# 601496; references are detailed in Baloh et al. [1998]. Four structurally related soluble factors-glial cell line-derived neurotrophic factor (GDNF), neurturin, persephin, and artemin-are the ligands of these multimolecular receptors in which the nature of the GFRalpha determines the ligand specificity of the complex [see Baloh et al., 1998, for references]. It is well documented that RET/GFRalpha-1/GDNF delivers a signal critical for the survival of the early neural crest-derived precursors that colonize the intestine below the rostral foregut and give rise to the enteric nervous plexuses [Gershon, 1997; Cacalano et al., 1998; Enomoto et al., 1998].

Drosophila Proteins↗