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PubMed1995

Loss of heterozygosity of tumor suppressor genes in testis cancer.

Little is known of the molecular changes that occur in germ cell tumors (GCT) of the testis. We studied three GCT cell lines and 44 tumors for loss of heterozygosity (LOH) of the tumor suppressor genes APC, MCC, DCC, RB, TP53, and WT-1. We observed that LOH occurred in 55% (21 of 38) of informative cases at DCC, in 28% (10 of 36) of informative cases at APC, in 23% (6 of 26) at MCC, in 30% (13 of 43) at RB, and in 27% (6 of 22) at WT-1. The LOH level in these tumors using anonymous primers mapping to the short and long arms of chromosome 19, which is cytogenetically normal in GCT, revealed LOH of 11 and 5%, respectively. We also observed a LOH of 22% in the TP53 gene, despite the fact that mutations in TP53 do not occur in testis cancer. Since a high frequency of LOH at DCC (18q21.3) occurs equally at all histological subsets in GCT, we conclude that the loss of the function of this gene is an early event in testicular GCTs. However, the observed LOH levels at APC/MCC (5q21), RB (13q14), and WT-1 (11p13) could represent a functional loss of the corresponding tumor suppressor gene in some GCTs or reflect the loss of sequences in the same general chromosome region but involving a different tumor suppressor locus. Therefore, detailed mapping of these chromosomes is required to define the precise locations of maximal LOH in testis cancer.

Base Sequence↗
PubMed1996

Outcome of functioning filtering blebs after pars plana vitrectomy.

BACKGROUND AND OBJECTIVE: To determine the status of filtering bleb function following pars plana vitrectomy. PATIENTS AND METHODS: The authors retrospectively reviewed patients with functioning filtering blebs undergoing pars plana vitrectomy. RESULTS: Twenty-three eyes with functioning filtering blebs underwent pars plana vitrectomy. Postoperatively, 7/23 (30 percent) of the eyes had moderate (5 to 20 mm Hg) intraocular pressure (IOP), 8/23 of the eyes had IOP persistently greater than 20 mm Hg, and 7/23 of the eyes had IOP of less than 5 mm Hg. One of 7 eyes that underwent vitrectomy within 6 weeks after trabeculectomy maintained bleb function, whereas 6 of 16 eyes that underwent trabeculectomy 6 weeks or later maintained bleb function. Loss of bleb function occurred in the early postoperative period in the majority of the patients. Prior antimetabolite therapy was not associated with preservation of bleb function. CONCLUSION: There is a substantial risk of bleb failure following vitrectomy, which is in part related to the often severe nature of the diseases requiring vitreoretinal surgery.

Adult↗
PubMedDate not supplied

[Preservation of hearing in labyrinthectomies for cholesteatoma].

Destruction of the membranous labyrinth can lead to sensorineural hearing loss. This is especially frequent in surgery for active otorrhea. However, destruction of the posterior labyrinth sometimes can be solved without loss of cochlear function. We report three cases of partial labyrinthectomy for intralabyrinthine cholesteatoma without functional loss. Current theories regarding the conservation of hearing are discussed.

Adult↗
PubMed1977

Effect of storage on normal neutrophils collected by discontinuous-flow centrifugation leukapheresis.

Storage limits for granulocytes have not been defined. The purpose of this study was to determine these limits for neutrophils collected by discontinuous-flow centrifugation and stored at 4 degrees-6 degrees C. The parameters studied were total leukocyte and absolute cell counts, viability measured by dye exclusion, morphology, percentage phagocytic neutrophils, number of Candida organisms ingested per phagocytic neutrophil, candidacidal activity by differential staining, and chemotaxis under agarose. There was a progressive loss of neutrophils on storage that was statistically significant by 48 hr. Phagocytosis was the best preserved function. Microbial killing measured by candidacidal activity was less well preserved. Chemotaxis was the most poorly maintained parameter. There was mild impairment at 24 hr and a severe functional loss at 48 hr. The data suggest the following: (1) the first functions lost on storage are the most highly integrated, i.e., chemotaxis, followed by microbial killing and then phagocytosis; and (2) assuming that these functional losses are irreversible, storage of normal neutrophils used for transfusion should be limited to approximately 24 hr because a severe defect in migration occurs between the first and second days.

Blood Preservation↗
PubMed2001

Gain- and loss-of-function Lyn mutant mice define a critical inhibitory role for Lyn in the myeloid lineage.

To investigate the role of the Lyn kinase in establishing signaling thresholds in hematopoietic cells, a gain-of-function mutation analogous to the Src Y527F-activating mutation was introduced into the Lyn gene. Intriguingly, although Lyn is widely expressed within the hematopoietic system, these mice displayed no propensity toward hematological malignancy. By contrast, analysis of aging cohorts of both loss- and gain-of-function Lyn mutant mice revealed that Lyn(-/-) mice develop splenomegaly, increased numbers of myeloid progenitors, and monocyte/macrophage (M phi) tumors. Biochemical analysis of cells from these mutants revealed that Lyn is essential in establishing ITIM-dependent inhibitory signaling and for activation of specific protein tyrosine phosphatases within myeloid cells. Loss of such inhibitory signaling may predispose mice lacking this putative protooncogene to tumorigenesis.

Aging↗
PubMed2004

[Hereditary retinochoroidal dystrophies. Part 2: differential diagnosis].

A generally accepted classification for inherited retinochoroidal dystrophies does not exist. The names given to certain disorders are either based on ophthalmoscopic findings, or on histologic, electrophysiologic and genetic findings. Future research on the molecular genetic background will result in better definition of clinical entities. The purpose of this project is to outline a practical approach to inherited retinochoroidal dystrophies. For this reason, disorders with similar clinical symptoms are grouped together. Generalized retinochoroidal dystrophies affecting all retinal areas can be distinguished from regional dystrophies. Generalized dystrophies can be subdivided into those with peripheral onset, usually associated with initial rod function loss (night blindness, peripheral field loss: e.g. retinitis pigmentosa, choroideremia) and those with central onset associated with cone function loss (visual acuity loss, central scotoma, color vision deficits: e.g. cone or cone-rod dystrophies). Regionally limited dystrophies include the multitude of macular dystrophies and the autosomal dominant vitreoretinochoroidopathy, which remains limited to the periphery. It is important for a differential diagnosis to exclude involvement of other organ systems in syndromic disorders. Stationary inherited retinal dysfunction (e.g. monochromatism, congenital stationary night blindness) and other inherited or acquired diseases have to be excluded as well. Guidelines for differential diagnosis are presented.

Choroid Diseases↗
PubMed2002

[Evaluation of functional results in conservatively treated boxer's fractures].

OBJECTIVES: The aim of this study was to evaluate the effect of dorsal angulations up to 30 degrees on the grip strength in conservatively treated boxer's fractures. METHODS: The grip strength of 18 patients was evaluated with the Jamar dynamometer following conservative treatment for neck fractures of the fifth metacarpal. All the patients were males with a mean age of 30.5 years. The results were compared with those of intact hands and a control group of 18 subjects (mean age 31.2 years). The mean follow-up period was 20 months (range 4 to 48 months). RESULTS: The mean dorsal angulations before and after closed reduction were 46 degrees (range 35 degrees -55 degrees ) and 28 degrees (range 10 degrees -30 degrees ), respectively. Compared to the grip strength of intact hands and controls, no statistically significant functional loss was found in conservatively treated hands (p>0.05). CONCLUSION: Since no significant functional loss occurs in the fifth metacarpal neck fractures having an angulation less than 30 degrees, the appropriate treatment seems to be conservative whenever this range of reduction is likely to be achieved.

Adult↗
PubMed1992

Collateral sensitivity to nitrosoureas in multidrug-resistant cells selected with verapamil.

We have examined the effects of the nitrosoureas, streptozotocin (STZ) and 1,3-bis(chloroethyl)-1-nitrosourea (BCNU), on a human multiple myeloma cell line, RPMI 8226, and its drug-resistant variants. Cell lines selected for doxorubicin (DOX) resistance alone displayed a STZ and BCNU cytotoxicity profile similar to that of the parent cell line. In contrast, two of the drug-resistant variants selected with DOX plus verapamil, an agent which inhibits P-glycoprotein-mediated multidrug resistance, displayed a collateral sensitivity to STZ and BCNU. Verapamil was included in the selection protocol because it has been shown to inhibit the P-glycoprotein-mediated multidrug resistance phenotype and is now in clinical trials as a chemosensitizing agent. The collateral sensitivity to these nitrosoureas seen in the DOX plus verapamil-selected cell lines is due to the functional loss of a DNA repair molecule, O6-Methylguanine DNA methyltransferase (MGMT). The functional loss of MGMT is secondary to the loss of MGMT gene expression. The loss of MGMT gene expression is not due to loss or gross rearrangement of the MGMT-coding region. If this selection pressure applied in vitro reflects the in vivo situation, then new chemotherapeutic strategies may be devised to exploit this phenomenon. These cell lines will serve as useful models for delineating mechanisms which govern MGMT expression.

Base Sequence↗
PubMed1998

Rare loss-of-function mutation of a death receptor gene in head and neck cancer.

The chromosomal region 8p21 contains a number of putative tumor suppressor genes and is a frequent site of translocations in head and neck cancers. Recently, a novel tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor gene, KILLER/DR5, a member of the tumor necrosis factor receptor family, was identified as a potential mediator in p53-dependent apoptosis and mapped to 8p21 by fluorescence in situ hybridization. We have determined the genomic structure of KILLER/DR5 and performed sequence analysis of all 10 coding exons in 20 primary head and neck cancers with allelic loss of chromosome 8p. To screen for a subset of mutations localized to the functional cytoplasmic death domain, we sequenced this region in an additional 40 primary head and neck cancers. We found two alterations in this domain, including a 2-bp insertion at a minimal repeat site, introducing a premature stop codon and resulting in a truncated protein. This KILLER/DR5 mutation was also present in the germ line of the affected patient, and the tumor did not have a p53 mutation by sequence analysis. Transfection studies in head and neck squamous cell carcinoma and colon and ovarian carcinoma cell lines revealed loss of growth-suppressive function associated with the tumor-derived KILLER/DR5 truncation mutant. These observations provide the first evidence for mutation of a TRAIL death receptor gene in a human cancer, leading to loss of its apoptotic function.

Base Sequence↗
PubMed1998

Research hypotheses on muscle wasting, aging, loss of function and disability.

Advancing age is accompanied by modifications in body composition such as increase in fat and decrease in bone and muscle mass. Loss of muscle mass or sarcopenia is characterized by a decrease in the total number of muscle fibers, a reduced cross-sectional area of the thigh, and decreased muscle density associated with increased intramuscular fat. Loss of skeletal muscle mass may be a common pathway by which multiple diseases contribute to the risk of disability. Decreases in muscle mass are associated with an increased risk of morbidity, mortality and disability in old age, but the mechanisms by which this occurs are not fully understood. Inflammatory cytokines interfere with muscle contraction and are linked with sarcopenia. Recent evidence showing that decline in left ventricular function is accompanied by sarcopenia and an increase in cytokines might help to understand the role of cytokines in muscle loss in aging and disease. The Health and Body Changes (Health ABC) study, a large population-based cohort study sponsored by the National Institute on Aging, will prospectively address the issues related to sarcopenia and incident disability. Defining modifiable risk factors of sarcopenia is the first step towards the identification of interventions for preventing or reversing disability in older persons.

Age Factors↗
PubMed2003

Loss-of-function and residual channel activity of connexin26 mutations associated with non-syndromic deafness.

Connexins are the protein subunits of gap junction channels that allow a direct signaling pathway between networks of cells. The specific role of connexin channels in the homeostasis of different organs has been validated by the association of mutations in several human connexins with a variety of genetic diseases. Several connexins are present in the mammalian cochlea and at least four of them have been proposed as genes causing sensorineural hearing loss. We have started our functional analysis by selecting nine mutations in Cx26 that are associated with non-syndromic recessive deafness (DFNB1). We have observed that both human Cx26 wild-type (HCx26wt) and the F83L polymorphism, found in unaffected controls, generated electrical conductance between paired Xenopus oocytes, which was several orders of magnitude greater than that measured in water-injected controls. In contrast, most recessive Cx26 mutations (identified in DFNB1 patients) resulted in a simple loss of channel activity. In addition, the V37I mutation, originally identified as a polymorphism in heterozygous unaffected individuals, was devoid of function and thus may be pathologically significant. Unexpectedly, we have found that the recessive mutation V84L retained functional activity in both paired Xenopus oocytes and transfected HeLa cells. Furthermore, both the magnitude of macroscopic junctional conductance and its voltage-gating properties were indistinguishable from those of HCx26wt. The identification of functional differences of disease causing mutations may lead to define which permeation or gating properties of Cx26 are necessary for normal auditory function in humans and will be instrumental in identifying the molecular steps leading to DFNB1.

Animals↗
PubMed2026

Loss of Function Dnmt3a Mutation Leads to Aberrant Neutrophil Migration.

Clonal hematopoiesis (CH), an age-related expansion of somatically mutated hematopoietic clones, is associated with increased risk of severe infections including coronavirus disease (COVID)-19, yet the underlying mechanisms remain unclear. Here, we investigated the impact of Dnmt3a deficiency in a murine model of influenza A virus (IAV) pneumonia. Dnmt3a-deficient mice exhibited increased pulmonary viral burden and reduced neutrophil accumulation in IAV-infected lungs despite comparable circulating neutrophil numbers. Functional analyses of neutrophils showed impaired chemotactic migration in vitro, whereas maturation, antimicrobial enzyme content, and metabolic capacity were unchanged. Transcriptomic profiling revealed downregulation of pathways involved in chemotaxis, cytokine signaling, and cellular activation, including reduced expression of Cxcr1. Supporting the translational relevance of these findings, proteomic analysis of plasma from individuals with germline DNMT3A mutations (Tatton-Brown-Rahman syndrome) revealed alterations in proteins associated with cell migration and cytoskeletal dynamics. Collectively, our findings demonstrate that Dnmt3a loss compromises innate immune defense by impairing neutrophil migration in a cell-intrinsic manner, leading to ineffective pathogen clearance. This work provides mechanistic insight into how CH-associated mutations contribute to age-associated susceptibility to infection and highlights altered leukocyte trafficking as a potential therapeutic target in aging populations with CH.

Animals↗
PubMed2000

Autosomal recessive disorder otospondylomegaepiphyseal dysplasia is associated with loss-of-function mutations in the COL11A2 gene.

Otospondylomegaepiphyseal dysplasia (OSMED) is an autosomal recessive skeletal dysplasia accompanied by severe hearing loss. The phenotype overlaps that of the autosomal dominant disorders-Stickler and Marshall syndromes-but can be distinguished by disproportionately short limbs, severe hearing loss, and lack of ocular involvement. In one family with OSMED, a homozygous Gly-->Arg substitution has been described in COL11A2, which codes for the alpha2 chain of type XI collagen. We report seven further families with OSMED. All affected individuals had a remarkably similar phenotype: profound sensorineural hearing loss, skeletal dysplasia with limb shortening and large epiphyses, cleft palate, an extremely flat face, hypoplasia of the mandible, a short nose with anteverted nares, and a flat nasal bridge. We screened affected individuals for mutations in COL11A2 and found different mutations in each family. Individuals from four families, including three with consanguineous parents, were homozygous for mutations. Individuals from three other families, in whom parents were nonconsanguineous, were compound heterozygous. Of the 10 identified mutations, 9 are predicted to cause premature termination of translation, and 1 is predicted to cause an in-frame deletion. We conclude that the OSMED phenotype is highly homogenous and results from homozygosity or compound heterozygosity for COL11A2 mutations, most of which are predicted to cause complete absence of alpha2(XI) chains.

Adult↗
PubMed1998

Loss of function of the tuberous sclerosis 2 tumor suppressor gene results in embryonic lethality characterized by disrupted neuroepithelial growth and development.

Germline defects in the tuberous sclerosis 2 (TSC2) tumor suppressor gene predispose humans and rats to benign and malignant lesions in a variety of tissues. The brain is among the most profoundly affected organs in tuberous sclerosis (TSC) patients and is the site of development of the cortical tubers for which the hereditary syndrome is named. A spontaneous germline inactivation of the Tsc2 locus has been described in an animal model, the Eker rat. We report that the homozygous state of this mutation (Tsc2(Ek/Ek)) was lethal in mid-gestation (the equivalent of mouse E9.5-E13.5), when Tsc2 mRNA was highly expressed in embryonic neuroepithelium. During this period homozygous mutant Eker embryos lacking functional Tsc2 gene product, tuberin, displayed dysraphia and papillary overgrowth of the neuroepithelium, indicating that loss of tuberin disrupted the normal development of this tissue. Interestingly, there was significant intraspecies variability in the penetrance of cranial abnormalities in mutant embryos: the Long-Evans strain Tsc2(Ek/Ek) embryos displayed these defects whereas the Fisher 344 homozygous mutant embryos had normal-appearing neuroepithelium. Taken together, our data indicate that the Tsc2 gene participates in normal brain development and suggest the inactivation of this gene may have similar functional consequences in both mature and embryonic brain.

Animals↗
PubMed1997

[Electromyography studies for objective assessment of loss of function of the lateral pterygoid muscles after dislocation fractures of the mandibular processes].

The aim of treatment for luxation fractures of the mandibular articular processes is not only complete anatomical restitution but also restoration of the mobility. In a retrospective study on 242 patients after operative and conservative treatment, it was possible to demonstrate that there are no correlations between fragment position and functional result. Functional restitution was observed after conservative treatment in 65% of cases and after operative treatment in 57%. In order to establish the causes for dysfunction of the lateral pterygoid muscle an electromyographical technique was developed to dissipate the action potentials of the muscle. Another retrospective study, performed in 23 patients with dysfunction of the mandible revealed loss of activity of the lateral pterygoid muscle after fracture treatment, independent of the treatment method, in 11.5% of cases (two patients). Without any connection to the treatment method, the remaining results permit to conclude that there are preoperative neurological defects. Therefore the pre- and posttherapeutic functions of muscles and nerves were investigated in a prospective study on 18 patients. Before the treatment 16.6% of the patients (n = 3) showed defects of the lateral pterygoid nerve with a resulting loss of muscle function. According to the findings, residual dysfunction of the lateral pterygoid muscle is determined by the extend of the traumatic nerve injury, independent of the treatment method. In the case of axonal defects of the pterygoid nerve, there can be no expectation of a restitutio ad integrum after the operative fragment position.

Adolescent↗
PubMed2004

Inhibitory modulation of distal C-terminal on protein kinase C-dependent phospho-regulation of rat TRPV1 receptors.

The vanilloid receptor TRPV1, previously known as VR1, has been implicated in pain sensation under both physiological and pathological conditions. The channel is highly expressed in sensory ganglion neurones and is activated by a range of noxious stimuli including irritant chemicals, acids and heat. In order to understand the structural basis underlying this polymodal activation and the regulation by intracellular signalling pathways, we have investigated the functional roles of the cytoplasmic C-terminal of rat TRPV1. A mutant with the maximal truncation of the distal C-terminal encompassing the last 88 residues was constructed. Of interest, this mutant exhibited a Ca(2+)-dependent functional loss; it was irresponsive to capsaicin in the presence of extracellular Ca(2+), but fully functional otherwise. Further studies of this construct revealed that extracellular Ca(2+) alone could activate the channel, and that the activation required protein kinase C (PKC) phosphorylation at S502, an event that was up-regulated by external Ca(2+) entry. We compared the truncation mutant with wild-type TRPV1 and demonstrated that it had a significantly increased sensitivity to PKC phosphorylation. These results suggest the distal C-terminal of TRPV1 can inhibit phosphorylation-induced potentiation of the wild-type channel. They also call into question some established functions of the distal C-terminal of TRPV1, including its roles in agonist binding and functional desensitization. We suggest that the functional loss of the truncation mutant, in the presence of extracellular Ca(2+), was not due to disruption of agonist binding or gating, but rather to desensitization promoted by unstimulated extracellular Ca(2+) entry.

Animals↗
PubMed1982

Slowing of paroxysmal tachycardia with loss of functional bundle-branch block.

Electrophysiological studies in a patient with paroxysmal supraventricular tachycardia disclosed anterograde dual atrioventricular nodal pathways, and a concealed left-sided anomalous atrioventricular pathway which was used as the retrograde limb of two circus movement tachycardias. Tachycardia No.1, reflecting anterograde fast pathway conduction, was characterised by functional left bundle-branch block and a stable cycle length of 330 ms. Paroxysmal loss of bundle-branch block resulted in tachycardia No.2, which reflected anterograde slow pathway conduction, and was characterised by narrow QRS and a stable cycle length of 355 ms. Tachycardia No.2 had a longer cycle length than tachycardia No.1 because the increment in AH interval (slow pathway instead of fast pathway condition) more than compensated for the decrement in ventriculoatrial interval (narrow QRS instead of bundle-branch block).

Adult↗