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Biomedical subjects

J H Thomas

Publications and source records attributed to J H Thomas.

At least 37 records · Page 2Linked to original sources
PubMed1999

A PDK1 homolog is necessary and sufficient to transduce AGE-1 PI3 kinase signals that regulate diapause in Caenorhabditis elegans.

An insulin receptor-like signaling pathway regulates Caenorhabditis elegans metabolism, development, and longevity. Inactivation of the insulin receptor homolog DAF-2, the AGE-1 PI3K, or the AKT-1 and AKT-2 kinases causes a developmental arrest at the dauer stage. A null mutation in the daf-16 Fork head transcription factor alleviates the requirement for signaling through this pathway. We show here that a loss-of-function mutation in pdk-1, the C. elegans homolog of the mammalian Akt/PKB kinase PDK1, results in constitutive arrest at the dauer stage and increased life span; these phenotypes are suppressed by a loss of function mutation in daf-16. An activating mutation in pdk-1 or overexpression of wild-type pdk-1 relieves the requirement for AGE-1 PI3K signaling. Therefore, pdk-1 activity is both necessary and sufficient to propagate AGE-1 PI3K signals in the DAF-2 insulin receptor-like signaling pathway. The activating mutation in pdk-1 requires akt-1 and akt-2 gene activity in order to suppress the dauer arrest phenotype of age-1. This indicates that the major function of C. elegans PDK1 is to transduce signals from AGE-1 to AKT-1 and AKT-2. The activating pdk-1 mutation is located in a conserved region of the kinase domain; the equivalent amino acid substitution in human PDK1 activates its kinase activity toward mammalian Akt/PKB.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed1999

Fluoxetine-resistant mutants in C. elegans define a novel family of transmembrane proteins.

Fluoxetine (Prozac) is an antidepressant that is thought to act by blocking presynaptic reuptake of the neurotransmitter serotonin. Despite widespread clinical use of fluoxetine, direct evidence for this mechanism has been difficult to obtain in vivo. We have determined that fluoxetine has an additional neuromuscular effect on C. elegans that is distinct from inhibition of serotonin reuptake. By screening for mutants resistant to this effect, we have identified seven genes. We report that two of these genes are homologous to each other and define a novel gene family that encodes over a dozen multipass transmembrane proteins. Our findings may have clinical implications for the mechanism of action of fluoxetine.

Amino Acid Sequence↗
PubMed1999

Characterization of seven genes affecting Caenorhabditis elegans hindgut development.

We have identified and characterized 12 mutations in seven genes that affect the development of the Caenorhabditis elegans hindgut. We find that the mutations can disrupt the postembryonic development of the male-specific blast cells within the hindgut, the hindgut morphology in both males and hermaphrodites, and in some cases, the expression of a hindgut marker in hermaphrodite animals. Mutations in several of the genes also affect viability. On the basis of their mutant phenotypes, we propose that the genes fall into four distinct classes: (1) egl-5 is required for regional identity of the tail; (2) sem-4 is required for a variety of ectodermal and mesodermal cell types, including cells in the hindgut; (3) two genes, lin-49 and lin-59, affect development of many cells, including hindgut; and (4) three genes, mab-9, egl-38, and lin-48, are required for patterning fates within the hindgut, making certain hindgut cells different from others. We also describe a new allele of the Pax gene egl-38 that is temperature sensitive and affects the conserved beta-hairpin of the EGL-38 paired domain. Our results suggest that a combination of different factors contribute to normal C. elegans hindgut development.

Aging↗
PubMed1999

The C. elegans gene lin-36 acts cell autonomously in the lin-35 Rb pathway.

The Caenorhabditis elegans gene lin-36 acts to antagonize Ras-mediated vulval induction in a pathway that includes genes with products similar to the mammalian retinoblastoma (Rb) protein and the Rb-binding protein p48. We report that lin-36 encodes a novel protein of 962 amino acids. We demonstrate that lin-36 functions in and is expressed in the vulval precursor cells, establishing that the lin-36 pathway is involved in intercellular signaling. We also report that the lin-36 pathway and/or another pathway that is functionally redundant with the lin-36 pathway antagonize a ligand-independent activity of the receptor tyrosine kinase/Ras vulval induction pathway.

Alleles↗
PubMed1998

Methuselah meets diabetes.

Mutations in the daf-2 and age-1 genes cause constitutive dauer larva formation and double adult life span in C. elegans. Their effect on life span has excited considerable interest and their effect on dauer formation has facilitated rapid progress in their genetic and molecular analysis. Two recent papers report that daf-2 encodes a member of the insulin-receptor family and that age-1 encodes a PI3 kinase subunit, a second-messenger producing enzyme known to act downstream of the mammalian insulin receptor. These findings provide the first mechanistic insight into the well-established link between metabolism and aging.

Aging↗
PubMed1998

Vena caval occlusion after bird's nest filter placement.

BACKGROUND: Inferior vena caval thrombosis as a result of intracaval barrier devices occurs in 6.5% of patients with Greenfield filters. The incidence is less well defined in patients in whom bird's nest filters have been placed. We reviewed our experience with bird's nest filters to determine the incidence of filter-induced caval thrombosis. METHODS: The records of 140 patients with bird's nest filters were reviewed, living patients were interviewed, and the inferior vena cava examined in 37 patients by duplex scanning. RESULTS: Ninety-three patients were available for evaluation. Five of these patients were found to have caval thrombosis by duplex scanning and 2 had clinical symptoms and signs compatible with caval thrombosis. The majority of these patients were on anticoagulants at the time of filter thrombosis. CONCLUSION: The incidence of filter-induced vena caval thrombosis in patients with bird's nest filters (7%) is comparable with that of Greenfield filters. Because of the catastrophic manifestations of this complication and the increasing application of vena caval filters, the role of these filters in the treatment of thrombotic disease needs further critical evaluation.

Adolescent↗
PubMed1998

The clinical course of asymptomatic mesenteric arterial stenosis.

PURPOSE: The incidence of subsequent symptomatic mesenteric vascular disease is unknown for patients who have asymptomatic mesenteric arterial stenosis. The purpose of this study was to determine the risk of developing acute and chronic mesenteric ischemia in patients identified by lateral aortography to have significant mesenteric artery stenosis. METHODS: From 1989 through 1995, 980 consecutive aortograms with anteroposterior and lateral projections were reviewed within 1 week of arteriography to identify patients who had significant mesenteric stenosis but no symptoms of mesenteric ischemia. Eighty-two patients were found to have 50% stenosis of at least one mesenteric artery and were monitored by interview to determine if symptoms of acute or chronic mesenteric ischemia developed. RESULTS: Ten patients were lost to follow-up, and 12 patients were withdrawn from the study because of mild mesenteric arterial disease (1% to 49% stenosis) in combination with more significant disease of other vessels. Follow-up was 1 to 6 years. The overall mortality rate was 40%, and mesenteric ischemia developed in four patients. Each of these four patients had significant (>50%) stenosis or occlusion of the celiac artery, superior mesenteric artery, and inferior mesenteric artery. Eighty-six percent of the 15 patients with significant three-vessel arterial disease had mesenteric ischemia, had other vague abdominal symptoms, or died. CONCLUSIONS: Patients with significant three-vessel mesenteric arterial stenosis should be considered for prophylactic mesenteric arterial reconstruction. Mesenteric arterial reconstruction should be routine when these patients undergo aortic reconstruction for aneurysmal or occlusive disease.

Acute Disease↗
PubMed1997

Genetics in rhythm.

Rhythmic phenomena are widespread in biology. Genetic analysis of 24 hour circadian rhythms has a long history, and recent studies of circadian clock genes in Drosophila and Neurospora provide insight into clock mechanisms, including rhythm generation, clock setting by external signals and temperature compensation of rhythm. Faster biological rhythms, called ultradian rhythms, vary widely in periodicity and are likely to be generated by diverse mechanisms. In animals, ultradian rhythms are important in many neuromuscular systems, such as heartbeat, peristalsis and breathing. Recent progress has been made in the genetic analysis of heartbeat in humans and an ultradian rhythm controlling defecation in Caenorhabditis elegans.

Activity Cycles↗
PubMed1997

aex-3 encodes a novel regulator of presynaptic activity in C. elegans.

C. elegans aex-3 mutations cause pleiotropic behavioral defects that are suggestive of reduced synaptic transmission. aex-3 mutations also show strong genetic interactions with mutations in unc-31 and unc-64, two other genes implicated in synaptic transmission. Physiological and pharmacological studies indicate that aex-3 defects are presynaptic. In aex-3 mutants, the synaptic vesicle-associated RAB-3 protein aberrantly accumulates in neuronal cell bodies and is reduced in synapse-rich axons. This localization defect is specific to RAB-3, since other synaptic proteins are localized normally in aex-3 mutants. aex-3 encodes a 1409 amino acid protein with strong homology to DENN, a human protein of unknown function. In C. elegans, aex-3 is expressed in all or nearly all neurons. These results suggest that AEX-3 is a novel regulator of presynaptic activity that interacts with RAB-3 to regulate synaptic vesicle release.

Aldicarb↗
PubMed1997

Behavioral defects in C. elegans egl-36 mutants result from potassium channels shifted in voltage-dependence of activation.

Mutations in the C. elegans egl-36 gene result in defective excitation of egg-laying and enteric muscles. Dominant gain-of-function alleles inhibit enteric and egg-laying muscle contraction, whereas a putative null mutation has no observed phenotype. egl-36 encodes a Shaw-type (Kv3) voltage-dependent potassium channel subunit. In Xenopus oocytes, wild-type egl-36 expresses noninactivating channels with slow activation kinetics. One gain-of-function mutation causes a single amino acid substitution in S6, and the other causes a substitution in the cytoplasmic amino terminal domain. Both mutant alleles produce channels dramatically shifted in their midpoints of activation toward hyperpolarized voltages. An egl-36::gfp fusion is expressed in egg-laying muscles and in a pair of enteric muscle motor neurons. The mutant egl-36 phenotypes can thus be explained by expression in these cells of potassium channels that are inappropriately opened at hyperpolarized potentials, causing decreased excitability due to increased potassium conductance.

Animals↗
PubMed1997

Identification and characterization of genes that interact with lin-12 in Caenorhabditis elegans.

We identified and characterized 14 extragenic mutations that suppressed the dominant egg-laying defect of certain lin-12 gain-of-function mutations. These suppressors defined seven genes: sup-17, lag-2, sel-4, sel-5, sel-6, sel-7 and sel-8. Mutations in six of the genes are recessive suppressors, whereas the two mutations that define the seventh gene, lag-2, are semi-dominant suppressors. These suppressor mutations were able to suppress other lin-12 gain-of-function mutations. The suppressor mutations arose at a very low frequency per gene, 10-50 times below the typical loss-of-function mutation frequency. The suppressor mutations in sup-17 and lag-2 were shown to be rare non-null alleles, and we present evidence that null mutations in these two genes cause lethality. Temperature-shift studies for two suppressor genes, sup-17 and lag-2, suggest that both genes act at approximately the same time as lin-12 in specifying a cell fate. Suppressor alleles of six of these genes enhanced a temperature-sensitive loss-of-function allele of glp-1, a gene related to lin-12 in structure and function. Our analysis of these suppressors suggests that the majority of these genes are part of a shared lin-12/glp-1 signal transduction pathway, or act to regulate the expression or stability of lin-12 and glp-1.

Animals↗
PubMed1997

The PAX gene egl-38 mediates developmental patterning in Caenorhabditis elegans.

Mutations in the C. elegans gene egl-38 result in a discrete set of defects in developmental pattern formation. In the developing egg-laying system of egl-38 mutant hermaphrodites, the identity of four uterine cells is disrupted and they adopt the fate of their neighbor cells. Likewise, the identity of two rectal epithelial cells in the male tail is disrupted and one of these cells adopts the fate of its neighbor cell. Genetic analysis suggests that the egl-38 functions in the tail and the egg-laying system are partially separable, as different egl-38 mutations can preferentially disrupt the different functions. We have cloned egl-38 and shown that it is a member of the PAX family of genes, which encode transcription factors implicated in a variety of developmental patterning events. The predicted EGL-38 protein is most similar to the mammalian class of proteins that includes PAX2, PAX5 and PAX8. The sequence of egl-38 mutant DNA indicates that the tissue-preferential defects of egl-38 mutations result from substitutions in the DNA-binding paired domain of the EGL-38 protein. egl-38 thus provides the first molecular genetic insight into two specific patterning events that occur during C. elegans development and also provides the opportunity to investigate the in vivo functions of this class of PAX proteins with single cell resolution.

Amino Acid Sequence↗
PubMed1996

Photodynamic therapy to control life-threatening hemorrhage from hereditary hemorrhagic telangiectasia.

BACKGROUND AND OBJECTIVE: Photodynamic therapy (PDT) was used to stop life-threatening hemoptysis from bleeding hereditary telangiectasia in bronchi in a 42-year-old man with a 4-year history of repeated embolotherapies, tracheostomies, and ventilator dependence. At the time of his first PDT, he was 10 days past his third embolotherapy, was being ventilated through a tracheostomy and bringing up 100-200 cc of blood daily, necessitating multiple transfusions of blood and platelets. STUDY DESIGN/MATERIAL AND METHODS: Four hours after intravenous injection (60 mg/m2 body surface) of the photosensitizer dihematoporphyrin ether (DHE), bronchoscopy through his tracheostomy showed continuous oozing of non-clotting blood from bronchial vessels in both lung fields, requiring continuous suction. We performed PDT to seven bronchial sites. The 630 nm wavelength light energy to activate the photosensitizer was generated by a tunable dye argon laser system and delivered to the endobronchus through a quartz fiber modified with a 2.5 cm diffusing tip passed through the biopsy channel of the bronchoscope. The light power was 500 mW per cm of diffuser and the light dose was 200 J per cm of diffuser. At the end of the treatments, the bleeding had decreased so as not to require suctioning. The following day we treated three other sites with the same light dose. At this time the only bleeding was from the LUL, which oozed briskly after passing the bronchoscope through it. At the end of the treatment bronchoscopy there was minimal bleeding. RESULTS: One week after PDT he was discharged with a tracheosotomy and mechanical ventilator. Four months later his tracheostomy was removed. He remained free of hemoptysis for 26 months when life-threatening hemoptysis recurred. Twenty-two hours after his second injection of DHE, we treated four different endobronchial sites with PDT for bleeding from both the right and left bronchial tree. Sixteen months after his second PDT he remains free of hemoptysis. Three other patients treated for uncontrollable life-threatening hemoptysis for bronchitis have remained free of hemoptysis for 9, 17, and 23 months. CONCLUSIONS: Photodynamic therapy causes thromobosis and can control bleeding from small vessels regardless of their location or etiology.

Adult↗
PubMed1996

Transhiatal versus transthoracic esophagectomy for adenocarcinoma of the distal esophagus and cardia.

BACKGROUND: Transhiatal esophagectomy is a popular method of resection because of its reported lower morbidity and mortality and similar survival rates compared to transthoracic esophagectomy. A review of recent experience with these two procedures for resection of distal esophageal and cardia adenocarcinoma is reported. METHODS: From 1988 to 1994, 48 patients with adenocarcinoma of the distal esophagus and gastric cardia were resected with intent to cure, 32 by transhiatal esophagectomy (group 1) and 16 by transthoracic esophagectomy (group II). The two groups were comparable in terms of patient demographics, preoperative risk factors, tumor stage, tumor differentiation, and involvement of resection margins (all not significant [NS]). RESULTS: There was no significant difference in median intensive care unit stay, median hospital stay, incidence of postoperative anastomotic leak, and stricture. Respiratory complications were higher in group I (41% versus 6%, P = 0.01). Hospital mortality was not significantly different for the two groups (group I 3.1% versus group II 0%, NS). Actuarial 5-year survival rates (Kaplan-Meier) were 12% for group I and 39% for group II (NS). CONCLUSIONS: These results suggest that when compared with transhiatal esophagectomy, the transthoracic approach is at least as safe, has comparable complication and survival rates, and remains an acceptable procedure for resection of adenocarcinomas of the distal esophagus and gastric cardia.

Adenocarcinoma↗
PubMed1996

Significance of lymph node metastases in patients with pancreatic cancer undergoing curative resection.

BACKGROUND: Recent reports suggest an improved survival following resection for patients with pancreatic carcinoma. However, the prognosis for patients with lymph nodes metastases remains uncertain. The purpose of this study was to determine if the presence of lymph node metastases significantly alters survival in patients with otherwise potentially curable pancreatic carcinoma. PATIENTS AND METHODS: Between 1970 and 1995, 401 patients with pancreatic adenocarcinoma, including 327 patients with pancreatic head tumors, were evaluated and treated. RESULTS: One hundred (31%) patients underwent pancreatoduodenectomy. Operative mortality was 3% and morbidity was 22%. Median survival for 97 patients discharged from the hospital following resection was 14 months (range 2 to 293). The estimated 1-, 2-, and 5-year survivals were 61%, 43%, and 20%, respectively. Median survival was 11.5 months (range 2 to 87) for patients with positive lymph nodes (n = 56) and 24 (range 0 to 293) months for patients with negative lymph nodes (n = 41; P = 0.0003). Ten patients (10%) survived longer than 5 years, and 9 (90%) of them had negative lymph nodes. Elderly patients (> or = 70 years) had a median survival twice as long as younger patients (24 versus 12 months, P = 0.03). CONCLUSIONS: Lymph node metastases are found in 56% of patients undergoing resection. Pancreatoduodenectomy can be performed with low operative mortality in patients of all ages. It offers good palliation for patients with lymph nodes metastases and encouraging long-term survival rates as well as a chance for cure in patients with negative lymph nodes.

Adenocarcinoma↗
PubMed1996

Chemosensory neurons function in parallel to mediate a pheromone response in C. elegans.

Formation of the C. elegans dauer larva is repressed by the chemosensory neurons ADF, ASI, and ASG. Mutant analysis has defined two parallel genetic pathways that control dauer formation. By killing neurons in these mutants, we show that mutations in one of these genetic pathways disrupt dauer repression by ADF, ASI, and ASG. One gene in this pathway is daf-7, which encodes a TGFbeta-related protein. We find that daf-7::GFP fusions are expressed specifically in ASI and that expression is regulated by dauer-inducing sensory stimuli. We also show that a different chemosensory neuron, ASJ, functions in parallel to these neurons to induce dauer formation. Mutations in the second genetic pathway activate dauer formation in an ASJ-dependent manner. Thus, the genetic redundancy in this process is reflected at the neuronal level.

Animals↗