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Biomedical subjects

J H Thomas

Publications and source records attributed to J H Thomas.

At least 19 recordsLinked to original sources
PubMed1996

Squamous cell carcinoma of the esophagus.

The role of surgery as primary treatment for patients with squamous cell carcinoma of the esophagus (SCCE) has been challenged by an improved response rate for radiotherapy that is made possible by adding radiosensitizing chemotherapy. The purpose of our study was to review our institution's treatment results for SCCE and to compare results of radiation versus surgery as primary treatment of early stage disease. A retrospective chart review was done on 241 patients who were treated with SCCE at Kansas University Medical Center and affiliated hospitals between 1970 and 1990. Patients were divided into five groups based on treatment received: (A) No Treatment; (B) Surgery Only; (C) Surgery plus Adjuvant Chemoradiotherapy; (D) Radiation Therapy Only; and (E) Chemoradiotherapy. Surgical treatment groups B and C had the best overall survival of all groups. To reduce any bias due to stage differences in groups, survival of groups was assessed only for early stage disease patients (Stage I, IIa, IIb). For Stage I and II patients receiving surgery as primary treatment (groups B and C), 29 per cent had a survival at 5 years compared to patients receiving primary radiation treatment (groups D and E) who had a combined survival of only four per cent. Although attempting comparison of risk groups is always a problem in nonrandomized studies, it is significant that only one 5-year survivor was in the nonresection radiation treatment groups D and E. Surgical resection for SCCE had the best survival in our study, especially in patients with early stage disease.

Adult↗
PubMed1995

Thermosensation. Some like it hot.

The ability of organisms to respond to fluctuating temperatures is ubiquitous but poorly understood. Recent studies of nematodes reveal specific sensory neurons and interneurons that mediate thermotaxis.

Animals↗
PubMed1995

Genes that control a temperature-compensated ultradian clock in Caenorhabditis elegans.

Substantial progress has been made in understanding the genetic basis of temperature-compensated circadian clocks. Ultradian rhythms, with a period shorter than 24 h, are at least as widespread as circadian rhythms. We have initiated genetic analysis of defecation behavior, which is controlled by an ultradian clock in Caenorhabditis elegans. The defecation motor program is activated every 45 sec, and this rhythm is temperature compensated. We describe mutations in 12 genes that either shorten or lengthen the cycle period. We find that most of these mutations also disrupt temperature compensation, suggesting that this process is an integral part of the clock. These genes open the way for molecular genetic dissection of this ultradian clock.

Activity Cycles↗
PubMed1995

Genomic imprinting proposed as a surveillance mechanism for chromosome loss.

One consequence of genomic imprinting is that loss of the transcriptionally active chromosomal homologue causes a change in gene expression that might permit surveillance of chromosome-loss events. Possible selective advantages of such surveillance include protection against cancer and early elimination of monosomic and trisomic fetuses. Potential mechanisms for such surveillance are discussed.

Animals↗
PubMed1995

Mutations affecting the chemosensory neurons of Caenorhabditis elegans.

We have identified and characterized 95 mutations that reduce or abolish dye filling of amphid and phasmid neurons and that have little effect on viability, fertility or movement. Twenty-seven mutations occurred spontaneously in strains with a high frequency of transposon insertion. Sixty-eight were isolated after treatment with EMS. All of the mutations result in defects in one or more chemosensory responses, such as chemotaxis to ammonium chloride or formation of dauer larvae under conditions of starvation and overcrowding. Seventy-five of the mutations are alleles of 12 previously defined genes, mutations which were previously shown to lead to defects in amphid ultrastructure. We have assigned 20 mutations to 13 new genes, called dyf-1 through dyf-13. We expect that the genes represented by dye-filing defective mutants are important for the differentiation of amphid and phasmid chemosensilla.

Animals↗
PubMed1995

Analysis of dominant mutations affecting muscle excitation in Caenorhabditis elegans.

We examined mutations that disrupt muscle activation in Caenorhabditis elegans. Fifteen of 17 of these genes were identified previously and we describe new mutations in three of them. We also describe mutations in two new genes, exp-3 and exp-4. We assessed the degree of defect in pharyngeal, body-wall, egg-laying, and enteric muscle activation in animals mutant for each gene. Mutations in all 17 genes are semidominant and, in cases that could be tested, appear to be gain-of-function. Based on their phenotypes, the genes fall into three broad categories: mutations in 11 genes cause defective muscle activation, mutations in four genes cause hyperactivated muscle, and mutations in two genes cause defective activation in some muscle types and hyperactivation in others. In all testable cases, the mutations blocked response to pharmacological activators of egg laying, but did not block muscle activation by irradiation with a laser microbeam. The data suggest that these mutations affect muscle excitation, but not the capacity of the muscle fibers to contract. For most of the genes, apparent loss-of-function mutants have a grossly wild-type phenotype. These observations suggest that there is a large group of genes that function in muscle excitation that can be identified primarily by dominant mutations.

Animals↗
PubMed1995

Genetic and pharmacological analysis of neurotransmitters controlling egg laying in C. elegans.

We have investigated the neurotransmitters used to control egg-laying in C. elegans. Previous studies suggested that 5-HT released by the HSN motor neurons stimulates egg laying, and that tricyclic antidepressants potentiate egg laying by blocking reuptake of 5-HT by the HSN neurons. We report studies of the wild type and a mutant that lacks detectable 5-HT that suggest 5-HT is not required for egg-laying. Furthermore, we find that ACh is required for egg laying in response to 5-HT, suggesting that 5-HT is not sufficient to activate egg laying. The dominant egl-2(n693) mutation, which causes animals to lay eggs in response to tricyclics but not 5-HT, also conflicts with the model for egg laying. Experiments in which the HSN neurons or 5-HT are removed from egl-2 animals indicate that the action of tricyclics cannot be explained by a block of 5-HT reuptake. We find that D2 family dopamine antagonists can also induce egg laying in egl-2(n693) mutants, and that dopamine inhibits egg laying in the wild type. These results suggest that dominant egl-2 mutations activate an inhibitory dopaminergic pathway that can be blocked by tricyclics and D2 antagonists. We also find that these drugs stimulate egg laying in mutants lacking 5-HT or the HSN neurons, consistent with a target on the egg-laying muscles. In contrast to tricyclics, fluoxetine and other selective 5-HT reuptake inhibitors appear to be specific for 5-HT reuptake in C. elegans egg laying.

Acetylcholine↗
PubMed1995

Reversal of a muscle response to GABA during C. elegans male development.

In the C. elegans hermaphrodite the expulsion step of defecation depends on the coordinated contraction of three enteric muscle groups: the anal depressor muscle, the intestinal muscles, and the sphincter muscle. These muscles are activated by excitatory GABA neurotransmission. Mutations in 13 genes that affect activation of these enteric muscles have previously been identified. We show that the larval male defecates by contracting the same set of enteric muscles, and that these contractions require 12 of these 13 genes. However, near the end of the last larval stage, the male anal region undergoes a developmental change, including dramatic hypertrophy of the anal sphincter muscle and the opening of a cloacal canal. We find that this modified sphincter must now relax to permit defecation. In contrast to the larval male, we find that in the adult male only 2 of the 13 genes required for enteric muscle contraction, unc-25 and unc-47, are important for sphincter muscle relaxation. unc-25 and unc-47 are required for the synthesis and utilization of GABA. We also find that two other genes, unc-46 and unc-49, previously implicated in the inhibitory action of GABA on body-wall muscle, are also required for normal adult male sphincter relaxation. In these mutants, failure to relax the sphincter muscle results in a constipated phenotype, and killing the sphincter muscle rescues this phenotype. We also find that a GABA agonist or GABA itself can suppress the adult male sphincter relaxation defect of unc-25 mutants.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1994

Sequence of C. elegans lag-2 reveals a cell-signalling domain shared with Delta and Serrate of Drosophila.

The lin-12 and glp-1 genes of Caenorhabditis elegans encode members of the Notch family of transmembrane proteins. Genetic studies indicate that the lin-12 and glp-1 proteins act as receptors in specific developmental cell interactions and that their functions are partially redundant. lin-12 glp-1 double mutants display certain embryonic defects not found in either single mutant. The phenotype of this double mutant is called Lag, and recessive mutations in either of the genes lag-1 or lag-2 can also result in the Lag phenotype, indicating that these two genes may participate in the same cell interactions that require lin-12 or glp-1. We report here that lag-2 encodes a predicted transmembrane protein of 402 amino acids. The predicted extracellular region of lag-2 is similar to amino-terminal regions of Delta and Serrate, two Drosophila proteins that are thought to function as ligands for Notch. The region of similarity includes sequences related to epidermal growth factor (EGF) repeats. We have isolated lag2(sa37), a dominant allele that shows specific genetic interactions with lin-12. The sa37 mutation causes a Gly-->Asp change in a conserved residue of an EGF motif. Because of its overall structure, its sequence similarity to Delta and Serrate, and its genetic interactions, we suggest that lag-2 encodes an intercellular signal for the lin-12 and glp-1 receptors.

Amino Acid Sequence↗
PubMed1994

The role of pancreatojejunostomy in patients without dilated pancreatic ducts.

OBJECTIVE: To determine the safety and efficacy of longitudinal pancreatojejunostomy in patients with chronic pancreatitis and intractable pain who do not have a markedly dilated pancreatic duct. BACKGROUND: Ductal decompression by side-to-side, longitudinal pancreatojejunostomy has become the operation of choice for patients with chronic pancreatitis and intractable pain when the pancreatic duct is markedly dilated. However, markedly dilated pancreatic ducts are found in less than 40% of patients with disabling pain. PATIENTS AND METHODS: Twenty-eight consecutive patients with intractable pain from chronic pancreatitis, most of whom had minimal or no dilation of the pancreatic duct, were treated with side-to-side, longitudinal pancreatojejunostomy between 1970 and 1993. RESULTS: There were 18 (64%) males and 10 (36%) females. The mean age was 41 years (range 11 to 72). The etiologies for chronic pancreatitis were alcohol (82%), gallstones (7%), trauma (7%), and familial trait (4%). Intractable pain was present for a mean of 4 years (range 0.5 to 12). Thirteen patients (46%) were dependent on narcotics prior to surgery. Twenty-five patients (89%) had minimal (< 8 mm) or no dilation of the pancreatic duct and 3 (11%) had markedly dilated pancreatic ducts (> 10 mm). All experienced complete pain relief in the immediate postoperative period. Twenty-four patients (86%) have remained free of pain after a mean follow-up of 3.5 years (range 1 to 8). CONCLUSIONS: In patients with chronic pancreatitis and intractable pain, small pancreatic duct size should not be considered a contraindication to side-to-side, longitudinal pancreatojejunostomy.

Adolescent↗
PubMed1994

A screen for nonconditional dauer-constitutive mutations in Caenorhabditis elegans.

In Caenorhabditis elegans, formation of the developmentally arrested dauer larva is induced by high levels of a constitutively secreted pheromone. Synergy between two groups of incompletely penetrant dauer-constitutive (Daf-c) mutations has recently led to a proposal that these two groups of genes are partially redundant and function in two parallel pathways that regulate dauer formation. A possible weakness in this reasoning is that the mutations used to identify the synergy were specifically obtained as incompletely penetrant mutations. Here we use screens to identify new Daf-c alleles without any requirement for partial penetrance. Nevertheless, 22 of the 25 new mutations are incompletely penetrant mutations in 6 previously identified genes. Among these are mutations in daf-8 and daf-19, genes for which only one mutation had been previously identified. Also included in this group are three daf-1 alleles that do not exhibit the maternal rescue characteristic of other daf-1 alleles. Two of the 25 new mutations are fully penetrant and are alleles of daf-2, the one gene in which a fully penetrant mutation had been found earlier. Finally, one of the 25 new mutations is semidominant, temperature-sensitive, and identifies a new gene, daf-28. The results demonstrate that an incompletely penetrant Daf-c phenotype is characteristic of mutations in most Daf-c genes other than daf-2. This finding strengthens the hypothesis that a branched genetic pathway controls dauer formation.

Alleles↗
PubMed1994

Multiple chemosensory defects in daf-11 and daf-21 mutants of Caenorhabditis elegans.

Phenotypic analysis of the daf-11 and daf-21 mutants of Caenorhabditis elegans suggests that they have defects in components shared by processes analogous to vertebrate taste and olfaction. daf-11 and daf-21 mutations were previously shown to cause inappropriate response to the dauer-inducing pheromone. By mutational analysis and by disabling specific chemosensory sensilla with a laser, we show that neurons in the amphid sensilla are required for this pheromone response. Using behavioral assays, we find that daf-11 and daf-21 mutants are not defective in avoidance of certain non-volatile repellents, but are defective in taxis to non-volatile attractants. In addition, both mutants are defective in taxis to volatile attractants detected primarily by the amphid neuron AWC, but respond normally to volatile attractants detected primarily by AWA. We propose that daf-11 and daf-21 mediate sensory transduction for both volatile and non-volatile compounds in specific amphid neurons.

Alleles↗
PubMed1994

The role of pancreatogastrostomy following pancreatoduodenectomy for trauma.

The records of all patients undergoing pancreatogastrostomy after pancreatoduodenal resection at the University of Kansas Medical Center were reviewed. Five patients with a mean age of 26 years (range, 20-32 years) and severe penetrating (n = 3) or blunt (n = 2) traumatic injuries have required pancreatoduodenectomy followed by pancreatogastrostomy (n = 4) or pancreatogastrostomy alone (n = 1) since 1975. Their mean Trauma Score was 12 (range, 9-16). All five patients had soft, previously normal pancreatic glands without induration or ductal dilatation. The mean duration of surgery was 6 hours (range, 5-7 hours), mean blood loss was 7200 mL (range, 1,000-17,500 mL), mean transfusion requirements were 14 units of blood (range, 2-32 units), and mean hospital stay was 37 days (range, 11-90 days). Two patients developed right upper quadrant abscesses that required a second procedure. There were no pancreatic anastomotic leaks, fistulas, or other complications related to the pancreatogastrostomy. At last examination, all five patients were alive and well and had not developed endocrine or exocrine pancreatic insufficiency after a mean follow-up of 4 years (range, 1-9 months). Pancreatogastrostomy following pancreatoduodenectomy for trauma has not been previously reported. Our experience demonstrates that pancreatogastrostomy is a safe and expeditious method for handling the pancreatic remnant following pancreatoduodenectomy. Furthermore, the results of this study suggest that pancreatogastrostomy has several advantages over pancreatojejunostomy for restoring pancreato-intestinal continuity in trauma patients.

Accidents, Traffic↗
PubMed1994

Regulation of a periodic motor program in C. elegans.

A three-part motor program mediates a defecation every 45 sec in well-fed wild-type Caenorhabditis elegans. Individual worms maintain this 45 sec rhythm with an SD of about 3 sec. We present evidence that the defecation cycle is controlled by an endogenous clock, most likely a neuronal pattern generator. The phase of the behavioral rhythm can be reset like pattern generators in other animals. The rhythm was reset by stimulating a well-characterized neuronal circuit mediating response to light touch. Also, animals that spontaneously stopped feeding interrupted their defecation rhythms. When they resumed feeding these animals reactivated the motor program in phase with the previously established rhythm, indicating that an endogenous clock continues to run even when the behavior is not expressed. Control of the defecation rhythm is independent of expression of the motor program. Most previously isolated mutations that affect the motor program (Thomas, 1990) do not alter the rhythm of the behavior; the motor steps themselves are defective but not the timing of their activation. Laser kills of identified motor neurons that affect particular parts of the motor program also did not change the defecation rhythm. Another sensory stimulus, food, strongly modulates defecation behavior: animals away from food rarely activated the motor program, and food dilution resulted in a graded lengthening of the cycle period. To elucidate further the relationship between feeding and defecation rhythms we studied a mutation, dec-8(sa200), that caused worms to continue to activate the motor program in the absence of food. The mutant did not require the presence of food to activate the motor program, although food made the rhythm more precise. In the presence of food, dec-8(sa200) animals exhibited tandem activations of the defecation motor program; the principal activation was followed by a more variable second activation. Further experiments suggested that the tandem activations of the motor program are not due to the activity of multiple oscillators.

Activity Cycles↗
PubMed1993

Chemosensory regulation of development in C. elegans.

The dauer larva is a specialized third-larval stage of Caenorhabditis elegans that is long-lived and resistant to environmental insult. The dauer larva is formed in response to a high external concentration of a constitutively secreted pheromone. Response to the dauer-inducing pheromone of C. elegans is a promising genetic model for metazoan chemosensory transduction. More than 20 genes have been identified that are required for normal pheromone response. The functions of these genes include production of the pheromone, exposure of sensory neuron endings to the environment, structural and functional integrity of those sensory endings, and the capacity of sensory neurons to make appropriate output. Genetic evidence suggests that two partially redundant sensory pathways act in concert to control dauer formation. At least two classes of chemosensory neurons, ADF and ASI, are implicated in the pheromone response. On the basis of on these findings, a speculative model for the pheromone response is proposed. In this model, the neurons ADF and ASI are pheromone sensors that repress dauer formation in the absence of pheromone and derepress dauer formation in response to pheromone. It is currently unclear whether or not the two genetically defined sensory pathways both act in ADF and ASI.

Adaptation, Physiological↗
PubMed1993

Thinking about genetic redundancy.

Partial functional redundancy among genes is frequently observed in a wide range of organisms and processes, but the selective value of such redundancy is not immediately apparent. Any fully redundant function should be evolutionarily unstable: unless selection acts to maintain the redundancy it will tend to be lost by mutational drift. I discuss four possible mechanisms by which selection might act to maintain genetic redundancy.

Animals↗