Biomedical subjects
Publications and source records attributed to J H Thomas.
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.
Of 35 patients with primary duodenal carcinoma (PDC), 13 were treated between 1960 and 1974 (group I) and 22 between 1975 and 1990 (group II). PDCs were found in the first 5 portions of the duodenum (14%), second 18 (51%), third 8 (23%), and fourth 4 (12%). Five patients (38%) in group I were deemed to have unresectable disease compared with only one patient (5%) in group II. Eight patients (62%) in group I underwent resection by either pancreatoduodenectomy (4) or segmental resection (4), and 20 patients (95%) in group II had pancreatoduodenectomy (17) or segmental resection (3). Operative mortality was 31% in group I and 0% in group II. Mean survival was 7 months (range: 0 to 22 months) in group I and 48 months (range: 6 to 218 months) in group II. None of the patients in group I survived for 2 years, whereas the 5-year survival for patients in group II was 62%. This experience suggests that resectability, operative mortality, and survival in patients with PDCs have improved markedly in recent years.
Thrombosis of the central venous system (CVT) occurs in 20% to 30% of patients with indwelling catheters. This complication is usually treated with anticoagulation, extremity elevation, and catheter removal. Thirty-eight patients with CVT at our institution were treated with thrombolytic therapy to rapidly resolve symptoms and avoid removal of the catheters. Complete clot lysis occurred in 36 of 38 patients (95%) within 1 to 5 days (mean: 2.4 days). Symptoms resolved with clot resolution. Thrombolytic therapy detected stenoses in 22 patients. Angioplasty was successful in 64% of these patients. Five catheters were removed. Complications occurred in six patients: nonfatal pulmonary embolus, three bleeding episodes, pain with infusion of urokinase, and an episode of septic phlebitis. This experience suggests that thrombolytic therapy is safe, rapidly resolves symptoms of thrombosis, uncovers anatomic abnormalities amenable to angioplasty, and allows central venous catheters to remain in place despite central venous thrombosis.
Between January 1980 and June 1990 we treated 21 patients with invasive carcinoma of the bladder and abdominal aortic aneurysm. Three distinct groups of patients were identified. Group 1 comprised 8 patients who were initially diagnosed with invasive bladder cancer and during cancer staging a concomitant abdominal aortic aneurysm was found. Group 2 consisted of 10 patients previously treated for invasive bladder cancer who had aneurysmal disease at a later date. Group 3 included 3 patients who underwent a previous aneurysm repair and subsequently had invasive carcinoma of the bladder. Total survival was 9 of 21 patients (43%) with a mean of 84 months of followup after initial diagnosis. This finding is comparable to long-term (greater than 5 years) survival in patients with invasive carcinoma of the bladder alone. In fact, none of the 21 patients studied experienced rupture of the aneurysm and/or died of aneurysmal disease. We found that patients with abdominal aortic aneurysm and invasive bladder cancer have a poor overall prognosis. Although aneurysm repair presents technical challenges, mortality is dependent upon the carcinoma and other vascular or medical diseases, and does not bear direct relationship to abdominal aortic aneurysm.
Dauer formation in Caenorhabditis elegans is induced by chemosensation of high levels of a constitutively secreted pheromone. Seven genes defined by mutations that confer a dauer-formation constitutive phenotype (Daf-c) can be congruently divided into two groups by any of three criteria. Group 1 genes (daf-11 and daf-21) are (1) strongly synergistic with group 2 genes for their Daf-c phenotype, (2) incompletely suppressed by dauer-formation defective (Daf-d) mutations in the genes daf-3 and daf-5 and (3) strongly suppressed by Daf-d mutations in nine genes that affect the structure of chemosensory endings. Group 2 genes (daf-1, daf-4, daf-7, daf-8 and daf-14) are (1) strongly synergistic with group 1 genes for their Daf-c phenotype, (2) fully suppressed by Daf-d mutations in daf-3 and daf-5 and (3) not suppressed by Daf-d mutations in the nine genes that affect chemosensory ending structure. Mutations in each group of genes also cause distinct additional behavioral defects. We propose that these two groups of Daf-c genes act in parallel pathways that process sensory information. The two pathways are partially redundant with each other and normally act in concert to control dauer formation.
Two hundred forty-five women (250 breasts) with early-stage breast cancer were treated between June 1982 and June 1990 with lumpectomy, immediate (boost) interstitial iridium-192 to 15-20 Gy, and external-beam irradiation to the entire breast to 45-50 Gy. There were 123 stage I cancers (T1N0M0), 123 stage II cancers (36 T1N1, 50 T2N0, 33 T2N1, four T3N0), and four stage III cancers (two T2N2, two T3N1). At a median follow-up of 69 months (range, 26-122 months), there were 14 recurrences in the treated breasts. Four were at the site of primary disease, eight were in other quadrants, and two were in both. With immediate interstitial boost, the 11-year actuarial recurrence rate in the breast is 7.7% and the recurrence rate at the site of primary disease is 3.2%.
Local-regional recurrences of the pelvis occur as an isolated event in 4 to 24 per cent of rectal cancer patients. While radiation therapy may provide temporary relief of pain due to recurrence, only a salvage pelvic exenteration offers hope of cure in these patients. We identified and reviewed 16 rectal cancer cases with local-regional recurrence who underwent salvage pelvic exenteration for cure. There were eight men and eight women. The primary cancer was treated by AP resection (3), low anterior resection (6), Hartman's resection (6), or local excision (1). Tumor at primary resection was Stage I for two patients, II for five patients, and nine patients were Stage III. Adjuvant radiation had been given to nine patients. The type of exenteration required for curative resection was anterior (3), posterior (6), total (4), or total-sacral (3). One patient died postoperatively. Survival calculations were from time of salvage exenteration until death or last follow-up. Only six deaths have occurred with a 5-year survival of 49 per cent. Mean survival for the total group was 31 months. Salvage pelvic exenteration should be given high priority in managing local-regional recurrences of the pelvis and provides worthwhile survival.
Twenty-one patients with pancreatic cystic neoplasms (PCNs) were treated from 1970 to 1991. Their mean age was 54 years (range: 30 to 78 years), and 15 (71%) were women. Symptoms were present for a mean of 18 months (range: 5 to 60 months) and included pain (95%), abdominal mass (52%), weight loss (38%), and jaundice (14%). Nine patients had had previous operations and were either misdiagnosed or incorrectly treated; another seven patients had preoperative misdiagnoses of pseudocysts. There were six (29%) serous cystadenomas and two (10%) mucinous cystadenomas. These were treated by excision (n = 2), distal pancreatectomy (n = 5), or pancreatoduodenectomy (n = 1). No recurrence or malignant degeneration occurred during the mean follow-up of 9 years (range: 1 to 19 years). There were 13 (62%) patients with mucinous cystadenocarcinomas. Of these 13 patients, 3 had unresectable tumors, underwent palliative procedures, and died at 4, 7, and 9 months, respectively. Ten patients underwent pancreatoduodenectomy (n = 4), distal (n = 4) pancreatectomy, or total (n = 2) pancreatectomy: 1 died of recurrence (survival: 8 months), and the remaining 9 patients had a mean survival of 6 years (range: 2 to 20 years) without recurrence. This experience suggests that patients with PCNs have a good prognosis and are curable if the cysts are diagnosed early and completely resected.
Fifty patients were studied prospectively to determine the value of diagnostic peritoneal lavage in the evaluation of acute peritonitis. Forty-five patients had a clinical diagnosis of acute peritonitis based on physical findings, and 5 patients were normal control subjects. All lavages were performed with an open technique in the operating room prior to laparotomy. Lavage fluid was analyzed for white and red blood cell counts, the differential, amylase, protein, bilirubin, and pH. Results were analyzed by multiple logistic regression. Thirty-two of the 45 patients with clinical peritonitis had the diagnosis confirmed at laparotomy. A white blood cell count in the lavage fluid greater than or equal to 200 cells/mm3 was associated with a 99% probability of peritonitis.
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Dauer larva formation in Caenorhabditis elegans is controlled by chemosensory cells that respond to environmental cues. Genetic interactions among mutations in 23 genes that affect dauer larva formation were investigated. Mutations in seven genes that cause constitutive dauer formation, and mutations in 16 genes that either block dauer formation or result in the formation of abnormal dauers, were analyzed. Double mutants between dauer-constitutive and dauer-defective mutations were constructed and characterized for their capacity to form dauer larvae. Many of the genes could be interpreted to lie in a simple linear epistasis pathway. Three genes, daf-16, daf-18 and daf-20, may affect downstream steps in a branched part of the pathway. Three other genes, daf-2, daf-3 and daf-5, displayed partial or complex epistasis interactions that were difficult to interpret as part of a simple linear pathway. Dauer-defective mutations in nine genes cause structurally defective chemosensory cilia, thereby blocking chemosensation. Mutations in all nine of these genes appear to fall at a single step in the epistasis pathway. Dauer-constitutive mutations in one gene, daf-11, were strongly suppressed for dauer formation by mutations in the nine cilium-structure genes. Mutations in the other six dauer-constitutive genes caused dauer formation despite the absence of functional chemosensory endings. These results suggest that daf-11 is directly involved in chemosensory transduction essential for dauer formation, while the other Daf-c genes play roles downstream of the chemosensory step.
Glomerulopathy and nephrotic syndrome were induced in rats by intravenous puromycin aminonucleoside. Ten days after the injection of puromycin, the animals have developed heavy proteinuria. During this phase, glomerular epithelial cell endocytosis was studied by injecting a conjugate of horseradish peroxidase and poly-L-lysine. This conjugate has been shown to be endocytosed by glomerular epithelial cells. The rats were serially sacrificed from 1 min to 24 h after this injection. Peroxidase was localised cytochemically and observed at light and electron microscopy. The early events of endocytosis in glomerulopathy (namely the binding to the plasma membrane, the membrane invagination and the formation of the early vesicles) were qualitatively similar to those in the normal. The later events (the fusion of the vesicles and their movement within the cells) were inhibited. The results show that puromycin aminonucleoside damages epithelial cell endocytotic activity and affects the later processing of the conjugate within the cells.
We describe two different cell interactions that appear to be required for the proper development of a pair of bilaterally symmetrical cells in Caenorhabditis elegans called the intestinal valve cells. Previous experiments have shown that at the beginning of the 4-cell stage of embryogenesis, two sister blastomeres called ABa and ABp are equivalent in development potential. We show that cell interactions between ABp and a neighboring 4-cell-stage blastomere called P2 distinguish the fates of ABa and ABp by inducing descendants of ABp to produce the intestinal valve cells, a cell type not made by ABa. A second cell interaction appears to occur later in embryogenesis when two bilaterally symmetrical descendants of ABp, which both have the potential to produce valve cells, contact each other; production of the valve cells subsequently becomes limited to only one of the two descendants. This second interaction does not occur properly if the two symmetrical descendants of ABp are prevented from contacting each other. Thus the development of the intestinal valve cells appears to require both an early cell interaction that establishes a bilaterally symmetrical pattern of cell fate and a later interaction that breaks the symmetrical cell fate pattern by restricting to only one of two cells the ability to produce a pair of valve cells.
Aortoesophageal fistula is a rare, frequently fatal cause of upper gastrointestinal bleeding. Although several causes have been described, it appears that the most common cause is rupture of a thoracic aortic aneurysm into the esophagus, occurring in approximately 12% of thoracic aneurysm ruptures. Although the entity was originally described in 1818, the diagnosis has rarely been made before death, and until 1983 no one survived surgery for aneurysm-associated aortoesophageal fistulas. Since that report of two cases, only two other survivors, including this patient, have been reported. Included herein is the report of a successfully managed case, along with a discussion of the causes, clinical features, and diagnostic approach to the disease, as well as the management of both the aortic and esophageal components of the fistula.
Forty-two patients (age range: 70 to 86 years) underwent pancreaticoduodenectomy between 1970 and 1990 for carcinomas of the pancreas (23), ampulla (8), common bile duct (5), duodenum (5), or islet cells (1). After resection, reconstruction was done by either pancreaticojejunostomy (13) or pancreaticogastrostomy (25); four patients had total pancreatectomy. The mean duration of operation was 5 hours, the mean blood loss was 2,200 mL, the mean transfusion requirement was 4 units of blood, and mean length of hospitalization was 22 days. There were no leaks or other complications related to the pancreatic anastomoses. Six (14%) major complications occurred including two (5%) operative deaths. Mean survival was 42 months (range: 2 to 219 months) for the entire group and 35 months for patients over the age of 80. This experience suggests: (1) pancreaticoduodenectomy can be performed with low operative morbidity and mortality in elderly patients, and advanced age should not be considered a contrainindication to this potentially curative procedure; (2) pancreaticogastrostomy is a safe and easy alternate method of reconstruction; and (3) prolonged survival is possible for elderly patients following pancreaticoduodenectomy for malignant pancreatic and periampullary neoplasms.
Twenty-two patients with groin or incisional pain and normal physical examinations underwent herniography. Eight patients were found to have 11 unsuspected hernias. Seven were direct, two indirect, and two incisional. Six of nine groin hernias were recurrent. Exploration confirmed the herniographic findings in all patients. Follow-up evaluation of patients undergoing herniorrhaphy revealed resolution of symptoms. Ten of the 14 patients with normal herniograms were asymptomatic 3 months after herniography. In these 22 patients, herniography resulted in a savings of $31,000. We conclude that herniography is cost-effective and useful in patients with abdominal wall pain of obscure etiology.
Twelve patients underwent transabdominal, supraceliac aortomesenteric bypass for celiac and superior mesenteric artery occlusive disease. Nine patients had bypass for intestinal ischemia (five acute, four chronic), and one patient each had bypass for arcuate ligament syndrome, thoracoabdominal aneurysm, and an infected aortic stump "blowout." Three aortoceliac, 9 aortohepatic, and 10 aortosuperior mesenteric artery bypasses were performed. Prosthetic grafts were used for the bypasses in 11 of the 12 patients. One death occurred in a patient with preexisting hepatic necrosis and renal failure secondary to acute mesenteric ischemia. During a mean follow-up of 26 months, one graft thrombosis occurred and required revision for recurrent symptoms. Supraceliac aortomesenteric bypass appears to be a safe and effective procedure for visceral revascularization.
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