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Small heat shock proteins (sHSPs) belong to a family of 12- to 43-kDa proteins that are ubiquitous and are largely conserved in amino acid sequence among all organisms. The principal heat-shock proteins that have chaperone activity (that is, they protect newly made proteins from misfolding) belong to five conserved classes: HSP100, HSP90, HSP70, HSP60 and the small heat-shock proteins (sHSPs). The sHSPs (which include alpha crystallin) can form large multimeric structures and have a wide range of cellular functions, including endowing cells with thermotolerance in vivo and being able to act as molecular chaperones in vitro; sHSPs do this by forming stable complexes with folding -or unfolding--intermediates of their protein substrates, probably the molten globule. This paper includes: a brief survey of the chaperone family, the small heat shock protein superfamily, transcription of sHSPs, sequence comparisons and structural models of small heat shock proteins--structural elements as potential drug targets, sHSPs as chaperone-like proteins, alpha crystallin chaperone-like activity, conformational diseases--the role of alpha crystallin small heat shock protein superfamily proteins, post-translational modification and useful pharmacological agents. Functionality of small heat shock proteins--targets and diseases where pharmacologically active agents are of importance, alpha crystallin--small heat shock proteins and prion diseases: specific targets for diagnostic tests and drug development, details of some specific small heat shock proteins as drug targets, structural and functional implications for treatment.

Hypermagnesemia is a well-known cause of hypotension and cardiac dysfunction but not well recognized is the induction of paralytic ileus. This report details the second and third adult patients reported with hypermagnesemia-induced paralytic ileus. The first patient was a 65-year-old white woman with normal renal function, who had consumed large amounts of magnesium citrate and milk of magnesia. As magnesium blood level fell from 5.1 mg/dl on admission to 2.4 mg/dl on day 3, the vomiting, obstipation, and abdominal distension resolved. The second patient was a 67-year-old woman with mild renal insufficiency, who consumed a large amount of Epsom salts containing magnesium sulfate to treat her constipation. Magnesium levels of 8.1 mg/dl on admission fell to below 3.1 mg/dl on the third hospital day and the paralytic ileus resolved. Mechanical obstruction was ruled out by colonoscopy, gastrographin enema, and barium small bowel series in both patients. Although the clinical findings of muscle weakness, flaccid paralysis, respiratory muscle paralysis or cardiac arrest due to hypermagnesemia are well described in the literature, intestinal smooth muscle dysfunction leading to paralytic ileus has only been reported in one other adult patient. The laboratory and clinical course of these two patients strongly suggest a causal relationship between hypermagnesemia and paralytic ileus.

In a series of 41 pancreatoduodenectomies the Whipple procedure was done in 27 patients and total pancreatoduodenectomy in 14 others with two postoperative deaths. Among 39 survivors, seven developed evidence of stomal ulcer 20 days to six years after operation; details of their courses are summarized. Proven stomal ulcer occurred in five of 14 patients who did not have concomitant vagotomy with pancreatoduodenectomy (36%). Each of these required vagotomy secondarily in management. When two patients with hematemesis in whom stomal ulcer was suspected but not proven are included, the incidence of stomal ulcer in nonvagotomized patients with pancreatoduodenectomy (7/14) is 50%. There were no stomal ulcers in patients with pancreatoduodenectomy who had concomitant vagotomy (0/25). It is logical to add the protective effects of vagotomy to pancreatoduodenectomy, especially when the disease process favors prolonged survival.

A clinical and body compositional study has been made of 150 patients with morbid obesity and their responses to four different dimensional alterations of jejunoileal bypass. Total body potassium was estimated by measuring 40K with the whole body counter and total body water by tritiated water dilution. Body compositional data derived from these measurements were compared in the 4 groups during followup periods up to 4 years and related to clinical results. Initially, patients were two or more times overweight due to excess (60 to 65%) body fat and increased hydration (21%) of lean tissues. The 80 end-to-end jejunoileal bypass procedures of Groups 3 and 4 (30 cm jejunum to 15 or 20 cm ileum) had better weight losses and clinical results in followup were rated "good" in 60% and 81% respectively. These results were accompanied by a greater degree of improvement in body composition than was observed in the other groups under study.

During the period 1952 to 1976 at Vanderbilt University Hospital 119 patients with pituitary-dependent hypercortisolism or Cushing's disease were studied. The less severe cases, which constitute a majority, were treated by pituitary irradiation with endocrinologic cure or improvement in two-thirds of the treated patients. Bilateral total adrenalectomy was reserved for the most severe cases and for failures of pituitary irradiation. In 29 patients with total bilateral adrenalectomy there was one postoperative death. Two of 28 survivors had incomplete relief of hypercortisolism and required additional therapy for its control. One patient with recent operation is improved and another with early improvement died suddenly at home three months after operation. The 24 other adrenalectomized patients, followed 6 months to 20 years, were considered endocrinologic cures of Cushing's disease. One patient in the group who had not received pituitary irradiation developed signs of expanding pituitary tumor after adrenalectomy (Nelson's syndrome) with satisfactory response to radiation therapy.

Fifty-nine patients with Cushing's syndrome, due to adrenocortical tumor, were studied and treated during the period 1953 through 1983 at Vanderbilt University Medical Center. Cushing's syndrome is caused by hypercortisolism that can be due to (1) medicinal use of steroids, (2) excess pituitary secretion of adrenocorticotropin (ACTH) (Cushing's disease), (3) adrenocortical tumor, benign or malignant, and (4) the ectopic ACTH syndrome. Clinical and endocrinologic features of Cushing's syndrome are described, and differential diagnosis of adrenocortical tumor by precise endocrinologic studies is detailed. Computerized axial tomographic (CAT) scan is currently the most accurate imaging modality for preoperative localization of tumors. Preoperative differential diagnosis between adrenocortical adenoma and carcinoma has become fairly accurate. Operative approaches in each category are described. Follow-up from 1 to 30 years has been completed for all patients, except for one who was lost after 7 years. Results of surgical treatment of adrenocortical adenomas are excellent, but the salvage from adrenocortical carcinomas is poor.

A comparative study has been made of three methods for the operative treatment of obesity. Of my own cases, 235 underwent a jejunoiliac bypass procedure, and the results have been analyzed: operative lethality 2.1%; postoperative complications 21%. Of the patients whose residual ileum was quite short (about 45 cm), about 70% reached their ideal weight. Metabolic late complications were considerable (e.g., liver damage in 15%, electrolyte deficit in 12%, and arthritis in 10%). In the late observation time of 14 years, 14 patients died, 10 of them as a result of the operation. Three different stomach-bypass procedures are described. The collective statistics compiled on 1585 patients indicated 1.6% postoperative lethality and 22% postoperative complications. Of the total patients. 90% were very satisfied with the procedure and in only 5% was a weight gain recorded after 5 years. The latest procedure is gastroplasty according to the Gomez method: the first 200 cases show 0.5% postoperative lethality and postoperative complications in 18.5%. Although this procedure is technically simple, the late observation time is not yet adequate for a definitive comparison.

Three patients with Menetrier's disease and protein-losing gastropathy who were studied during a 12 year period have been presented. The characteristic findings which differentiate them from patients with hypertrophic hypersecretory gastropathy, including the Zollinger-Ellison syndrome, are: 1) hypertrophy of gastric mucosa with giant rugal folds involving the fundus, cardia and body of the stomach but sparing the antrum; 2) muscosal hypertrophy consisting of gastric mjcus-secreting cells while parietal cells and chief cells are diminished in number and may be absent from many microscopic sections; 3) gastric secretion of large volume containing excess mucus, low to absent hydrochloric acid and protein concentration 5 or 6 times normal (1.7 mg/ml); 4) hypoalbuminemia and hypoglobulinemia due to loss of serum proteins fron gastric mucosa into the gastric lumen; 5) rare association with gastric ulcer. Unlike the Zollinger-Ellison syndrome none of our patients had duodenal ucler or multiple endocrine adenomatosis or a family history of these conditions. We have found no authenticated reports in the literature which document a relationship of Menetrier's disease ( as defined above) with multiple endocrine adenomatosis. Menetrier's disease with protein-losing gastropathy is a potentially lethal disorder of unknown cause with no specific treatment. Resection of the site of gastric protein losses as first done by Waugh is logical and effective. One of our three patients died in hospital before gastrectomy was done. Two others have done well for 11 months and 12 years, respectively, after total gastrectomy with Roux-en-Y esophagojejunostomy and Hunt-Lawrence jejunal pouch.

Coarctation of the aorta is the most frequent cause of hypertension in infants and children. Ninety-eight per cent of coarctations occur in the descending aorta near the ligamentum arteriosus. Five patients are presented with the relatively rare problem of coarctation of the abdominal aorta. The anatomic,pathophysiologic and clinical aspects in these patients cover a range of variants. Clinical and laboratory studies of the genesis of hypertension in coarctation are reviewed in chronologic outline. An experimental model of abdominal coarctation with hypertensive and renin-angiotensin II correlations suggests but does not prove a renal mechanism for the hypertension. The same conclusion must be drawn from study of the clinical cases.

From September 1925 through December 1978 at Vanderbilt University Hospital, 1,279 patients with adenocarcinoma of the colon and rectum underwent operations. Reports of this cumulative series have been published previously; the last report in 1970 included 1,022 patients. The current report examines the progress made in our recognition and management of colorectal cancer. During this 54-year period, there has been a relative decrease in the incidence of carcinoma of the rectum and a relative increase in carcinomas elsewhere in large bowel. Resectability rate has steadily increased, culminating in a rate of 98.4% in the recent period (1969-1978). The operative mortality rate fell to 4.3% (1956-1960) but has shown a slight rise to 5.4% in the recent period (1969-1978). This reflects the increased number of patients in the eighth to the tenth decades of life. Five-year survival rates in 99% of 1,218 patients were computed. Absolute five-year survival for the recent period was 43.7%, compared with 17% for the initial period. Five-year survival rates for patients in the recent decade with Dukes A, B, and C lesions were 67%, 58.6%, and 33.3%, respectively. Comparison of survival data in the last two decades shows little improvement. However, in the last 20 years, 78 to 80% of patients had more advanced lesions.

Psychological adaptation to jejunoileal bypass procedures in 34 morbidly obese patients was evaluated preoperatively and followed postoperatively for an average of 23 months. Preoperative emotional disturbances were mainly those of mild personality disorders with passive-aggressive, passive-dependent, and emotionally immature traits. Following discharge from the hospital, nine patients (or 24 per cent) developed psychiatric difficulties, characterized by either increased neurotic symptoms and interpersonal problems, or the emergence of psychosis. Male patients and those with the greatest weight loss were statistically more likely to have psychiatric complications. The remaining patients expressed satisfaction with the operation, noted relief from the burden of dieting, experienced less excitement associated with eating, and felt more self-confident and hopeful.

Gastroduodenostomy (Billroth I) is our reconstruction of choice following gastric resection for gastroduodenal ulcer. Dissatisfaction with a Billroth II anastomosis has led us in recent years to employ a Roux-en-Y diversion in selected cases, particularly those in which the pathologic state of the pyloroduodenal canal would render a Billroth I anastomosis unsafe. During the past 7 years, truncal vagotomy-antrectomy and Roux-en-Y (VARY) has been carried out in 50 selected patients: duodenal ulcer (DU) 13 patients, gastric ulcer (GU) 11 patients, and stomal ulcer (SU) 26 patients. Fourteen patients (28%) developed postoperative complications, of which nine (18%) were of major degree and five (10%) of a lesser degree. No hospital death occurred among the 50 patients. Five patients (10%) developed postoperative delayed gastric emptying and two of the five required revision of the Roux. Forty-five patients had no clinical problems with delayed emptying. Overall results showed a Visick grading of I in 72%, Visick II in 24%, and Visick III in 4%. Further analysis revealed that of the 13 patients with DU who had VARY, 62% were Visick I, 30% Visick II, and 8% Visick III. The 11 GU patients with VARY were graded Visick I 73% and Visick II 27%. Of 26 patients with SU who underwent VARY, 77% were Visick I, 19% Visick II, and 4% Visick III. Mild to moderate dumping took place in 8% of the 50 patients, mild diarrhea 10%, weight loss 10%, and no patient experienced alkaline reflux gastritis. Long-range postoperative gastric emptying studies among nine patients using a radionuclide revealed varying patterns of emptying. Overall clinical results have been satisfactory and we are continuing to use VARY in selected cases, particularly those in which a Billroth I reconstruction appears contraindicated.

Arthritis and other inflammatory processes are well established complications of intestinal bypass operations, and recently have been reported after other gastrointestinal procedures. Bacterial overgrowth in blind intestinal loops, actual or functional, appears to be the underlying pathophysiologic mechanism responsible for these systemic inflammatory disorders. In the case we have reported, arthritis was the primary manifestation of blind loop remaining after incomplete reversal of a jejunoileal bypass. Surgical elimination of the blind loop was curative.

Summary Congenital and acquired lesions of the mitral valve can produce symptoms of sufficient severity during the first two decades of life to warrant operation. During the past 8 years, 25 patients under the age of 21 years have required surgery for mitral valvular disease at the Vanderbilt University Medical Center. Sixteen patients had rheumatic mitral stenosis, and 1 patient had congenital mitral stenosis. The age range was from 8 to 20 years. Pulmonary hypertension was a constant finding in those patients who had cardiac catheterization. Transatrial or transventricular fracture of the mitral valve was possible for 14 patients, but open cardiotomy was necessary for 3 patients. Microscopic examination of the atrial appendage revealed an unexpectedly high incidence of active myocarditis. No patient died as a result of operation. All but 3 patients had sustained improvement postoperatively. Eight patients, ranging in age from 6 to 18 years, had surgical treatment for severely incapacitating mitral insufficiency. In 2 of the patients the lesion was congenital. Mitral annuloplasty was utilized in 2 early cases; both of these patients succumbed. Replacement of the mitral valve with a Starr prosthesis of adult size was accomplished in the other 6 patients. Four of these patients survived and are greatly improved. The two deaths occurred in patients with coexistent lesions which were simultaneously corrected. This study indicates the feasibility and generally good results following surgery for severe mitral valvular disease during childhood and adolescence.

A clinical trial of vagotomy and pyloroplasty in the treatment of benign gastric ulcer was performed in forty-eight patients. The incidence of recurrent gastric ulcers was 15 per cent. The results were satisfactory in patients undergoing emergency operation for massive bleeding from a gastric ulcer if the patient had not been on ulcerogenic drugs. However, the operation has not been as satisfactory as antral resection for the management of intractable gastric ulcer.

During the past five years 75 patients aged 90 years or more had 85 major surgical procedures at the Metropolitan Nashville General and Vanderbilt University hospitals. The most common operation was exploratory laparotomy. The second was lower extremity amputation for peripheral vascular disease and/or gangrene. Fifty-seven percent had general endotracheal anesthesia. Associated medical problems were common, and included congestive heart failure (24%), hypertension (21%), diabetes mellitus (13%), chronic arrhythmias (9%), history of myocardial infarction (8%), and history of cerebrovascular accident (5%). Eleven patients (13.4%), six of whom had general anesthesia, died after operation. Of these, two had postoperative pneumonia, two did not recover from bowel perforation and peritonitis, one had a postoperative myocardial infarction, another had a cerebrovascular accident, and one had sepsis. One patient's sudden death was likely due to myocardial infarction or pulmonary embolus. The other three deaths occurred in patients with extensive carcinomas (gallbladder carcinoma in one and widely metastatic carcinoma of unknown origin in two). These three patients died of the disease for which they were operated upon when the operation failed to alter its course. When surgical procedures are necessary to prolong and/or improve the quality of life in elderly patients, these procedures may be done in most cases with acceptable results.

Despite the rarity of chronic relapsing pancreatitis in children, in the last 15 years at Vanderbilt University Medical Center and its Children's Hospital we have used longitudinal pancreaticojejunostomy in treatment of eight patients whose symptoms began in childhood. Duration of symptoms ranged from 2 to 36 years. Seven of the eight patients had hereditary pancreatitis. Recurrent epigastric pain was characteristic and serum amylase was elevated in all patients on admission or shortly thereafter. Demonstration of an obstructed dilated pancreatic duct in all and stones in seven of eight patients by operative pancreatography in three early patients and by endoscopic retrograde cholangiopancreatography (ERCP) in five others established the therapeutic problem and facilitated treatment by removal of stones and longitudinal pancreaticojejunostomy. Results were uniformly excellent, both in the early postoperative period and in long-range follow-ups. Early diagnosis and early surgical drainage of the obstructed pancreatic duct by longitudinal pancreaticojejunostomy are desirable objectives in chronic relapsing pancreatitis with onset in childhood.

The incidence of sarcomas of the gastrointestinal tract has remained the same, but gastrointestinal lymphomas are gradually contributing a larger percentage of malignant gastrointestinal neoplasms. The authors have examined their more recent experience with these relatively rare lesions. Twenty-eight patients (13 with lymphoma, 15 with sarcoma) have been treated at the Vanderbilt University and the Metropolitan Nashville General Hospital since 1976. There were eight men in the group with lymphoma and six in the group with sarcoma. The average age for patients with lymphoma was 66 years; the average age was 57 years in the patients with sarcoma. Seven patients with lymphoma and eight patients with sarcoma had been treated for 6 months to 3 years for presumed peptic ulcer disease. Eight of these 15 patients were found to have perforated tumors at the time of surgical exploration. Three patients (all in the group with sarcoma) had metastatic liver disease or peritoneal implants at the time of diagnosis. Treatment for most patients included resection of the tumor, followed by chemotherapy or radiation in cases of tumor perforation or metastatic disease. The survival rate for patients with lymphoma has averaged 5.5 years, with a 55% 5-year survival rate. Patients with cleaved cell tumors survived longer than those with other types of lymphoma. In the group with sarcoma, the survival rate has been 3.1 years on the average, with a 21% 5-year survival rate.

A role for bacterial colonization of the intestines in the pathogenesis of hepatic abnormalities after jejunoileal bypass was sought. Dogs were divided into groups according to the disposition of the bypassed segment; resection (group I), exteriorization as an ileal mucous fistula (group II), and drainage via an ileocolonic anastomosis (group III). Weight loss, abnormalities in liver function, and hepatic steatosis were significantly greater in groups II and III than in group I. Concomitantly, there was a significant increase in the total number of bacterial colony-forming units in groups II and III. Moreover, a greater number of specific anaerobic genera was isolated in group III than in group II. It is concluded that: (1) retention of the bypassed intestinal segment is associated with greater changes in liver function and structure than when the segment is resected; (2) the changes in the liver correlated with bacterial proliferation in the bypassed intestinal segment; and (3) despite a greater number of anaerobic genera in the ileocolostomy than in the mucous fistula, both procedures were associated with hepatic abnormalities.

During the past two years, six patients with systemic mastocytosis have required general or regional anesthesia for operative correction of various surgical problems. Mastocytosis constitutes an extremely difficult problem in diagnosis and management. A large experience with patients with mastocytosis in the Vanderbilt Medical Center in the last decade has enhanced awareness of this disorder and increased its early recognition. The hazardous problems of systemic mastocytosis and the difficulties of its diagnosis and management are summarized and focussed on the increased hazard of those patients with this disease who require various surgical operations. Close collaboration between anesthesiologists, surgeons, and internists in this medical center in the past two years has made it possible to carry six of these patients through anesthesia, operation, and the postoperative period safely and without fatality.