Increased acylCoA-cholesterol ester acyltransferase activity in gallbladder mucosa in patients with gallbladder cholesterolosis

OBJECTIVE: Although cholesterolosis of the human gallbladder is a relatively common disease, its etiology has not been fully understood. The aim of this study was to determine this etiology. METHODS: The lipid composition of the gallbladder mucosa and gallbladder bile and the enzyme activities (acylCoA-cholesterol ester acyltransferase [ACAT] and cholesterol ester hydrolase [CEH]) of the gallbladder mucosa were measured in control subjects, patients with cholesterolosis, and patients with cholesterol gallstone disease. RESULTS: Levels of cholesterol ester in gallbladder mucosa in patients with cholesterolosis (n = 12) were higher than those in control subjects (n = 8). With regard to the lipid content in gallbladder bile, no differences were found in concentrations of cholesterol, phospholipids, and bile acids among control subjects (n = 11), patients with cholesterolosis (n = 13), and those with cholesterol gallstone disease (n = 15). In gallbladder mucosa, ACAT activity was significantly higher in patients with cholesterolosis (n = 10) than in control subjects (n = 8), whereas CEH activity did not differ between the two groups. As a result, the ACAT/CEH activity ratio was higher in patients with cholesterolosis than in control subjects. CONCLUSIONS: It would be suggested that cholesterol ester synthesis of gallbladder mucosa might play an etiological role in the development of cholesterolosis.     

Effects of ursodeoxycholic acid therapy on in vitro gallbladder contractility in patients with cholesterol gallstones

PURPOSE: Ethambutol is an essential medication in the management of tuberculosis. However, it can cause an optic neuropathy of uncertain etiology. Ethambutol toxicity was therefore studied in rodent retinal cells, and agents that might block its toxicity were considered. METHODS: The toxicity of ethambutol and related agents was evaluated in rodent retinal dissociated cell preparations and whole eyes. Calcium fluxes and mitochondrial function were evaluated by fluorescent and staining techniques. For in vivo assays, adult rats were administered oral ethambutol over a 3-month period. Cell survival was assessed by stereology. RESULTS: Ethambutol is specifically toxic to retinal ganglion cells in vitro and in vivo. Endogenous glutamate is necessary for the full expression of ethambutol toxicity, and glutamate antagonists prevent ethambutol-mediated cell loss. Ethambutol causes a decrease in cytosolic calcium, an increase in mitochondrial calcium, and an increase in the mitochondrial membrane potential. CONCLUSIONS: The visual loss associated with ethambutol may be mediated through an excitotoxic pathway, inasmuch as ganglion cells are rendered sensitive to normally tolerated levels of extracellular glutamate. Ethambutol perturbs mitochondrial function. Its toxicity may depend on decreased ATPase activity and mitochondrial energy homeostasis. Glutamate antagonists may be useful in limiting the side effects seen with ethambutol.     

Cerebrospinal fluid findings in asymptomatic patients with reactive serum fluorescent treponemal antibody absorption tests

It is common to examine the cerebrospinal fluid in untreated or inadequately treated asymptomatic patients with a reactive serum fluorescent treponemal antibody absorption (FTA-ABS) test before initiating antibiotic therapy for syphilis. This prospective study evaluated the usefulness of such examination. Four hundred thirty-two patients over 40 years old, reporting for annual physical examination, had a serum FTA-ABS test. Thirty-seven (8.6%) patients and 2 of 4 spouses were reactive repeatedly. Of the 39 patients with reactive tests, 7 had a history of penicillin therapy for syphilis, 5 had received heavy metal therapy, and 27 had no history of syphilis. These 39 patients had a neurological examination, serum VDRL, Treponema pallidum immobilization (TPI), and repeat FTA-ABS tests by two other laboratories. The TPI test was reactive in 30 (77%). Four had nonspecific neurological signs. Routine CSF examination (cells, total protein, VDRL, glucose, IgG%) on 30 patients with a history of inadequate treatment had a low diagnostic yield. Two patients had an unexplained total protein elevation (57 and 61 mg/dl) and 1 had a mildly increased IgG% (15%). All cell counts, VDRL tests, and glucose levels were normal. Agarose electrophoresis demonstrated one or more CSF immunoglobulin bands in 10 (36%) of 28 patients, possibly representing an immunological marker of past or latent central nervous system infection.     

Biliary electrolytes and enzymes in patients with and without gallstones

pH, osmolarity, various electrolytes, nine enzymes, and bile acid were determined in hepatic and gallbladder biles from 108 and 100 patients, respectively, relating to various types of gallstones. The pH, osmolarity, and electrolytes were essentially identical in all groups of patients except for slightly higher Ca and Mg in the hepatic bile in patients with muddy pigment stones. The gallbladder bile contained much higher inorganic cations yet remained isosmotic as a result of their sequestration into bile acid micelles. Excluding extremely high values, the activities of nine enzymes in the bile showed only minor differences among four groups of patients except for a high beta-glucuronidase activity in the hepatic bile in patients with muddy pigment stones. The biliary baseline activities of various enzymes and the relation to their serum levels were determined by their sources and subcellular localization in the hepatocytes. We concluded that biliary electrolytes and enzymes were basically similar in patients with and without gallstones except for higher levels of Ca, Mg, and beta-glucuronidase in hepatic bile in patients with muddy pigment stones.     

Fundoplication for major reflux in patients with gallstones

Patients referred with gallstones were screened for symptoms of reflux. Positive clinical history led to investigation with an upper gastrointestinal series as well as esophageal pH and manometric studies to identify and quantify reflux. Selected patients with symptomatic reflux in whom major or surgical reflux was discovered underwent the combined procedures of cholecystectomy and fundoplication. In all, 250 patients with gallstones were screened. Sixty patients with symptoms of reflux were considered for further study; of that group, 48 patients had major reflux, 38 of whom underwent the combined operative procedures. Fundoplication alone or in combination with cholecystectomy was carried out on 126 occasions upon 121 patients without a death. The combination of fundoplication and cholecystectomy did not prolong the hospital stay significantly, did not materially increase the incidence of postoperative complications and did not compromise the control of reflux symptoms. The postfundoplication syndrome did not occur following the combined procedures and was observed in only one patient in the entire series. Results of our study justify the liberization of indications for fundoplication in selected patients with gallstones who fulfill the criteria of major reflux, as already outlined.     

Histological and functional studies of small intestinal mucosa in intestinal tuberculosis

Twelve cases of peptic ulcer with diabetes mellitus were found in 165 hospitalized diabetics. All of them had gastric ulcer and no duodenal ulcers were found. The incidence of peptic ulcer in diabetics was comparatively higher than the previously reported series. But there was nosignificant correlation between the duration of diabetes and the onset of gastric ulcer. The gastric ulcer with poorly controlled diabetes showed more intractability than those without triopathy and well-controlled diabetes.     

Gastric emptying in control subjects and patients with duodenal ulcer before and after vagotomy

The emptying of a solid meal labelled with Indium 113mDTPA from the stomach was studied with a gamma camera in 26 normal subjects, 27 patients with duodenal ulcer, on 41 occasions after truncal vagotomy and pyloroplasty and 38 times after highly selective vagotomy. Applying the method of principal component analysis to the results, differences were detected between control and duodenal ulcer subjects and two probable subgroups of duodenal ulcer were observed. Half emptying times did not reveal these patterns. After vagotomy, delayed emptying was general at one week. At one month, patients after highly selective vagotomy had a more normal result than those with truncal vagotomy and pyloroplasty (TV), but by six months no significant difference in overall emptying rate was found, although changes in the pattern of gastric emptying persisted in some patients after TV.     

Divergent association of apolipoprotein E polymorphism with vascular disease in patients with NIDDM and control subjects

We analysed a well-characterized group of 83 patients (43 men, 40 women; mean age +/- SEM: 65.5 +/- 0.6 years at the 10-year examination) with non-insulin-dependent (Type 2) diabetes mellitus (NIDDM) and in 123 control subjects (56 men, 67 women; mean age +/- 0.9 years) retrospectively for the relationship of apolipoprotein E (apo E) genotypes (E2/3, E3/3 vs E3/4, E4/4) to the incidence of clinical macrovascular disease and its risk factors and the incidence of microvascular complications of diabetes during the first 10 years of NIDDM, as well as carotid intima-media thickness measured by B-mode ultrasound at the 10-year examination. In patients with NIDDM, apo E4 genotype showed no relationship to clinical events or carotid intima-media thickness. However, in the control subjects with apo E4, the incidence of non-fatal myocardial infarction during the follow-up was increased (apo E4 positivity: 17.1%; apo E4 negativity 5.1%; p = 0.035) and they had higher common carotid intima-media thickness than those with apo E2/3 or apo E3/3 (1.15 +/- 0.05 mm vs 1.01 +/- 0.03 mm, p = 0.008). Apo E genotype groups showed no relationship to microvascular complications of diabetes, although control subjects with apo E4 positivity showed a higher frequency of microalbuminuria than those lacking apo E4. We conclude that apo E4 was a marker of vascular disease and increased atherosclerosis in non-diabetic subjects, whereas in the diabetic patients these relationships were absent. It is likely that NIDDM per se influences the vascular risk so overwhelmingly that the effects of other risk factors are obscured.     

The elevated mRNA content as a potential indicator of precancerous states of the gallbladder mucosa in patients with pancreaticobiliary maljunction

Pancreaticobiliary maljunction (PBM) patients have a high incidence of cancer in the gallbladder. In the present study, we showed that precancerous lesions in the gallbladder of PBM such as hyperplasia or metaplasia, indicated high concentration of the amount of total mRNA. The mRNA content could be easily measured by our new technique utilizing a GenePlate, which is a poly (dT) oligonucleotide immobilized plastic plate, and Yoyo-1, a fluorescent DNA intercalator. To standardize the mRNA contents, we utilized which was defined as the ratio of total mRNA contents to total nucleic acids in a same sample. The mRNA index of the proliferating cells was significantly higher than that of the resting cells, and the mRNA index of cancer cells, such as gastric cancer, colon cancer, bile duct cancer, and gallbladder cancer also showed significantly higher concentration than that of normal mucosa. In the study of precancerous lesion, PBM, the mRNA index was significantly higher than that of mild cholecystitis but less than that of gallbladder cancer, suggesting that in the gallbladder mucosa of PBM, a precancerous state was able to be diagnosed by the mRNA index.     

Behavior of various cholesterol crystals in bile from patients with gallstones

Besides classical plate-like cholesterol monohydrate crystals, a variety of crystal shapes have recently been described in model biles but their relevance for human gallstone formation is unknown. We therefore studied crystallization behavior in gallbladder bile from cholesterol stone patients (54 untreated, 13 ursodeoxycholate-treated) and 6 pigment stone patients. Bile preparation by ultrafiltration or ultracentrifugation left biliary lipid composition unchanged but plates and their aggregates, and arcs and needles crystallized more extensively while spirals and tubules crystallized less extensively in ultra-centrifuged bile than in ultrafiltered bile. Plates, aggregates, and arcs/needles were seen in 90 percent, 36 percent, and 18 percent of the cases respectively of fresh unfiltered biles of untreated cholesterol stone patients, while spirals and tubules were always absent. In ultrafiltered biles arcs/needles, plates and aggregates progressively developed as persistent forms. Spirals and tubules occurred transiently and were associated with increased deoxycholic acid (+41 percent, P = .039) and with more extensive cholesterol crystallization. Rate/extent of crystallization of all crystal forms was higher (P < .0001) for multiple than solitary cholesterol stone patients. Ursodeoxycholate-treated patients had atypical platelike cholesterol crystals in fresh unfiltered biles that decreased in size at prolonged observation and in 2 cases even dissolved after 15 and 20 days. No crystals ever developed in ultra-filtered bile of ursodeoxycholic acid (UDCA)-treated patients during 21 days. Pigment stone patients seldom developed crystals. Thus, plates, aggregates and arcs/needles are persistent forms with high crystallization rate in multiple cholesterol stone patients. Tubules and spirals are transient forms that are associated with more extensive crystallization. Patients treated with ursodeoxycholate often have atypical crystals in their fresh bile.     

Histological features of the contralateral ovary in patients with unilateral ovarian cancer: a case control study

It has been suggested that schizophrenia and alcoholism are associated with violent behavior. But so far there are no published studies from unselected cohorts quantifying the actual risk associated with schizophrenia both with and without comorbid alcoholism. In this study, an unselected birth cohort (n = 11,017) was prospectively followed to the age of 26, and data on psychiatric disorders and crimes were collected from national registers. The odds ratios for violent offenses and recidivism were calculated for each diagnostic group. Men who abused alcohol and were diagnosed with schizophrenia were 25.2 (95% confidence interval (CI) 6.1-97.5) times more likely to commit violent crimes than mentally healthy men. The risk for nonalcoholic patients with schizophrenia was 3.6 (95% CI 0.9-12.3) and for other psychoses, 7.7 (95% CI 2.2-23.9). None of the patients with schizophrenia who did not abuse alcohol were recidivists (> 2 offenses), but the risk for committing more crimes among alcoholic subjects with schizophrenia was 9.5-fold (95% CI 2.7-30.0). This study suggests that to prevent the crimes being committed by people with schizophrenia, it is important that clinicians watch for comorbid alcohol abuse.     

General health factors and denture function in patients with burning mouth syndrome and matched control subjects

A total of 30 denture-wearing patients with burning mouth syndrome (BMS) referred to a Pain Clinic Unit and 26 age- and sex-matched control subjects were examined and compared with respect to general health factors and denture function. The study demonstrated a significantly higher frequency of multiple chronic diseases, psychosocial stress factors, and tenderness/pain in masticatory, neck, shoulder, and suprahyoid muscles in patients with BMS. Denture function differed also between the two groups as patients with BMS had significantly less daily use of dentures, reduced tongue space, incorrect placement of occlusal table and increased vertical dimension. Pain interview with the use of the McGill Pain Questionnaire demonstrated that pain in parts of the body other than the oral cavity were reported more frequently and that the intensity of past pain experiences was not rated higher except for pain in the head in patients with BMS. The results suggested a complex interaction between several general health factors, psychosocial stressors and denture dysfunction in order to explain an idiopathic burning pain in the anterior part of the oral cavity. The existence of demonstrable load factors does not seem to support the suggestion that BMS is primarily a psychogenic disorder.     

Increased expression of interleukin-16 in bronchial mucosa of subjects with atopic asthma

We have made hinge variants of two human Fab's in order to investigate the factors involved in the formation of dimeric Fab's in the periplasm of E. coli. Hinges containing one or more copies of the IgG1 hinge with various numbers of spacing residues were tested. Fab's with hinges based on the gamma2, gamma3 and gamma4 isotypes were also tested. We find that the IgG1 hinge sequence can form approximately 35% F(ab')2 in vivo in shake flask experiments, but that only (approximately) 5% F(ab')2 can be produced during fermentation. IgM and IgA tail-pieces added to Fab's did not effect their multimerisation. The possible role of growth conditions upon F(ab')2 formation in vivo is discussed.     

Alveolar bone levels in AIDS and HIV seropositive patients and in control subjects

Alveolar bone levels were studied from intraoral radiographs of 24 non-hospitalized patients with AIDS, 17 HIV seropositive subjects, and 39 matched control subjects. The AIDS/HIV subjects were seeking dental care in a faculty practice. The matched control subjects came from those non-HIV-infected patients seeking dental care at the University of Washington. Magnified intraoral radiographs were used to assess the distance between the cemento-enamel junction (CEJ) and the alveolar bone level (BL). The extent of vertical defects and furcation invasions was also assessed. The mean age of the AIDS, HIV, and control subjects was 38.9 +/- 6.6 years, 37.1 +/- 7.6, and 39.9 +/- 5.6, respectively, and was not statistically different. Among the AIDS patients, 75% were smokers, while 88.2% of the HIV subjects were cigarette smokers. Therefore, the matched control subjects were also smokers to the same extent. The mean difference in distance CEJ-BL was 0.1 mm (mesial) and 0.3 mm (distal) and greater in the HIV/AIDS group than in the control group, but not statistically different. No vertical defects > or = 3.0 mm were found in 69.2% of the control subjects and in 58.5% of the combined HIV/AIDS group. None of the HIV/AIDS subjects had more than 5 defects > 3.0 mm, while 7.6% of the control subjects had such defects. Significant associations were found between smoking and extent of alveolar bone loss (distance) (P < 0.001) as well as the number and extent of vertical defects (P < 0.01), but were not associated with HIV status. The extent of furcation invasions, as read radiographically, did not differ between groups. In conclusion, smoking but not HIV status was the primary factor for alveolar bone loss.