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Disease-induced variability of genetic correlations: ascites in broilers as a case study.

Breeding against a production disease is complicated by multiple relationships between productivity, disease, and environment. Ascites in broilers is such a disease. The combination of the reasonably well understood etiology (a physiological/pathological cascade due to inadequate oxygen supply) and the practical relevance makes ascites a relevant case for demonstrating and partly revealing these complex relationships. Chickens (n = 2,788) were tested in an ascites-challenging (cold) environment. Genetic analysis of mortality and pathology in combination with performance and physiological traits (especially blood gas traits) revealed ample opportunities for selection against ascites expression. The genetic correlation structure indicated that different mortality traits and pathology traits roughly represent one common characteristic. Direct selection against pathology is more effective than selection on the basis of growth or blood gas traits. The observed negative correlation (-0.26) between productivity and ascites was unexpected. From the etiology of ascites (inadequate supply of oxygen relative to the demand), a positive (unfavorable) correlation was expected. To demonstrate that the actual disease occurrence caused this apparent contradiction, the data from the undiseased subpopulation were reanalyzed. In the undiseased subpopulation, the genetic correlation between productivity and ascites was positive (0.29). This discrepancy was confirmed by comparing regression of ascites expression on actual performance with regression of ascites on independently assessed performance breeding values. The lability of the genetic correlation was explained from complex interactions between productivity, disease susceptibility, and actual occurrence of the disease. The revealed mechanism can be generalized to other production-related diseases and results in systematically lower genetic correlations between disease and productivity. It was inferred that genetic correlations between productivity and such diseases will always be prone to the demonstrated environmental sensitivity, which complicates index selection against production-related diseases.

Animals↗

Intraperitoneal transplantation of ascitic cancer cells from a 7,12-dimethylbenz[a]anthracene (DMBA)-induced ovarian cancer.

Intra-abdominal implantation of 7,12 dimethylbenz[a]anthracene (DMBA)-induced rat ovarian cancer tissue produces intraperitoneal carcinomatosis with a high incidence. The peritoneal carcinoma produces malignant ascites in 62% of the donor rats. The ascites is bloody in appearance and includes an average of 1.2 x 10(6) cancer cells/ml. To observe the transplantability of the ascites, 0.1 ml of a condensed ascites with 4 x 10(6) cancer cells was injected into the abdominal cavity of 118 infant rats that were 2 to 4 days old. In 103 rats (87%), the ascitic cells were successfully transplanted. Twelve rats were sacrificed each week from the 2nd to the 6th week following the inoculation. The omentum was the first site at which the metastastic tumor appeared following the inoculation. Then the tumor disseminated throughout the intraperitoneal cavity and produced bloody ascites by the 3rd week. Eighty-four rats were observed to determine the survival, and it was 34 +/- 10 days. Cytologically the ascites had clusters of tumor cells resembling bunches of grapes. The ultrastructure of the ascitic cells was globular shaped with many microvilli and epithelial attachments. The histology of the developed tumor was that of an adenocarcinoma. Due to morphological similarity with advanced human ovarian cancer and the high reproducibility, this experimental system could be a feasible model for human ovarian cancer, especially the type which produces malignant ascites.

9,10-Dimethyl-1,2-benzanthracene↗

The contact system in human malignant and benign ascites.

The plasma contact system was studied in ascites and plasma from patients with gastrointestinal cancer and patients with liver failure. Our study demonstrates the presence of factor XII, factor XI, and prekallikrein and their main inhibitors in ascites and plasma from both patient groups. Both factor XII-like and plasma kallikrein-like activities were detected in the malignant ascites. The kallikrein-like activity in malignant ascites was found in complex with alpha 2-macroglobulin. In plasma samples from the patients functional values of factor XII and prekallikrein were decreased compared to controls. In benign ascites the proenzyme levels were significantly lower than in malignant ascites. Functional inhibition values in ascites and plasma from patients were unexpectedly high. Our findings indicate that the plasma contact system is activated in the ascites from cancer patients. Activation of the contact system generates vasoactive mediators, which may play a role in the accumulation of malignant ascites.

Aged↗

Heritability of ascites and the ratio of right to total ventricle weight in broiler breeder male lines.

The objectives of this study were to induce ascites in three pure male line populations by subjecting them to cold stress, and to calculate heritability estimates for ascites (ASCITES) and the ratio of right to total ventricle weight (RATIO) in these populations under cold stress. Data were collected during the winter of 1993 to 1994 from 3,436 cockerels representing three commercial broiler breeder male lines. The male lines used in this study were characterized by: rapid growth rate and good feed efficiency (RG), moderate growth, good conformation, and excellent livability (MG), and maximum white meat yield and rapid growth (YD). Birds were cold stressed and euthanatized at 8 wk of age. Ratios of right to total ventricle weight and ascites (birds with fluid in the abdominal cavity) were recorded on every bird. Line means for the incidence of ascites were 17.5, 18.7, and 33.5% for RG, MG, and YD, respectively. Lines RG and MG did not differ from each other for ascites, but both were less than YD (P < .05). Means and standard deviations for the ratio of right to total ventricle weight (RATIO) were .299 +/- 0.9, .297 +/- .08, and .294 +/- .09 for RG, MG, and YD, respectively. Line means for RATIO did not differ. Heritability estimates of RATIO were .21 +/- .09, .21 +/- .09, and .27 +/- .08 for RG, MG, and YD, respectively; and heritabilities of ascites were .36 +/- .10, .11 +/- .08, and .44 +/- .09, respectively. Phenotypic correlations of ASCITES with RATIO were .54, .43, and .50 in RG, MG, and YD and genetic correlations of ASCITES with RATIO were .69 +/- .13, .46 +/- .33, and .78 +/- .10 in RG, MG, and YD, respectively.

Animals↗

Increased sympathetic outflow in cirrhosis and ascites: direct evidence from intraneural recordings.

OBJECTIVE: To determine if central sympathetic outflow is increased in patients with cirrhosis and ascites. PATIENTS: Eleven patients with cirrhosis and ascites, 8 patients with cirrhosis but without ascites, and 7 age-matched and 8 young healthy volunteers. METHODS: With subjects supine, direct microneurographic recordings of efferent post-ganglionic muscle sympathetic nerve activity were obtained from the peroneal nerve, and sympathetic burst frequency was compared with subjects' blood pressure, heart rate, sodium excretion, catecholamines, and plasma renin activity. All patients with cirrhosis were studied at least 5 days after withdrawal from all medications and after 7 days of a 20 mmol/d sodium, 1-L fluid-restricted diet. Age-matched volunteers were studied after 7 days of 20 mmol/d sodium intake and young healthy volunteers after 7 days of 150 mmol/d sodium intake. RESULTS: Sympathetic nerve activity in ascitic patients (65 +/- 15 bursts/min; mean +/- SD) was markedly increased, whether compared with patients with cirrhosis but without ascites (34 +/- 16 bursts/min; P less than 0.001), age-matched healthy volunteers on similar sodium intake (27 +/- 22 bursts/min; P less than 0.001), or young healthy subjects (21 +/- 10 bursts/min; P less than 0.001). The frequency of muscle sympathetic nerve discharge was directly related to plasma norepinephrine and epinephrine concentrations, plasma renin activity, and heart rate, all of which were increased in those patients with cirrhosis and ascites, and inversely related to 24-hour urinary sodium excretion, the fractional excretion of sodium, and subjects' pulse pressures. Sympathetic nerve activity fell from 78 to 6 bursts/min in one patient after liver transplantation. CONCLUSIONS: This study provides the first direct evidence that elevated plasma norepinephrine concentrations in patients with cirrhosis and ascites are due to increased central sympathetic outflow. Sympathetic nerve activity is not increased in patients with cirrhosis but without ascites. Because there were direct positive correlations of sympathetic nerve activity with plasma norepinephrine concentrations, plasma epinephrine concentrations, plasma renin activity, and heart rate, the increase in central sympathetic outflow in patients with cirrhosis and ascites appears generalized and not restricted to muscle nerves. The anti-natriuretic effects of parallel increases in renal and muscle sympathetic nerve activity could account for the inverse correlation between muscle sympathetic nerve activity and sodium excretion.

Adult↗

Accuracy of clinical manoeuvres in detection of minimal ascites.

A study was conducted to assess the clinical accuracy of various clinical manoeuvres and signs used routinely for detection of ascites. Sixty-six patients admitted in medical ward of a teaching hospital after initial screening by a consultant were selected. Exclusion criteria were; cases with previous history of ascites, who had undergone paracentesis in the recent past or with evidence of ascites from history. Another clinician blind to history and clinical details assessed the presence of ascites by the selected methods a sonographer blind of clinical and historical details assessed the cases for presence of ascitic fluid. The clinical findings were compared using ultrasonographic (USG) findings as gold standard. Ascites was detected in 35 patients by USG. the mean weight and abdominal girth of study subjects with or without ascites were comparable (p > 0.05). Sensitivity of auscultatory percussion was highest (65.7%) followed by flank dullness (57.1%) and least for fluid wave sign (20.0%). Fluid wave sign had the highest specificity (100%). We found that none of the manoeuvres studied for detection of ascites was both highly sensitive and specific. However, auscultatory percussion could be useful for initial screening of patients to detect ascites.

Adult↗

Comparative pathology of heart and liver lesions of broiler chickens that died of ascites, heart failure, and others.

Pathologic changes of 120 dead broilers from a flock of 1000 birds were compared. Macroscopically, the changes were divided into three pathologic types: ascites (retention of ascitic fluid), heart failure (right heart dilation and/or hydropericardium without retention of ascitic fluid), and others (without ascites or heart failure). The rates of ascites, heart failure, and others were 55.8% (67/120), 33.3% (40/120), and 10.8% (13/120), respectively. Histologically, cardiac histologic changes (myocardial degeneration with calcification and epicardial fibrosis) were seen in 40 of 67 (59.7%) ascites cases. Hepatic histologic changes (hepatocytic degeneration/necrosis and hepatic capsule fibrosis) were seen in 64 of 67 (95.5%) ascites cases. Cardiac histologic changes were seen in 24 of 40 heart failure cases (60.0%). Hepatic histologic changes were seen in 36 of 40 (90.0%) heart failure cases. Six of 13 others had hepatic histologic changes, but the remaining seven birds had no significant histologic changes. Ascites and heart failure cases had almost the same percentages of hepatic and cardiac histologic changes. This study indicates that two pathologic types, ascites and heart failure, may be closely related conditions and that hepatic histologic changes may be common and fundamental lesions in the pathogenesis of these pathologic types.

Animals↗

[Role of surgery in the treatment of refractory ascites in cirrhotic patients].

Ascites, generally directly reflecting portal hypertension, is the commonest cause of hospitalisation in patients with cirrhosis. In almost 10% of patients with ascites, optimal medical treatment combining bed rest, salt and water restriction, and diuretic treatment, is unable to induce sodium excretion and decrease the volume of the ascites, corresponding to the definition of refractory ascites. In other cases, it is the treatment of ascites itself (salt and water restriction and diuretics) which induce complications: water and electrolyte disturbances, functional renal failure, encephalopathy, the development of which also corresponds to refractory ascites. The therapeutic armamentarium for the management of refractory ascites remains varied, with the use of aspiration of ascites with compensation, peritoneovenous shunts, transhepatic or surgical porto-systemic anastomoses, and finally, liver transplantation. At the present time, each therapeutic measure must be taken while keeping in mind the possibility of subsequent liver transplantation and the potential risk of compromising liver transplantation by inappropriate treatments. In this context, the authors review and analyse the respective places of the various therapeutic modalities in the management of refractory ascites in cirrhotic patients.

Ascites↗

Analysis of chemokines and chemokine receptor expression in ovarian cancer ascites.

PURPOSE: Ascitic disease is a common occurrence in human ovarian cancer, but it is unclear how the cellular composition of ascitic fluid is determined. Because chemokines can determine host cell infiltration in solid ovarian cancer, we assessed CC chemokine protein and CC chemokine receptor expression in ovarian cancer ascites. EXPERIMENTAL DESIGN: We used reverse transcription-PCR and RNase protection assay to determine CC chemokine and chemokine receptor mRNA expression and ELISA to measure CC chemokine protein levels. Flow cytometry was used to identify cell populations and their chemokine receptor protein expression. RESULTS: mRNA for the CC chemokines CCL2, -3, -4, -5, -8, and -22 was expressed in cell isolates from ascites samples, and the corresponding proteins were detected in ascitic fluid. mRNA for CC chemokine receptors CCR1, -2a, -2b, -3, -4, -5, and -8 was detected in cells from ascites. Fluorescence-activated cell-sorting analysis showed variable numbers of macrophages and CD3(+) T lymphocytes (predominantly CD4(+)) within ovarian cancer ascites. CD14(+) macrophages within ascites consistently expressed protein for CCR1, -2, and -5. CCR1 was expressed by >60% of all T cells, but more CD4(+) than CD8(+) T cells expressed CCR2 and -5. A direct correlation was found between the CCL5 concentration and CD3(+) T-cell infiltration. CONCLUSIONS: We conclude that there is a complex chemokine/chemokine receptor network in ovarian cancer ascites. However, associations between chemokine receptor expression, chemokine levels, and cell counts were limited.

Ascites↗

Detection of allelic imbalance in ascitic supernatant by digital single nucleotide polymorphism analysis.

PURPOSE: Cytological examination of ascitic fluid is critical for clinical management of patients with peritoneal or pelvic diseases. Such morphological examination can only achieve a sensitivity of <62%, and thus a molecular test that is able to distinguish benign versus malignant ascites could be clinically useful. In this study we determined the presence of allelic imbalance (AI) in tumor-released DNA in ascitic supernatant by directly counting the alleles using a newly developed technology, digital single nucleotide polymorphism (SNP) analysis. EXPERIMENTAL DESIGN: Allelic status was assessed using a total of seven SNP markers that commonly demonstrated AI in ovarian, colorectal, and pancreatic cancers. RESULTS: With digital SNP analysis, AI in at least one SNP marker was found in 19 of 20 (95%) ascitic fluid DNA samples obtained from patients with cytologically proven carcinomas in ascitic fluid. In contrast, AI was detected in only 1 of 20 patients with negative cytology. This latter patient with AI in her ascites had known stage III ovarian carcinoma at the time of cytology sampling. The ascitic specimen of this patient demonstrated the presence of carcinoma cells in culture with an identical AI pattern found in the ascitic supernatant and surgical specimen. CONCLUSIONS: These findings suggest that detection of AI using digital SNP analysis can be a useful adjunct for the detection of ovarian and other types of cancer in ascitic fluid.

Alleles↗

[The significance of low levels of total proteins, albumins, globulins and complement factors in ascitic fluid and the development of spontaneous bacterial peritonitis in patients with liver cirrhosis].

Spontaneous bacterial peritonitis is one of the most common complications of ascitic fluid in patients with liver cirrhosis. The aim of this study was to investigate the role of total protein, albumin, globulin and complement ascitic fluid concentrations in development of spontaneous bacterial peritonitis in patients with liver cirrhosis. In patients with liver cirrhosis and spontaneous bacterial peritonitis (n = 8) the ascitic fluid total protein, albumin and globulin concentrations were significantly lower than in patients with sterile ascites (n = 11) (p < 0.01). The ascitic fluid complement C3 and C4 concentrations were significantly lower in patients with spontaneous bacterial peritonitis than in patients with sterile ascites (9.1 +/- 3.1 mg/dL to 22.9 +/- 17.4 mg/dL, p < 0.01; 3.8 +/- 5.9 mg/dL to 8.2 +/- 5.9 mg/dL, p < 0.01, respectively). The ascites total protein, albumin, globulin and complement concentrations in cirrhotic patients with spontaneous bacterial peritonitis were significantly lower than in patients with sterile ascites demonstrating the importance of those factors in ascitic fluid defense against secondary bacterial infection.

Albumins↗

HLA-G is a potential tumor marker in malignant ascites.

PURPOSE: Molecular approaches as supplements to cytological examination of malignant ascites may play an important role in the clinical management of cancer patients. HLA-G is a potential tumor-associated marker and that one of its isoforms, HLA-G5, produces a secretory protein. This study is to assess the clinical utility of secreted HLA-G levels in differential diagnosis of malignant ascites. EXPERIMENTAL DESIGN: We used ELISA to assess whether secretory HLA-G (sHLA-G) could serve as a marker of malignant ascites in ovarian and breast carcinomas, which represent the most common malignant tumors causing ascites in women. RESULTS: On the basis of immunohistochemistry, 45 (61%) of 74 ovarian serous carcinomas and 22 (25%) invasive ductal carcinomas of the breast demonstrated HLA-G immunoreactivity ranging from 2 to 100% of the tumor cells. HLA-G staining was not detected in a wide variety of normal tissues, including ovarian surface epithelium and normal breast tissue. Revese transcription-PCR demonstrated the presence of HLA-G5 isoform in all of the tumor samples expressing HLA-G. ELISA was performed to measure the sHLA-G in 42 malignant and 18 benign ascites supernatants. sHLA-G levels were significantly higher in malignant ascites than in benign controls (P < 0.001). We found that the area under the receiver-operating characteristic curve for sHLA-G was 0.95 for malignant versus benign ascites specimens. At 100% specificity, the highest sensitivity to detect malignant ascites was 78% (95% confidence interval, 68-88%) at a cutoff of 13 ng/ml. CONCLUSIONS: Our findings suggest that measurement of sHLA-G is a useful molecular adjunct to cytology in the differential diagnosis of malignant versus benign ascites.

Ascites↗

Cancer antigen 125 levels in serum can predict the recurrence of ascites in patients with cirrhosis of the liver.

The relationship between the risk of ascites recurrence and the level of cancer antigen 125 (CA 125) in serum was studied in two independent groups of patients with cirrhosis of the liver. The first group included 17 patients admitted to hospital due to ascites. When the episode was resolved, diuretic treatment was suspended and the CA 125 level in serum was determined. Eight patients had CA 125 levels above 35 U/ml (200.5 +/- 152.1 U/ml) when discharged from hospital, and ascites reappeared in all these cases within 30 days. The other nine cases (25.1 +/- 17.1 U/ml) remained free of ascites (p less than 0.005). In the second group, no evidence of ascites was found in 21 patients during 28 out-patient physical examinations. At the time of the examinations, abdominal echographic studies and CA 125 measurements were carried out. In 17 examinations, ascitic fluid was not detected by echography. CA 125 levels were normal (10.8 +/- 9.1 U/ml), and none of these subjects developed ascites. Echography detected peritoneal fluid during the remaining 11 examinations and CAH 125 levels in these cases were above 35 U/ml (278 +/- 276.9) (p less than 0.001). Six of these patients developed ascites within 30 days. We conclude that CA 125 levels can predict ascites recurrence in patients with cirrhosis of the liver.

Adult↗

[Chylous ascites in cirrhosis. Retrospective study of 20 cases].

Chylous ascites is a rare complication of cirrhosis. We report 20 cirrhotic patients with chylous ascites seen between 1976 and 1989. Hepatocellular carcinoma was associated in 2 cases and, in 5 cases, chylous ascites followed surgery (portosystemic shunt in 4 cases). Chylous ascites was spontaneous in the 13 other cases. Prevalence of chylous ascites was 1.1 p. 100 in the cirrhotic population with ascites observed between 1983 and 1988. Chylous ascites, whether spontaneous or postoperative, was almost always refractory to medical treatment (16 of 18 patients). Treatment by Le Veen shunt was unsuccessful in 4 patients and lead to infection in 2 cases. Four of 6 patients treated by portocaval shunt died during the first postoperative month. Repeated paracentesis should be preferred, but this can be complicated by malnutrition. Seven of 10 alcoholic cirrhotics with spontaneous chylous ascites and 2 of 4 patients with postoperative chylous ascites died during the year following diagnosis. In view of this poor prognosis, hepatic transplantation should be considered early in selected patients.

Adult↗

Natural history of repaired umbilical hernias in patients with and without ascites.

A retrospective chart review was undertaken to determine the natural history of repaired umbilical hernias in patients with and without a history of ascites. Eighty-five patients underwent umbilical herniorrhaphy during the interval from January 1973 to March 1983. The length of hospital stay was significantly longer for the 22 patients who had a history of ascites; however, the complication rate of elective repair of umbilical hernias that were caused by ascites was not different from that of the 63 patients without a history of ascites. There was no operative mortality in either group. Sixty-eight patients were reevaluated at least 1 month postoperatively. Of the 51 patients who had never had ascites, six (12%) developed a recurrent hernia. Of the 17 patients whose hernias were caused by ascites, eight (47%) developed recurrences. Of the 11 herniorrhaphies performed when ascitic fluid was present, eight (73%) resulted in a recurrence, whereas only one (17%) patient had a recurrence among the group of seven patients who underwent herniorrhaphy at a time when the ascitic fluid was no longer present. Umbilical hernias caused by ascites can be repaired with acceptable morbidity and probably should be repaired after the fluid has been medically removed.

Ascites↗

Trace element composition of ascitic fluid.

The relationship between trace elements in the serum and ascites of the cirrhotic patient was investigated because there is an interchange of protein, particularly albumin, between serum and ascitic fluid. To study this relationship, serum and ascitic fluid were obtained from 13 patients with biopsy-proved Laennec's cirrhosis. The trace element content of the ascitic fluid studied was less (22% to 73%) than that in serum. Protein fractions were all decreased in ascitic fluid compared with serum. Levels of zinc, calcium, copper, selenium in ascitic fluid correlated well with the ascitic fluid protein fractions. Thus, the trace element composition of ascitic fluid differed appreciably from that of serum, and seemed to correlate with the protein composition of the ascitic fluid in the case of zinc, copper, calcium, and selenium.

Aged↗

New approach to management of malignant ascites with a streptococcal preparation, OK-432. II. Intraperitoneal inflammatory cell-mediated tumor cell destruction.

Twelve patients with malignant ascites caused by gastric cancer were treated with intraperitoneal injections of a streptococcal preparation, OK-432. All had resolution of the ascites after OK-432 treatment. Neutrophils, macrophages, and lymphocytes increased in number in ascitic fluid samples. Some of the OK-432-induced inflammatory cells were attached to tumor cells. The absolute number of tumor cells decreased as the number of infiltrating inflammatory cells increased. Infiltrating lymphocytes were mainly E rosette-forming cells. Infiltrating macrophages were in an activated state. The infiltrating neutrophils, lymphocytes, and macrophages could inhibit DNA synthesis of the patient's own tumor cells in the ascitic fluid after OK-432 injection, but not before the injection. These results indicate that OK-432-induced neutrophils, lymphocytes, probably T cells, and activated macrophages may play an important role in tumor cell destruction in ascites. Moreover, as the number of tumor cells decreased, the ascitic fluid protein levels decreased. Decrease of the ascitic fluid protein level may suppress further accumulation of ascitic fluid, and the low protein level in ascitic fluid is likely to facilitate the reabsorption of the fluid into the bloodstream.

Adenocarcinoma↗

[Ascitic pH and infection in alcoholic cirrhosis].

The pH values of 108 samples of ascitic fluid in 94 alcoholic cirrhotic patients were analyzed in order to assess their diagnostic and prognostic value. The mean pH value of ascitic fluid was significantly lower (p less than 0.001) in patients with spontaneous bacterial peritonitis (7.23 +/- 0.22) or with suspected diagnosis of spontaneous bacterial peritonitis (7.29 +/- 0.15) than in patients with sterile ascites (7.45 +/- 0.06). However, there was an important overlap between these groups. In patients with and without spontaneous bacterial peritonitis, measurement of the difference between blood and ascitic pH was more discriminative than the ascitic pH alone: a difference of 0.10 or more was detected in all patients with spontaneous bacterial peritonitis, in 2 of 5 patients with suspected diagnosis of spontaneous bacterial peritonitis and in 3 of 97 patients with sterile ascites. When the ascitic pH value was lower than 7.15, death occurred rapidly. Ascitic pH rapidly increased when treatment of spontaneous bacterial peritonitis was clinically effective. These results suggest that measurement of pH in ascitic fluid is contributive to the diagnosis and prognosis of spontaneous bacterial peritonitis in alcoholic cirrhosis.

Adult↗