Cross cultural comparison of constipation profiles at tertiary care centers between India and USA.

BACKGROUND: Despite potential differences in patient perception of chronic constipation (CC) in geographically and culturally distinct regions, head-to-head studies comparing the clinical profile, constipation severity, impact on quality of life (QOL) and economic impact are lacking. METHODS: We conducted a cross-sectional cohort study of patients presenting with CC to tertiary care centers in the USA and India. Standardized instruments were used to assess constipation subtype, disease severity, disease-specific QOL, somatization, and psychiatric comorbidities. We used multivariable linear regression to determine the predictors of QOL and number of healthcare visits. KEY RESULTS: Sixty-six and 98 patients with CC were enrolled in the USA and India, respectively. Indian patients with CC had significantly more frequent bowel movements/week compared to their USA counterparts (Median 5 vs 3, P < .0001). The proportion of patients with Bristol stool form scale type 1 and 2 was significantly higher in the USA compared to India (65.5% vs 48%, P = .04). Higher depression score (P = .001), more severe constipation symptoms (P = .001) and site of the study being USA (P = .008) independently predicted worse QOL. Indian patients (P < .001) and worse QOL (P = .02) were independent predictors of number of healthcare visits in the last 12 months. CONCLUSIONS AND INFERENCES: Indian patients with CC have more frequent and softer bowel movements compared to those in the USA suggesting significant differences in perception of CC in different geographic and cultural settings. QOL and economic impact related to constipation varies with geographic/cultural setting irrespective of other clinical and psychosomatic features.

Yes-associated protein mediates immune reprogramming in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a high degree of inflammation and profound immune suppression. Here we identify Yes-associated protein (Yap) as a critical regulator of the immunosuppressive microenvironment in both mouse and human PDAC. Within Kras:p53 mutant pancreatic ductal cells, Yap drives the expression and secretion of multiple cytokines/chemokines, which in turn promote the differentiation and accumulation of myeloid-derived suppressor cells (MDSCs) both in vitro and in vivo. Pancreas-specific knockout of Yap or antibody-mediated depletion of MDSCs promoted macrophage reprogramming, reactivation of T cells, apoptosis of Kras mutant neoplastic ductal cells and pancreatic regeneration after acute pancreatitis. In primary human PDAC, YAP expression levels strongly correlate with an MDSC gene signature, and high expression of YAP or MDSC-related genes predicts decreased survival in PDAC patients. These results reveal multifaceted roles of YAP in PDAC pathogenesis and underscore its promise as a therapeutic target for this deadly disease.

Acquisition of estrogen independence induces TOB1-related mechanisms supporting breast cancer cell proliferation.

Resistance to therapies targeting the estrogen pathway remains a challenge in the treatment of estrogen receptor-positive breast cancer. To address this challenge, a systems biology approach was used. A library of small interfering RNAs targeting an estrogen receptor (ER)- and aromatase-centered network identified 46 genes that are dispensable in estrogen-dependent MCF7 cells, but are selectively required for the survival of estrogen-independent MCF7-derived cells and multiple additional estrogen-independent breast cancer cell lines. Integration of this information identified a tumor suppressor gene TOB1 as a critical determinant of estrogen-independent ER-positive breast cell survival. Depletion of TOB1 selectively promoted G1 phase arrest and sensitivity to AKT and mammalian target of rapmycin (mTOR) inhibitors in estrogen-independent cells but not in estrogen-dependent cells. Phosphoproteomic profiles from reverse-phase protein array analysis supported by mRNA profiling identified a significant signaling network reprogramming by TOB1 that differed in estrogen-sensitive and estrogen-resistant cell lines. These data support a novel function for TOB1 in mediating survival of estrogen-independent breast cancers. These studies also provide evidence for combining TOB1 inhibition and AKT/mTOR inhibition as a therapeutic strategy, with potential translational significance for the management of patients with ER-positive breast cancers.

Intermittent testicular pain: fix the testes.

OBJECTIVE: To analyse the presenting features, signs and operative findings of children presenting with intermittent testicular pain, as testicular torsion is a relatively common and serious emergency in children that can lead to testicular loss in up to 80%, although half of these children have previous episodes of pain suggestive of intermittent torsion. PATIENTS AND METHODS: Data were collected prospectively for all patients presenting with recurrent pain between December 2000 and June 2001. Variables assessed included presenting symptoms, age, size, lie and position of the testis when supine and erect, the operative findings and follow-up. RESULTS: Eight children had at least two previous episodes of testicular pain; four of these were admitted on six occasions. Two had undergone previous scrotal exploration. On clinical examination, six boys had a transverse testicle and two a discrepancy in testicular size. All children had their testes fixed. At operation in all patients there was abnormal attachment of the tunica vaginalis with a typical 'bell clapper' deformity. On follow-up only one patient still complains of pain. CONCLUSION: In view of high incidence of abnormalities we consider that to improve the testicular salvage rate and prevent testicular atrophy, bilateral testicular fixation is recommended for boys with intermittent testicular pain and positive clinical findings.

Jejunoileal atresia and associated malformations: correlation with the timing of in utero insult.

PURPOSE: Duodenal atresia is associated with a higher incidence of associated congenital malformations than jejunoileal atresia, supporting the hypothesis that the duodenal obstruction occurs early in fetal life. In this study, the authors analyzed the incidence of major associated malformations in jejunal atresia (JA) and ileal atresia (IA) to determine if there is a positive correlation between the proximity of the intestinal atresia and the association of other major anomalies. METHODS: Records of all patients with jejunoileal atresias treated at the authors' institution between 1980 and 1997 were examined. RESULTS: There were 83 patients with jejunoileal atresias, 38 with JA, and 45 with IA. Sixteen (42%) of the JA patients had an associated major congenital malformation, whereas only 1 (2%) of the IA patients had an associated malformation. A single atresia was found in 18 (47%) of JA patients and 41 (91%) of IA patients. Twenty (53%) of the JA patients had either multiple or apple-peel atresia. Thirteen patients (16%) died, 11 with JA, and 2 with IA. Of the 11 patients with JA who died, 6 had multiple atresias, 4 had cystic fibrosis, and 1 had small bowel volvulus. CONCLUSION: The higher incidence of associated major congenital extraintestinal malformations in JA compared with IA patients suggests that some cases of JA may arise from a malformative process.

Hepatic overexpression of MHC class II antigens and macrophage-associated antigens (CD68) in patients with biliary atresia of poor prognosis.

The pathogenesis of biliary atresia (BA) is still unknown. Progression to cirrhosis despite restoration of bile flow by successful portoenterostomy suggests that it is a progressive disease of the liver and biliary tree. Whether immunologic factors play any role in the development of this disease remains uncertain. Aberrant expression of major histocompatibility complex (MHC) Class II antigens of HLA-DR on hepatocytes and biliary epithelium is regarded as important in the progression of hepatocellular and biliary damage mediated by cytotoxic T cells. This study was undertaken to evaluate expression of MHC Class II antigen and macrophage-associated antigens (CD68) in liver of patients with biliary atresia to determine their prognostic usefulness and possible role in the pathogenesis of the disease. Liver biopsy specimens from infants with BA (n = 15), neonatal hepatitis (n = 3), and normal livers (n = 6) were studied using an indirect immunoperoxidase staining using antibodies against MHC Class II antigen and macrophage-associated antigens (CD68) as well as routine H&E and Masson's trichome stain. In patients with biliary atresia, the liver biopsy specimen was obtained at the time of Kasai portoenterostomy. Expression of HLA-DR antigens and CD68 antigens was either absent or minimal in normal liver biopsy specimens. There were a few HLA-DR antigens and a few CD68-positive cells around portal tracts in all patients with neonatal hepatitis and five of the seven biliary atresia patients with successful Kasai portoenterostomy. In contrast, there was strong expression of HLA-DR antigen in bile ductules, inflammatory cells, and adjacent damaged hepatocytes and marked CD68-positive macrophage infiltrate in the portal tracts as well as hepatic lobules in two patients with good prognosis and in all eight patients with bad prognosis. Hepatic expression of MHC Class II antigen and CD68 antigens correlated well with the severity of clinical course in patients with BA and may act as a prognostic factor in these patients.

Effects of hyperoxia and caffeine on the expression of fragile site at Xq27.3.

To enhance the cytogenetic expression of the fragile X chromosome, we studied the effects of hyperoxia and caffeine on the induction of fragile Xq27.3. A lymphoblastoid cell line (GM 06912) derived from a fragile X male proband was cultured in RPMI 1640 containing 16% dialyzed fetal calf serum. The cells were synchronously subjected to one of 3 different atmospheric oxygen tensions (21%, 21.3 kPa, normoxic; 40%, 40.5 kPa, hyperoxic; or 60%, 60.8 kPa, hyperoxic) during the last 24 hours of the 72 hour culture, immediately after the addition of 2'-deoxy-5-fluorouridine (FUdR) at 25 ng/ml. To study the enhancing effect of caffeine, with or without hyperoxia, a second set of cultures was additionally subjected to caffeine (2.5 mM) during the last 6 hours of the culture. When the fragility of hyperoxic cells (38.1 kPa dissolved oxygen) was compared to that of normoxic control cells (13.3 kPa dissolved oxygen), the difference was significant (P < 0.05). These data suggest that there is a mean increase in the fragile Xq27.3 expressivity as the dissolved oxygen tension increases. Additionally, we observed that caffeine, with or without hyperoxia, significantly (P < 0.05) suppressed the expression of the fragile X site in this lymphoblastoid cell line.

Serum intercellular adhesion molecule (ICAM-1), a marker of renal scarring in infants with vesico-ureteric reflux.

OBJECTIVE: To determine if serum intercellular adhesion molecule (ICAM-1) levels correlate with renal scarring in children with vesico-ureteric reflux (VUR). PATIENTS AND METHODS: Serum ICAM-1 levels were measured in 81 children (29 boys and 52 girls, age range 2 months-13 years) with VUR using an enzyme-linked immunosorbent assay (ELISA) and compared with levels in a control group of 24 children (16 boys and eight girls, age range 2 days-13 years) with no urological abnormalities. RESULTS: The mean serum ICAM-1 level in the control group was 202 +/- 79 ng/mL (mean +/- 1 SD) compared with 347 +/- 96 ng/mL in children with VUR (P < 0.001). Fifteen of 26 children under 2 years of age demonstrated renal scarring while 18 of 44 children older than 2 years exhibited renal scarring. The mean serum ICAM-1 level in patients who were < 2 years of age and had renal scarring was 408 +/- ng/mL, significantly higher than in those who had no renal scarring (296 +/- 68 ng/mL, P < 0.01). In contrast, there was no difference in serum ICAM-1 levels in patients > 2 years of age with or with no renal scarring (353 +/- 87 and 325 +/- 91 ng/mL, respectively). CONCLUSION: Serum ICAM-1 levels are significantly higher in children with VUR and may represent a valuable marker of tubular damage in younger children with VUR.

Constitutional heteromorphism of 9q13 --> q21 in a patient with chronic myelogenous leukemia.

Cytogenetic studies were carried out in a 44-year-old white male because of newly diagnosed chronic myelogenous leukemia. His initial bone marrow study revealed 46,XY, var(9)(q13 -->q21)/46,XY,var(9) (q13-->q21), t(9;22)(q34;q11) karyotypes and later he also acquired a 47,XY,+8,var(9)(q13-->q21), t(9;22)(q34;q11) clone. The var(9)(q13-->q21) heteromorphism was observed in the normal 9 homolog, in 200 GTG-banded bone marrow metaphases in seven cytogenetic studies (1988-90). This heteromorphism was observed in the normal cell line, in the two chronic myelogenous leukemia-related clones, as well as in 100 mitogen-induced peripheral blood lymphocytes, indicating its constitutional nature. This seems to be the first report of var(9)(q13 --> q21) heteromorphism, involving GTG-positive euchromatic band, in a chronic myelogenous leukemia proband.

Scarring following renal trauma in children.

OBJECTIVE: To assess factors relating to renal scarring following kidney injury. PATIENTS AND METHODS: A total of 25 children who had documented renal injury between 1981 and 1988 were included in the study and 19 were followed up for 1 month to 12 years (mean 5.5 years) and the development of hypertension and renal scars assessed using ultrasonography and radionuclide scans (dimercapto-succinic acid, DMSA). RESULTS: Of the 19 children 13 had renal contusions, four had renal lacerations and two sustained severe renal injury, one of whom had pelvi-ureteric disruption. Eighteen patients presented with macroscopic or microscopic haematuria except the patient with pelvi-ureteric junction disruption who presented 3 weeks later with abdominal distension, vomiting and hypertension. All the patients were managed without an operation except the latter patient who required nephrectomy. Renal scarring was demonstrated in four children at a mean follow-up of 3.5 years, one following renal contusion (5% scarring), two after renal laceration (50% scarring) and one after rupture of the kidney (100% scarring). In one patient intravenous pyelography did not reveal a renal scar but a radionuclide scan performed 5 years later demonstrated a scar. Transient hypertension was noted in only two patients but peripheral plasma renin levels were normal. CONCLUSION: Renal scars developed in four of 19 patients with renal trauma and more than half of the patients with severe renal injury. Long-term follow-up including a radionuclide scan is therefore necessary in patients with renal injury. Although no sustained hypertension was noted in any patients in this study, long-term blood pressure assessments would seem prudent.

Intestinal neuronal dysplasia is a possible cause of persistent bowel symptoms after pull-through operation for Hirschsprung's disease.

The proximal margin of the resected bowel specimens from 33 consecutively treated patients undergoing a definitive pull-through operation for Hirschsprung's disease (HD) and control specimens consisting of suction rectal biopsy specimens obtained from 24 age-matched patients evaluated for constipation (and proven not to have HD) were examined using conventional H&E staining and acetylcholinesterase (AChE) histochemistry. Complete resection of the aganglionic segment was confirmed in 31 patients. In one patient, the proximal margin was found to be aganglionic; in another, the proximal margin was in a transitional zone. In both patients, frozen sections at the time of surgery were interpreted as having ganglion cells. In 10 of 31 patients, intestinal neuronal dysplasia was demonstrated in the proximal margin of the resected bowel. The abnormalities included hyperplasia of the submucous plexus, giant ganglia (with > 7 ganglion cells), and ectopic ganglion cells (all 10 patients) and increased AChE activity in the lamina propria (5 patients). All ten patients with IND had persistent bowel problems after the definitive operation for HD, such as enterocolitis, soiling, or constipation. Only four of the other 21 patients had persistent bowel symptoms. This study suggests that IND is commonly associated with HD. It also emphasizes the importance of histochemical examination of the resected segment to predict postoperative bowel function in patients with HD.

Subureteric Teflon injection (STING). Results of a European survey.

Subureteric Teflon injection (STING) has been successfully used by several investigators for treating vesicoureteric reflux (VUR) in children. This multicentre European survey reviews the results of STING in 6,216 ureters. Twenty-two paediatric surgeons/urologists from 18 centres in Europe answered an enquiry regarding their experience with STING in the treatment of VUR. 6,216 refluxing ureters were injected with Polytef paste in 4,166 children during 1984-1990. There were 975 boys and 3,191 girls. Their ages ranged from 2 months to 14 years (mean 5.1 years). The reflux was grade I in 4.4% of ureters, grade II in 36.1%, grade III in 40.2%, and grades IV and V in 19.3% of ureters. All patients were followed up for periods ranging from 3 months to 81/2 years and 90% were followed up for more than 2 years. 76.3% of all ureters stopped refluxing after a single injection of Teflon paste, cure rate increased to 84.9% after a second injection. A further 10.2% of refluxing ureters showed significant improvement in the grade of reflux after a single injection and needed no further treatment. 1.3% of ureters were cured after a third or fourth injection. Failure to correct or improve VUR was seen in 224 ureters (3.6%), necessitating reimplantation. Twenty ureters (0.32%) developed vesicoureteric junction obstruction following STING and these were reimplanted without difficulty. Results of this multicentre survey confirm that STING is an effective day care procedure for treatment of all grades of VUR. 95% of all ureters were cured or showed significant improvement after two injections of Teflon paste.(ABSTRACT TRUNCATED AT 250 WORDS)

Small intestinal atresia: effect on fetal nutrition.

The peak velocity for fetal weight gain occurs in the last few weeks of pregnancy. As the fetus matures, it swallows and absorbs an increasing amount of amniotic fluid, which contributes to the growth of the fetus. The authors studied cases of small intestinal atresia (IA) treated over 9 years to determine whether amniotic fluid has any nutritive role in the development of human fetus, and if it does, at what stage of gestation is the contribution of amniotic fluid significant to fetal nutrition. Fifty-nine newborns had IA (24 jejunal, 35 ileal). Ten of the patients had associated anomalies (3 cystic fibrosis, 2 congenital heart disease, 1 neural tube defect, 1 microcephaly, 2 malrotation, 1 vesicoureteric reflux). Among the 24 babies with jejunal atresia, one was a twin, and birth weight was not recorded for another. These two patients were excluded from the study. Of the remaining 22 patients with jejunal atresia, 10 were born before 36 weeks' gestation; only five of 35 patients with ileal atresia were born before 36 weeks' gestation. Fourteen patients were below the 10th percentile for birth weight after correction for gestational age, one was born before 36 weeks, and 13 were born after 36 weeks. Five (41.7%) of the 12 patients with jejunal atresia who were born after 36 weeks' gestation were underweight, as were eight (26.7%) of the 30 patients with ileal atresia. Thus, it appears that amniotic fluid contributes to the fetal growth in the last few weeks of gestation, and the higher the obstruction in the small intestine, the more pronounced the effect on the nutrition of the fetus.

The influence of trisomy 21 on outcome in children with Hirschsprung's disease.

The association of Hirschsprung's disease (HD) and trisomy 21 has been well recognised. Seventeen (13%) of 135 patients presenting with HD between 1975 and 1992 had trisomy 21. Nine (53%) presented in the neonatal period, with intestinal obstruction (5), enterocolitis (2), or perforation of the colon (2). Eight patients presented after the neonatal period, with constipation. Pathological involvement included rectosigmoid (12), long segment (4), and total colonic aganglionosis (1). Definitive surgery was performed in 14 patients. At the mean follow-up of 8 years (4 to 15 years), only one of the 13 patients has normal bowel function. Eight have persistent soiling, and two have reverted to permanent stomata. There were two deaths in the series; one resulted from enterocolitis complicating HD, and the other from congenital cardiac disease. These data suggest that long-term bowel function in children with HD and trisomy 21 is poor and should be taken into consideration when planning the management.

Iatrogenic ascent of the testis: an under-recognized complication of inguinal hernia operation in children.

OBJECTIVE: To determine the incidence of iatrogenic ascent of the testis following inguinal hernia repair in children. PATIENTS AND METHODS: A total of 627 children underwent 747 groin explorations for inguinal hernia between January 1981 and December 1984. A retrospective review of their charts until December 1991 was undertaken. RESULTS: Nine patients subsequently required orchidopexies at a mean interval of 3 years 171 days (range 229 days-6 years 6 months). The incidence of iatrogenic ascent of the testis was 1.3% (6/459) for patients under 2 years of age at the initial operation, 1.3% (2/155) for those between 2 years and 5 years and 0.75% (1/133) for those above 5 years. CONCLUSION: The incidence of iatrogenic ascent of the testis was 1.2% after groin exploration for inguinal herniotomy in children, indicating the need for long-term follow-up.

Is contralateral exploration necessary in infants with unilateral inguinal hernia?

Between 1973 and 1985, 165 infants (aged 1 week to 6 months) underwent unilateral inguinal herniotomy at our hospital. An attempt was made to trace these 165 children. It proved possible to contact and examine 116 children (104 boys and 12 girls). Age at follow-up ranged from 5 to 17 years. Parents were asked whether their children had attended any hospital for the treatment of contralateral hernia. All children were examined for the evidence of contralateral hernia. Boys were also examined for the position and size of the testis. Testicular volume was assessed with the help of Prader's Orchidometer. Twelve children (10.3%), 11 boys and 1 girl, subsequently developed contralateral inguinal hernia. The mean time interval between initial hernia operation and subsequent development of contralateral hernia was 164 days (range, 7 days to 18 months). Diminished size of testes was observed on the side of the operation in six patients and one patient had complete testicular atrophy. Three boys had a testis in the groin, presumably hitched up at operation and all three required orchidopexy. In view of the relatively low incidence of contralateral hernia and increased risk of damage to testes, we feel that routine contralateral exploration is not justified.

Limitations of extracorporeal shock wave lithotripsy for urinary tract calculi in young children.

Despite success rates with a variety of urinary tract calculi, there is growing concern that extracorporeal shock wave lithotripsy (ESWL) has limitations and that its role needs to be redefined. We report the outcome of 28 consecutive children (age range, 6.5 months to 7 years; mean, 3.6 years) with urinary calculus disease, treated over a 5-year period. Thirteen patients had ESWL monotherapy, and 8 achieved stone clearance. The other 5 children in the ESWL monotherapy group, all with multiple calculi, required surgery to render them stone free. A further 14 patients (6 staghorn calculi, 6 multiple calculi, 1 solitary renal, and 1 child with multiple bladder calculi) were considered unsuitable for ESWL and had primary surgery. Twelve of those 14 were cleared by open surgery, one had residual fragments successfully treated by ESWL, and one still awaits adjuvant ESWL. One child had a solitary renal calculus (5 mm) which passed spontaneously. This study demonstrates that ESWL monotherapy cleared stones in only 8 of 28 patients and clearance in a further 6 was achieved with surgery. Surgery will continue to play an important role in the management of paediatric urolithiasis for large staghorn, multiple urinary tract calculi and lithotripsy failures.