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.

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.

Acute myelomonocytic leukemia (M-4 subtype) with abnormal marrow eosinophilia and a normal chromosome 16.

A variety of chromosome 16 abnormalities, including inversion, deletion, and translocation in patients with acute myelomonocytic leukemia and abnormal marrow eosinophilia have been reported recently. The authors have identified an AMML patient who had a normal karyotype in 50 metaphases. In particular, chromosome 16 was closely examined for abnormality and was found to be entirely normal. In addition, the authors describe new cytochemical and ultrastructural features of the associated abnormal eosinophils.

Tumours of heterotopic salivary tissue in the upper cervical region in children.

Heterotopic salivary tumours in the upper neck are rare. Three children, one with mucoepidermoid carcinoma and two with pleomorphic adenoma in ectopic cervical sites are presented. Local complete excision was successful in the patients with pleomorphic adenoma. More extensive surgery was undertaken for the mucoepidermoid carcinoma. All three patients remain disease free at 3-6 years follow-up. Oncogenesis of heterotopic salivary tissue entrapped in an upper cervical lymph node during embryogenesis is a possible etiological mechanism. In a patient with a cervical malignant salivary tumour, a careful search should be made to find a primary tumour. In the event of a negative search, this should be considered the primary tumour and treated appropriately.

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.

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.

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.

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.

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.

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.

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.

Focal dermal hypoplasia.

A case of focal dermal hypoplasia (FDH) or Goltz syndrome is described. The patient is a black female infant whose syndrome was first diagnosed at birth. This is a disorder of the mesoectoderm which is manifested by pigmentary skin changes similar to other disease entities, eg, incontinentia pigmenti and Rothmund-Thomson disease, but it is easily confirmed by specific significant histologic findings. The characteristic features are all noted in this infant throughout her follow-up, viz, atrophy and linear pigmentation of the skin, localized alopecia, papilloma and marked syndactyly. FDH is an X-linked condition and any physician caring for children should consider this diagnosis of the illness of the patient (especially female) who presents with the above dermal and skeletal changes.

Heterotopic gastric cyst of the tongue in a newborn.

Gastrointestinal heterotopia in the tongue is a rare condition. A male newborn was noted to have a cystic swelling in the anterior part of the dorsum of the tongue. This was surgically excised. Histology revealed it to be a heterotopic gastrointestinal cyst. A literature review was undertaken because of the rarity of this lesion. As most of these cysts are present from birth, they are likely to be developmental in origin.

Are the selection criteria for the conservative management in spina bifida still applicable?

Management of spina bifida is still controversial. At one extreme is the policy of total care in all cases while some form of selection is practised in many centres. We reviewed 104 patients treated over the last five years. Forty-nine patients, who had one or more adverse criteria, were managed conservatively. Twenty-four of these 49 patients required VP shunt insertions subsequently. Four patients had delayed closure of back lesions, three of them were followed by shunts. There was an overall increased (57%) incidence of surgical intervention in conservatively managed patients over the last five years as compared with 34% from our previous report. We found no difference in the timing of insertion of shunts in actively and conservatively managed patients in this study. The mortality in the actively and conservatively managed patients was 7% and 47% respectively. Eighty-five per cent of the patients who had no surgery died at an average age of 23 days. Patients who died without surgical intervention did not survive long enough to warrant surgery, while the mortality was 20% and had among those who survived surgical intervention. Paraplegia alone was not a predictor of high mortality but the presence of two or more adverse criteria were more accurate indicators of poor prognosis. As 78% of all the deaths in conservatively managed patients occurred within three months, reappraisal of management policy is necessary in the infants surviving beyond three months of age as death is less likely after this time.

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.