Photoperiodic changes in endocannabinoid levels and energetic responses to altered signalling at CB1 receptors in Siberian hamsters.

Siberian hamsters (Phodopus sungorus) adapt to seasonal environmental conditions with marked changes in body mass, primarily in the form of adiposity. Winter-like conditions (e.g. short days) are sufficient to decrease body mass by approximately 30% in part via reductions in food intake. The neuroendocrine mechanisms responsible for these changes are not well understood, and homeostatic orexigenic/anorexigenic systems of the hypothalamus provide little explanation. We investigated the potential role of endocannabinoids, which are known modulators of appetite and metabolism, in mediating seasonal changes in energy balance. Specifically, we housed hamsters in long or short days for 0, 3, or 9 weeks and measured endocannabinoid levels in the hypothalamus, brainstem, liver and retroperitoneal white adipose tissue (RWAT). An additional group of males housed in short days for 25 weeks were also compared with long-day controls. Following 9 weeks in short days, levels of the endocannabinoid 2-arachidonoylglycerol (2-AG) were significantly elevated in RWAT and reduced in brainstem, although they returned to long-day levels by week 25 in short-day males that had cycled back to summer-like energy balance. Endocannabinoid levels in these tissues correlated significantly with adiposity and change in body mass. No photoperiodic changes were observed in the hypothalamus or liver; however, sex differences in 2-AG levels were found in the liver (males > females). We further tested the effects of CB(1) receptor signalling on ingestive behaviour. Five daily injections of CB(1) antagonist SR141716 significantly reduced food intake and body mass but not food hoarding. Although the CB(1) agonist arachidonyl-2-chloroethylamide did not appreciably affect either ingestive behaviour, body mass was significantly elevated following 2 days of injections. Taken altogether, these findings demonstrate that endocannabinoid levels vary with sex and photoperiod in a site-specific manner, and that altered signalling at CB(1) receptors affects energy balance in Siberian hamsters.

Leiomyomatosis-like lymphangioleiomyomatosis of the colon in a female with tuberous sclerosis.

Smooth muscle lesions of the large bowel, excluding the rectum, are generally rare, and diffuse smooth muscle lesions, termed leiomyomatosis, are even rarer. In this report, we document, for the first time, leiomyomatosis-like lymphangioleiomyomatosis (LAM) of the ascending, transverse, and descending colon in association with bilateral renal angiomyolipoma (AML) in a 30-year-old Chinese female with tuberous sclerosis complex (TSC). She presented with protracted constipation for which a colectomy was performed. Histology disclosed multiple confluent nodular CD34 and CD117 negative smooth muscle proliferation within the large bowel wall, whereas the renal biopsy revealed typical features of AML. Interestingly, the epithelioid smooth muscle cells of both the colonic and renal lesions were HMB45 positive, suggesting that leiomyomatosis-like LAM of the colon, pulmonary LAM and AML are closely related entities. The patient remained free of complications for the last five years after surgery. Leiomyomatosis-like LAM of the large bowel probably represents another manifestation of the tendency of TSC to be associated with proliferative lesions.

Unusual sites (thorax and umbilical hernial sac) of endometriosis.

Extra-pelvic endometriosis in the thorax or umbilical hernia is rare. We report a case of thoracic endometriosis presenting with isolated chest pain and a case of endometriosis in an umbilical hernial sac mimicking incarceration. The clinical course and management of the patients and a literature review of these two unusual sites of endometriosis are discussed.

Prevalence of Helicobacter pylori in gastric cancer in a South-East Asian population by 14C-urea breath test.

BACKGROUND: Helicobacter pylori is believed to play an important role in the aetiology of gastric cancer. There is a great variability in seropositivity and histological frequency of H. pylori in gastric cancer. The present prospective study investigates the prevalence of H. pylori infection in gastric cancer patients using 14C-urea breath testing. METHODS: Patients with endoscopic biopsy-proven gastric cancer were fasted for 6 h prior to ingesting 18.5 x 104 Bq of 14C-urea cocktail orally. Breath samples were collected after 20 min by asking them to blow into a hyamine solution and measurements were read in a scintillation counter. RESULTS: Fifty out of 51 patients (98%) with gastric cancer were positive on the 14C-urea breath test compared to 29 patients (61%) who were positive on histology. There was no association between sex, age or tumour site, stage, differentiation, Lauren type and H. pylori status. The test was negative in one patient with cardial tumour in which histology of the resected specimen was also negative for the bacteria. CONCLUSIONS: Active H. pylori infection is highly prevalent in gastric cancer in a South-East Asian population. The 14C-urea breath test is a highly sensitive method for detecting the presence of H. pylori even in gastric adenocarcinoma irrespective of the stage.

TEL-JAK2 mediates constitutive activation of the phosphatidylinositol 3'-kinase/protein kinase B signaling pathway.

A subset of chromosomal translocations that participate in leukemia involve activated tyrosine kinases. The ets transcription factor, TEL, undergoes translocations with several distinct tyrosine kinases including JAK2. TEL-JAK2 transforms cell lines to factor independence, and constitutive tyrosine kinase activity results in the phosphorylation of several substrates including STAT1, STAT3, and STAT5. In this study we have shown that TEL-JAK2 can constitutively activate the phosphatidylinositol 3'-kinase (PI 3'-kinase) signaling pathway. The regulatory subunit of PI 3'-kinase, p85, associates with TEL-JAK2 in immunoprecipitations, and this was shown to be mediated by the amino-terminal SH2 domain of p85 but independent of a putative p85-binding motif within TEL-JAK2. The scaffolding protein Gab2 can also mediate the association of p85. TEL-JAK2 constitutively phosphorylates the downstream substrate protein kinase B/AKT. Importantly, the pharmacologic PI 3'-kinase inhibitor, LY294002, blocked TEL-JAK2 factor-independent growth and phosphorylation of protein kinase B. However, LY294002 did not alter STAT5 tyrosine phosphorylation, indicating that STAT5 and protein kinase B activation mediated by TEL-JAK2 are independent signaling pathways. Therefore, activation of the PI 3'-kinase signaling pathway is an important event mediated by TEL-JAK2 chromosomal translocations.

Concurrent de novo autoimmune hepatitis and recurrence of primary biliary cirrhosis post-liver transplantation.

Primary biliary cirrhosis (PBC) is well known to recur after liver transplantation (LT). The recurrence is usually subclinical and evident only on histological examination. Recently, a new entity of de novo autoimmune hepatitis (AIH) has emerged that occurs after LT in patients who underwent transplantation for diseases other than AIH. This new condition occurs more often in children; however, there was a recent report of the first 2 cases in adults who originally underwent LT for PBC. We report the first case of concurrent de novo AIH and recurrence of PBC documented on the liver biopsy of an adult patient who underwent LT for end-stage PBC. Unlike the earlier report of 2 adults, our patient manifested an antinuclear antibody titer of more than 1/800 from a previously negative titer pre-LT, as well as fulfilled the International AIH Group criteria for a definite diagnosis of AIH. PBC recurrence was evidenced by typical florid duct lesion, antimitochondrial antibody titer increasing from 1/40 to greater than 1/800, and an elevated serum immunoglobulin M level. After the addition of azathioprine to baseline immunosuppression of tacrolimus and prednisolone, the patient responded rapidly, with complete normalization of liver test results.

Primary leiomyoma of the liver.

This case report describes a primary hepatic leiomyoma presenting as a mass lesion detected on ultrasonography of the abdomen in an asymptomatic hepatitis B carrier on routine surveillance. Primary leiomyomata of the liver are rare occurrences, with only 9 cases reported in the literature. The presenting features of primary hepatic leiomyomata and diagnostic approach towards such lesions are discussed. The significance of such tumours in the immunocompromised is also mentioned.

Early hepatocellular carcinoma presenting with biliary ductal invasion--a case report.

Early and small hepatocellular carcinoma (HCC) rarely presents with biliary ductal invasion. We present a case of early HCC presenting with biliary invasion, in the absence of a mass on computed tomographic scanning. The patient, a hepatitis B carrier, was initially diagnosed to have "liver fluke infection" after a "leaf-like structure" was found within the right hepatic duct on endoscopic retrograde cholangiopancreatography (ERCP). The specimen was retrieved with a Dormia basket. Histology revealed HCC. This report highlights an unusual case of early and small HCC presenting with biliary ductal invasion. A high index of suspicion has to be entertained in the background of hepatitis B regardless of the atypicality of presentation.

Fusion of the ets transcription factor TEL to Jak2 results in constitutive Jak-Stat signaling.

To study constitutive Janus kinase signaling, chimeric proteins were generated between the pointed domain of the ets transcription factor TEL and the cytosolic tyrosine kinase Jak2. The effects of these proteins on interleukin-3 (IL-3)-dependent proliferation of the hematopoietic cell line, Ba/F3, were studied. Fusion of TEL to the functional kinase (JH1) domain of Jak2 resulted in conversion of Ba/F3 cells to factor-independence. Importantly, fusion of TEL to the Jak2 pseudokinase (JH2) domain or a kinase-inactive Jak2 JH1 domain had no effect on IL-3-dependent proliferation of Ba/F3 cells. Active TEL-Jak2 constructs (consisting of either Jak2 JH1 or Jak2 JH2+JH1 domain fusions) were constitutively tyrosine-phosphorylated but did not affect phosphorylation of endogeneous Jak1, Jak2, or Jak3. TEL-Jak2 activation resulted in the constitutive tyrosine phosphorylation of Stat1, Stat3, and Stat5 as determined by detection of phosphorylation using activation-specific antibodies and by binding of each protein to a preferential GAS sequence in electrophoretic mobility shift assays. Elucidation of signaling events downstream of TEL-Jak2 activation may provide insight into the mechanism of leukemogenesis mediated by this oncogenic fusion protein.

Salvia miltiorrhiza reduces experimentally-induced hepatic fibrosis in rats.

BACKGROUND/AIMS: Hepatic fibrosis occurs as a result of injury to the liver parenchyma and biliary system. We have studied the effect of the traditional Chinese medicinal herb, Salvia miltiorrhiza, in an experimental model of hepatic fibrosis and evaluated its effect on various paradigms involved in hepatic fibrosis. METHODS: Liver fibrosis was induced in male Wistar rats by chronic administration of carbon tetrachloride for 10 weeks. The carbon tetrachloride-treated rats were randomly assigned to three groups: no treatment, Salvia for 12 weeks from the onset of carbon tetrachloride treatment, and Salvia for 2 weeks after the completion of the 10-week course. The normal control groups in the study were: neither carbon tetrachloride nor Salvia, and Salvia only for 12 weeks. The livers were graded histologically and analyzed by reverse transcription-polymerase chain reaction for the transcription of genes involved in liver fibrosis, namely, transforming growth factor-beta1 and the extracellular matrix components procollagens I and III, tissue inhibitor of metalloproteinase-1 and matrix metalloproteinase-13. The transcripts were normalized against that of glyceraldehyde-3-phosphate dehydrogenase and analyzed statistically. RESULTS: The histological evaluation showed that Salvia could reverse the fibrosis caused by carbon tetrachloride treatment. Rats treated with the herb had reduced levels of transforming growth factor-beta1, procollagens I and III and tissue inhibitor of metalloproteinase-1 transcripts and an increased level of matrix metalloproteinase-13 transcript, when compared to the disease control. CONCLUSION: Salvia miltiorrhiza, a cheap and widely available herb, significantly reduces carbon tetrachloride-induced hepatic fibrosis in rats.

Young age is not a poor prognostic marker in colorectal cancer.

BACKGROUND: There is still considerable controversy and debate regarding the features and prognosis of colorectal cancer in young patients. METHODS: One hundred and ten patients (5.1 per cent) under the age of 40 years with colorectal cancer (group Y; male: female ratio 48:62) were compared with 2064 patients with colorectal cancer aged 40 years or more (group O; 917 women, 1147 men). Mode of presentation, stage at diagnosis, tumour characteristics and survival were analysed. RESULTS: Predisposing malignant conditions and family history of colorectal cancer were present in 20.9 per cent of patients in group Y versus 2.2 per cent in group O (P < 0.001). Common chief complaints included change in bowel habits, bleeding from the rectum and a significantly higher incidence of abdominal pain in group Y. There was no difference in stage at presentation between the two groups (the proportion of Dukes stage A, B, C and 'D' lesions in group Y was 8.2, 24.5, 37.3 and 30.0 per cent respectively versus 10.5, 27.9, 33.4 and 28.1 per cent in group O). Tumour site and characteristics were similar in both groups. The incidence of mucinous/signet ring cell and poor grade tumours was 6.9 and 11.8 per cent respectively in group Y and 4.5 and 10.5 per cent in group O. With a mean follow-up of 31.8 months, the overall 5-year survival rate was 54.8 per cent in group Y and 54.1 per cent in group O. Comparing stage for stage, survival was not significantly different in the two groups. However, the adjusted hazard ratios of the age groups Y, M (40-59 years), S (60-79 years), and E (80 years and above) were 1.3, 1 (baseline for calculations), 1.4 and 2.4 respectively, suggesting an adverse outcome for patients in group Y compared with patients aged 40-59 years. CONCLUSION: This study revealed no difference in tumour characteristics and survival in patients with colorectal cancer aged less than 40 years compared with those aged above 40 years. However, a higher hazard ratio in the youngest group may connote a worse prognosis than that for those aged 40-59 years. A significant family history of colorectal cancer and predisposing conditions in the young warrants aggressive screening, surveillance and treatment of the underlying conditions. The detection of colorectal cancer in young patients should be no different from that in the old but demands a high index of suspicion.

Local recurrence following rectal resection for cancer.

Recurrent rectal carcinoma following surgery carries an extremely poor prognosis and subsequent intervention is usually palliative. The incidence of local recurrence (LR) following curative surgery for rectal cancer has been reported to range from 3.7 to 50%. Current treatment strategy for rectal cancer aims at minimizing LR by either pre-operative radiotherapy or adjuvant chemoradiotherapy. Three hundred and fifty-four patients underwent surgical resection for rectal cancer in our department between April 1989 and March 1994, of which 47 (13%) were Dukes A, 88 (25%) Dukes B, 143 (40%) Dukes C and 76 (22%) Dukes D. Two hundred and seventy-eight (79%) patients were defined as having had curative resection (Dukes A, B and C). Overall, total LR occurred in 43 (12.2%) of 354 patients, while LR following curative resection occurred in 16 (9.4%) of the 278 patients. The incidence of LR became higher with increasing depth of invasion and lymph nodal involvement as shown by its direct relationship to stage of disease: Dukes A (0%), B (5.7%), C (14.6%) and D (22.3%). Local recurrence following resection for rectal cancer in our series is low. Pre-operative radiotherapy or adjuvant chemoradiotherapy may not further reduce this low incidence of LR significantly and its role needs to be re-evaluated for institutions with low local recurrence rates.

CMV colitis masquerading as colon cancer--an unusual presentation of acquired immunodeficiency syndrome.

We present a case-report of a patient with a typical history and a barium enema study diagnostic of right-sided colonic cancer. Laparotomy and right hemicolectomy was carried out. Histological examination revealed Cytomegalovirus (CMV) colitis and the patient was subsequently tested positive for Human immunodeficiency Virus (HIV). Gastrointestinal symptoms are common in patients with Acquired Immune Deficiency Syndrome (AIDS) and up to 10% of all AIDS patients have CMV colitis. The diagnostic criteria for CMV colitis is reviewed. AIDS is likely to become more common and we stress the awareness of this condition as well as the need for preoperative colonoscopy and histological diagnosis in patients with radiological diagnosis of colorectal carcinoma.

Distortion in TGF beta 1 peptide immunolocalization in biliary atresia: comparison with the normal pattern in the developing human intrahepatic bile duct system.

Biliary atresia is an important cause of neonatal obstructive jaundice in which there is inflammation, sclerosis and eventual obliteration of the bile duct system. Its onset may be antenatal, affecting the normal development of the biliary system. The intrahepatic biliary system is derived from the ductal plate, a sheath of cuboidal epithelium that appears at the hepatocyte-mesenchymal junction around the portal vein branches at 6 weeks gestation. This epithelial structure is moulded into a network of tubular bile ducts by the proliferating mesenchyme. Certain portions of the ductal plate are selected to become definitive bile ducts, while redundant biliary epithelium is deleted. The molecular dynamics controlling the intra-uterine development of the biliary system in humans are not yet clearly understood. Transforming growth factor-beta 1 is a cytokine that stimulates mesenchymal proliferation and inhibits epithelial growth, and has been shown to be important in organogenesis. In the present study, the pattern of TGF beta 1 peptide immunolocalization was investigated with the aid of computerized image analysis, in normal human bile duct development and in biliary atresia. TGF beta 1 peptide was detected within hepatocytes and ductal plate epithelium from 7 weeks gestation; increased TGF beta 1 immunoreactivity was present within the epithelium of developing bile ducts at 13 weeks gestation, and apical polarization of the cytokine was observed from 16 weeks gestation. In biliary atresia, the TGF beta 1 immunoreactivity pattern within the bile duct structures at the porta hepatis and within intrahepatic portal tracts resembled that of the primitive ductal plate, and there was no significant apical polarization. This may indicate a developmental arrest in the normal ductal plate remodelling process in biliary atresia, and suggests an underlying epithelial-mesenchymal interactive disorder.

Solitary rectal ulcer syndrome: the clinical entity and anorectal physiological findings in Singapore.

The clinical pattern and physiological abnormalities in solitary rectal ulcer syndrome (SRUS) occurring in Singapore, were investigated. Since April 1989, 25 patients have presented with histologically proven SRUS. There were 13 males and 12 females (20 Chinese, 4 Malay and 1 Indian) with a mean age of 47.5 (+/- 3.1) years. Ninety-six per cent presented with rectal bleeding, 92% strained at stools, 40% had mucus discharge, 40% felt incomplete defecation and 32% digitated to defecate. Four had previous haemorrhoidectomies that did not cure their symptoms. The lesions were at a mean 6.8 (+/- 0.5) cm above the anal verge, usually anteriorly (64%) but one was circumferential. Anorectal physiology performed on 14 patients was compared with 13 age and gender matched normal controls. The measured mean resting perineum level in SRUS (1.4 +/- 0.3 cm) was significantly lower than in normals (P < 0.01). The mean anal electrosensory threshold (2.5 +/- 0.52 mV) was also significantly higher than in the controls (P < 0.05). Fifteen patients were successfully treated with a high fibre diet and avoidance of straining. Three patients required surgery and the most recent seven patients have responded well to biofeedback treatment. Awareness of this uncommon anorectal condition is necessary for early diagnosis and appropriate management. The physiological findings support a pelvic straining pathophysiology resulting in perineal descent, with less sensitive rectal mucosa prolapsing into, and raising, the anal canal electrosensory threshold. Treatment strategies aimed at correcting the straining have usually been successful.

Histoanatomy of anal glands.

PURPOSE: This study was designed to investigate the histology of adult anal glands using conventional as well as immunochemical methods. METHODS: Fifteen fresh human ani were prepared and stained with conventional and immunohistologic stains. RESULTS: The median number of anal glands in each anus was six (range, 3-10). Sixty-eight (80 percent) of 85 anal glands found were submucosal in extent, seven (8 percent) extended to the circular internal sphincter, seven (8 percent) to the longitudinal internal sphincter, two (2 percent) to the intersphincteric space, and only one (1 percent) penetrated the external anal sphincter. Ampulla-like dilations were noted in anal glands from ten patients only, occurring at the submucosal level in seven ani and at the circular internal sphincter in three ani. Lymphocytic infiltrations were noted around the glands in all ani studied. Mucus-secreting cells were found in all ani, and many glands showed the presence of intraluminal secretions. Immunostaining for smooth muscle actin showed the presence of one to two cell layers of myoepithelial cells surrounding all anal glands. CONCLUSIONS: Anal glands are definite preformed structures with secretory activity.

Sudden postoperative death from ruptured intracranial vascular malformations in a patient receiving total parenteral nutrition.

A 30-year-old female patient underwent oesophagectomy and colonic transposition for multiple oesophageal strictures associated with epidermolysis bullosa dystrophica. On the 9th postoperative day, she had convulsions and died, whilst in a state of severe hyperglycaemia, which was presumably iatrogenically induced by total parenteral nutrition. Autopsy and subsequent histological examination revealed that the cause of death was acute subarachnoid haemorrhage from ruptured, intracranial cryptic arteriovenous malformations. Postmortem vitreous biochemistry confirmed that death had occurred in a state of hyperglycaemia. The pathology of intracranial vascular malformations and the medico-legal implications of this case are discussed.

Gross and histological abnormalities of the foregut in familial adenomatous polyposis: a study from a South East Asian Registry.

Polyps in the stomach and duodenum are frequently found in familial adenomatous polyposis. Cancer arising from some of these polyps may be an important cause of death in patients who have had large bowel resections. This study aims to determine the nature and distribution of foregut polyps in Chinese patients. Twenty-five patients with familial adenomatous polyposis were gastroscoped by a single operator using the end viewing video-endoscopy system. Representative biopsies of normal mucosa or polyps where appropriate were taken from the gastric fundus, antrum and the duodenum. Twenty-five patients were studied. Male = 17, female = 8. Median age was 32 years (range = 17-63 yrs). Nineteen patients were found to have macroscopically visible polyps in the foregut. Ten patients had gastric polyps alone, three patients had duodenal polyps alone whilst six patients had both gastric and duodenal polyps. Twelve, one and three patients had more than 20 polyps in the gastric fundus, antrum and duodenum respectively. Only one patient had polyps which were larger than 10 mm. The commonest polyp in the gastric fundus was the fundic gland polyp whilst hyperplastic and adenomatous polyps were the commonest polyps in the gastric antrum and duodenum respectively. Five patients had adenomatous polyps of which four had duodenal adenomas alone whilst one patient had adenomas in the duodenum, gastric antrum and fundus. Seventy-six per cent of our patients with familial adenomatous polyposis had foregut polyposis. Adenomatous polyps were found in 56% of patients with duodenal polyps or 20% of patients with foregut polyps but hyperplastic and hamartomatous polyps occur commonly in patients with familial adenomatous polyposis as well.

Hepatic granulomas--an experience over the last 8 years.

Twenty cases of hepatic granulomas seen in the Department of Medicine over the period of 8 years from 1981-1988 were reviewed. Prolonged fever and jaundice were the commoner presentations. While the aetiology was varied, patients with tuberculosis and idiopathic causes formed the major groups. There were also 2 rare causes, one due to cytomegalovirus infection and the other a result of allopurinol hypersensitivity. The idiopathic group of cases fared well but those with tuberculosis did badly and 2 out of 6 died. The absence of pulmonary involvement and the high incidence of jaundice and liver dysfunction in the patients with tuberculosis were the other striking features.