Intussusception of the small bowel discovered incidentally by computed tomography

Three cases of asymptomatic intussusception in adults are reported, discovered incidentally during a CT scan of the abdomen. It is being increasingly observed in adults, possibly aided by the reformatting capabilities of the new multislice CT scanners. It has been documented in children where it is considered to be transient and of no clinical significance.     

Risk factors for detecting germline BRCA1 and BRCA2 founder mutations in Ashkenazi Jewish women with breast or ovarian cancer

We ascertained 184 Ashkenazi Jewish women with breast/ovarian cancer (171 breast and 13 ovarian cancers, two of the former also had ovarian cancer) in a self-referral study. They were tested for germline founder mutations in BRCA1 (185delAG, 5382insC, 188del11) and BRCA2 (6174delT). Personal/family histories were correlated with mutation status. Logistic regression was used to develop a model to predict those breast cancer cases likely to be germline BRCA1/BRCA2 mutation carriers in this population. The most important factors were age at diagnosis, personal/family history of ovarian cancer, or breast cancer diagnosed before 60 years in a first degree relative. A total of 15.8% of breast cancer cases, one of 13 ovarian cancer cases (7.7%), and both cases with ovarian and breast cancer carried one of the founder mutations. Age at diagnosis in carriers (44.6 years) was significantly lower than in non-carriers (52.1 years) (p<0.001), and was slightly lower in BRCA1 than BRCA2 carriers. Thirty three percent of carriers had no family history of breast or ovarian cancer in first or second degree relatives. Conversely, 12% of non-mutation carriers had strong family histories, with both a first and a second degree relative diagnosed with breast or ovarian cancer. The predicted values from the logistic model can be used to define criteria for identifying Ashkenazi Jewish women with breast cancer who are at high risk of carrying BRCA1 and BRCA2 mutations. The following criteria would identify those at approximately 10% risk: (1) breast cancer <50 years, (2) breast cancer <60 years with a first degree relative with breast cancer <60 years, or (3) breast cancer <70 years and a first or second degree relative with ovarian cancer.     

Mitogenic signal transduction caused by monomethylarsonous acid in human bladder cells: role in arsenic-induced carcinogenesis.

Previous studies have shown that human bladder cells (UROtsa), a target of arsenic-induced cancer, can biotransform arsenite to monomethylarsonous acid (MMA(III)), which is more cytotoxic and capable of transforming the UROtsa cells following long-term, low-level exposure. Cyclooxygenase-2 (COX-2) causes hyperplasia in bladder cells and is considered a key biomarker in bladder cancer. To investigate the role of mitogenic pathway stimulation in MMA(III)-induced transformation, UROtsa cells were treated with 50nM MMA(III) for 12, 24, or 52 weeks and analyzed by Western blot for COX-2 expression. Elevations in COX-2 expression were noted following chronic MMA(III) exposure, and this induction increased with duration of exposure, suggesting that COX-2 or the signal transduction pathways responsible for COX-2 protein expression may play a role in MMA(III)-induced transformation. Acute exposure studies found MMA(III) treatment (10, 50, and 100nM, 4 h) induced COX-2 in UROtsa cells with the lowest doses (10 and 50nM) causing the strongest induction. Using pharmacological inhibitors of various pathways, it was shown that epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (ERK-1/-2), phosphoinositide 3-kinase (PI3K), and src were important in the induction of COX-2 by MMA(III). ERK-2 phosphorylation was verified by Western blot analysis with a peak at 15 min, and c-jun was translocated to the nucleus following 50nM MMA(III) treatment. To determine MMA(III) targets, receptors of the erythroblastosis oncogene family (ErbB) family were further investigated. Chronic MMA(III) exposure led to upregulation of the EGFR or ErbB1. Short-term MMA(III) treatment caused the phosphorylation of ErbB2 in its autophosphorylation site. To verify the importance of these signaling pathways to the growth of the MMA(III)-transformed UROtsa cells in soft agar, various inhibitors were used to block pathways and monitor cells growth. Pathways of importance in anchorage-independent growth of UROtsa cells chronically exposed to MMA(III) are src, PI3K, and COX-1 and -2. As COX-2 is an important mediator that contributes to carcinogenesis via promotion of cell proliferation, inhibition of cell death, induction of angiogenesis, and facilitation of invasion, and it is highly upregulated both acutely and chronically in the MMA(III)-transformed cells, it is likely that activation of the mitogen-activated protein kinase pathway and increased COX-2 expression is a plausible mechanism for MMA(III) bladder carcinogenesis.     

Binding of the anticancer prodrug CB1954 to the activating enzyme NQO2 revealed by the crystal structure of their complex

CB1954 is an attractive prodrug for directed-enzyme prodrug therapy (DEPT) and a conventional prodrug against tumors in which the enzyme NQO2 is highly expressed. We have determined the crystal structure of the NQO2-CB1954 complex to 2.0 A resolution. The binding of the prodrug is governed by hydrophobic forces, while two key electrostatic contacts determine the specific orientation of the ligand. The structure also reveals an unfavorable interaction, therefore suggesting possible avenues for DEPT-tailored engineering studies.     

Migration of binucleate cells in the sheep placenta during normal pregnancy

Summary The maternofetal interface in the placentomes of the sheep placenta consists of a fetal cellular chorion layer whose apical microvilli interdigitate with those of a syncytial layer which borders the maternal connective tissue. Most of the granulated binucleate cells found in the chorion epithelium reach neither its basement membrane nor its microvillar junction apex. However, up to one fifth of the binucleate cells can be shown to be part of or push pseudopodia across the microvillar junction or are located within the syncytium.The syncytium and chorionic binucleate cells both have a nuclear chromatin structure and distinctive cytoplasmic granules which are not found in any other placental cells. This suggests that most, if not all, of the syncytium is derived by fusion of fetal binucleate cells which have migrated across the microvillar junction from the chorion, and that the immunological maternofetal junction does not lie between chorion and syncytial layers.     

Crohn's Disease: A Review of 122 Cases

Summary: One-hundred-and-twenty-two patients with Crohn's disease were admitted to Royal Prince Alfred Hospital from 1966 to 1977. Thirty-seven had disease confined to small bowel, 37 to colon and 48 had combined small and large bowel involvement. The disease was twice as common in females as in males. Pain was the major symptom in patients with small bowel disease and was associated with diarrhoea if both small and large bowel were involved. Disease confined to the colon most commonly produced diarrhoea with bleeding. Perianal disease occurred more often in patients with colonic disease. Systemic complications were also more frequent in the group with disease confined to colon, and these complications were often multiple. Medical treatment with corticosteroids, salazopyrine or azathioprine, was generally unsuccessful. One in two patients required surgery, usually in the form of resection. Following resection, recurrence occurred in more than one half of the patients but was less frequent in those with colonic disease. Three-quarters of patients with a recurrence required a further resection, emphasising the unsatisfactory long-term results of surgery in this disease.