Lewis and related tumor-associated determinants on ovarian carcinoma

Monoclonal antibodies that defined blood group and related determinants bind to sections of fixed tissues from epithelial ovarian carcinoma in immunoperoxidase assays. Seventy-eight carcinomas and 27 normal tube and ovarian tissues were examined. Lewis (Le)a and Leb determinants were expressed on 58% of the serous carcinomas, on 60% of the endometrioid tumors, and on 78% of the mucinous carcinomas. Sialylated Lea, gastrointestinal cancer-associated antigen (GICA), and lacto-N-fucopentaose (LNF) III, another Le-related determinant, have a similar distribution pattern. Of 10 normal ovaries and fallopian tubes tested from patients without cancer, one reacted with anti-Lea, anti-Leb, or anti-LNF III monoclonal antibodies. Anti-GICA antibodies reacted with tissue from one patient. Le and Le-related antigenic determinants could be useful markers for ovarian cancer.     

Structure-activity relationships of phencyclidine derivatives in rat cerebellum

The depressant effects of phencyclidine [1-(1-phenylcyclohexyl) piperidine, PCP] and three of its analogs (m-amino-PCP, m-nitro-PCP, and PCP-methyliodide) on the spontaneous action potential discharge of cerebellar Purkinje neurons in urethane-anesthetized rats were examined in this study. Both intraperitoneal injection and micro-pressure ejection were employed as routes of drug administration. The relative potency after parenteral administration corresponded closely with previous findings in behavioral test paradigms. PCP and m-amino-PCP were equipotent, m-nitro PCP was less potent than either PCP or m-amino-PCP, and PCP-methyliodide showed almost no activity. After local administration onto neurons, m-amino-PCP was significantly more potent than PCP, while PCP, m-nitro-PCP, and PCP-methyliodide were equipotent. Tritiated PCP, m-nitro PCP, and m-amino PCP have similar distribution and metabolism in cerebellum. PCP-methyliodide, a quaternary ion, does not cross the blood brain barrier. M-nitro PCP is appreciably less ionized at pH 7.4 than PCP or m-amino-PCP and, therefore, may be more easily sequestered into lipids. Differences between PCP and its analogs found in experiments which employ parenteral administration may reflect differences in drug distribution. These differences are minimized when these drugs are administered directly onto neurons via pressure microejection.     

Immunoglobulin-like domain containing receptor 1 mediates fat-stimulated cholecystokinin secretion

Cholecystokinin (CCK) is a satiety hormone produced by discrete enteroendocrine cells scattered among absorptive cells of the small intestine. CCK is released into blood following a meal; however, the mechanisms inducing hormone secretion are largely unknown. Ingested fat is the major stimulant of CCK secretion. We recently identified a novel member of the lipoprotein remnant receptor family known as immunoglobulin-like domain containing receptor 1 (ILDR1) in intestinal CCK cells and postulated that this receptor conveyed the signal for fat-stimulated CCK secretion. In the intestine, ILDR1 is expressed exclusively in CCK cells. Orogastric administration of fatty acids elevated blood levels of CCK in wild-type mice but not Ildr1-deficient mice, although the CCK secretory response to trypsin inhibitor was retained. The uptake of fluorescently labeled lipoproteins in ILDR1-transfected CHO cells and release of CCK from isolated intestinal cells required a unique combination of fatty acid plus HDL. CCK secretion secondary to ILDR1 activation was associated with increased [Ca²⁺]_i, consistent with regulated hormone release. These findings demonstrate that ILDR1 regulates CCK release through a mechanism dependent on fatty acids and lipoproteins and that absorbed fatty acids regulate gastrointestinal hormone secretion.     

Linkage heterogeneity of end-stage renal disease on human chromosome 10

BACKGROUND: The human syntenic region of the rodent renal failure-1 gene (Rf1), an attractive candidate region for end-stage renal disease (ESRD) susceptibility, is located on chromosome 10q24-q26. In an attempt to assess for linkage between markers on human chromosome 10 and ESRD, we performed a linkage analysis in 356 African American sib pairs concordant for ESRD [199 sib pairs concordant for non-diabetic etiologies (hypertension-associated, chronic glomerulonephritis and unknown) and 157 sib pairs concordant for diabetic ESRD]. METHODS: Linkage was tested between 30 polymorphic markers spanning chromosome 10 and ESRD using GeneHunter software. RESULTS: In all 356 sib pairs, the maximum likelihood ratio z-score (Zlr) occurred near locus D10S677 (Zlr = 3.33, P = 0.0004, lod = 3.40), with a lesser peak near D10S1435 (Zlr = 1.77, P = 0.04, lod = 1.42). The locus at D10S677 contributed significantly to both diabetic ESRD (Zlr = 2.39, P = 0.008, lod = 2.08) and non-diabetic ESRD (Zlr = 2.35, P = 0.009, lod = 2.03). Additionally, the D10S677 peak was observed in both early onset (< or =50 years) and late onset (>50 years) ESRD (Zlr = 2.96, P = 0.002, lod = 2.82 in early onset and Zlr = 1.96, P = 0.03, lod = 1.60 in late onset ESRD families, respectively). The lesser peak at D10S1435 was observed in families with non-diabetic etiologies of ESRD (Zlr = 1.94, P = 0.02, lod = 1.58) and in those with early onset ESRD (Zlr = 1.89, P = 0.03, lod = 1.53). CONCLUSIONS: These results suggest that the region near D10S677, adjacent to the human homolog of the Rf1 gene, contributes to ESRD susceptibility in African Americans. They confirm that the region on 10p, near D10S1435, appears to be involved in early onset, non-diabetic etiologies of ESRD in African Americans.     

Effects of nicotine on hippocampal and cingulate activity during smooth pursuit eye movement in schizophrenia.

BACKGROUND: Abnormal smooth pursuit eye movement (SPEM) in schizophrenic patients is a well known phenomenon, but the neurophysiological mechanisms underlying the deficit are unknown. Nicotine temporarily improves SPEM and has been associated with reduced hippocampal hemodynamic activity in schizophrenics. Nicotine's effect on brain activity in control subjects performing SPEM has not been studied. The purpose of this work was to determine if nicotine differentially affects brain activity in schizophrenic and control subjects during pursuit eye tracking. METHODS: 16 subjects with schizophrenia and 16 control subjects underwent functional MR imaging during SPEM after receiving placebo or nicotine gum. Four brain regions were analyzed for main effects of group, drug, and interactions: hippocampus, cingulate gyrus, frontal eye fields, and area MT. RESULTS: Nicotine reduced hippocampal activity in both groups, but the effect was greater in control subjects. A group by drug interaction was observed in the anterior cingulate gyrus, where nicotine decreased activity in control subjects and increased activity in schizophrenic subjects. There were no significant effects of group, drug, or interactions in frontal eye fields or area MT. CONCLUSIONS: Nicotine may improve SPEM performance in people with schizophrenia through cholinergic stimulation of the hippocampus and cingulate gyrus. Potential mechanisms include improved inhibitory function and attention.     

Quantifying axonal loss after optic neuritis with optical coherence tomography

OBJECTIVE: To determine to what degree changes in retinal nerve fiber layer (RNFL) thickness after optic neuritis (ON) correlate with either visual recovery or impairment. METHODS: ON can cause visible defects within the RNFL, which can be quantified using optical coherence tomography (OCT). It may be possible to predict visual recovery by measuring RNFL loss after ON. Fifty-four patients underwent repeated evaluations with optical coherence tomography and standardized ophthalmic testing after ON. Regression analyses were used to determine the relationship between RNFL thickness and visual function. RESULTS: Thinning of the RNFL was seen in the majority of patients (74%), and it tended to occur within 3 to 6 months of ON. The average RNFL value was thinner (p<0.0001) in the affected (78 microm) compared with the unaffected eye (100 microm). Patients with incomplete visual recovery demonstrated greater RNFL loss after ON. Regression analyses demonstrated a threshold of RNFL thickness (75 microm), below which RNFL measurements predicted persistent visual dysfunction. INTERPRETATION: Determination of RNFL thickness may predict visual recovery after ON, and lower RNFL values correlate with impaired visual function. Optical coherence tomography may have a potential role as a surrogate marker for axonal integrity within the optic nerve among patients with ON.     

Margin index: a useful tool for the breast surgeon?

Background

In breast conservation surgery (BCS) for breast cancer, the appropriate surgical margin is controversial. Margin index, a mathematical relationship between tumor size and closest margin, has been shown to be predictive of the probability of residual cancer after BCS for early stage breast cancer. We applied this tool to the same population of patients at our institution to evaluate its ability to predict residual disease after BCS.

Methods

We retrospectively reviewed a prospectively maintained database of women undergoing BCS between 1980 and 2010 at the University of Pennsylvania. A total of 246 women underwent re-excision because of close margins. Average margin index between groups with and without residual disease in the re-excision specimen was compared using the Student t-test. A receiver operating curve was created using logistic regression to assess the overall diagnostic ability of the margin index on the presence or absence of residual disease.

Results

Of patients who underwent re-excision, 29% of patients had residual disease. We analyzed several cutoff values for margin index, but none proved to be significant predictors of residual disease. Average margin index was significantly higher for patients without residual disease compared with patients with residual invasive cancer but not for patients with residual ductal carcinoma in situ.

Conclusions

In women undergoing BCS for early stage breast cancer at our institution, margin index was not predictive of the presence of residual cancer on re-excision. We hypothesize that the predictive ability of a margin index is likely limited by several factors including the presence of ductal carcinoma in situ and the location and extent of the close margin.     

Immunologic heterogeneity of diffuse large cell lymphoma

The cellular lineage of 57 diffuse large-cell lymphomas (DLCLs) was determined using a panel of monoclonal antibodies directed against lineage-restricted and -associated T, B, and monocyte antigens. The majority (82%) were of B cell lineage as determined by the expression of sig and/or B1, with the remaining 16% being of T cell lineage and 2%, of monocyte-myeloid lineage. By the expression of other B cell- restricted and -associated antigens, two major and two minor subgroups could be identified. These subgroups expressed the following phenotypes: (1) B1+B4+sIG+B2- (51%); (2) B1+B4+sIg+B2+ (29%); (3) B1+B4+sIg-B2+ (10%); and (4) B1+B4-sIg+B2- (10)%. The morphology of transformed lymphocytes, the weak to absent expression of the early B cell antigens B2 and sIgD, and the absence of the late B cell differentiation antigens PCA-1 and PC-1 suggested that these tumors were the neoplastic counterparts of normal B cells at the mid-stages of differentiation. Further support for the notion that B-DLCLs correspond to transformed B lymphocytes was concluded from the observation that B cells could be identified in normal spleen that expressed the cell surface phenotype and morphological appearance of the majority of B- DLCLs.     

Separation of lymphoid and myeloid blasts in the mixed blast crisis of chronic myelogenous leukemia: no evidence for Ig gene rearrangement in CALLA-positive blasts

Recent studies suggest that lymphoid blast crisis cells of chronic myelogenous leukemia (CML) expressing the common acute lymphoblastic leukemia antigen (CALLA) are B precursor cells, based on the demonstration of immunoglobulin (Ig) gene rearrangement similar to common acute lymphocytic leukemia. There is little evidence to suggest whether the cells with similar lymphoid characteristics in the mixed blast crisis of CML are also committed to B cell lineage. A patient in "mixed" blast crisis of CML was studied. On the basis of morphology, cytochemistry, and immunological studies, the blasts were classified as having either lymphoid or myeloid characteristics. A proportion of the leukemic blasts expressed CALLA, whereas others expressed My7 antigen. In order to characterize both populations of cell further, CALLA+ blasts and My7+ (myeloid) blasts were isolated by fluorescence-activated cell sorting. The My7+ cells were highly proliferative in cell culture blast colony assays, retained the Ph1 chromosome, and were indistinguishable from acute myelogenous leukemia blasts. The CALLA+ cells were also Ph1-chromosome positive, but in contrast, were poorly proliferative in vitro. Of particular note was their retention of germline configuration of Ig genes, thus distinguishing them from blasts in the lymphoid crisis of CML. We conclude that the lymphoid component in mixed blast crisis may represent a stage of differentiation prior to commitment to B lineage.     

Influence of coronary collateral blood flow on the development of exertional ischemia and Q wave infarction in patients with severe single-vessel disease

The functional significance of coronary collateral flow from a nonobstructed supply artery was studied in 121 patients with severe (greater than or equal to 80%) single-vessel disease, 64 with and 57 without Q wave infarction. All patients underwent exercise thallium imaging and coronary angiography. On angiography, collateral flow was present in 85% of 74 occluded arteries compared with only 17% of 47 arteries with subtotal obstruction (p less than .001). Collateral flow was not seen in arteries with lesions of less than 90% obstruction. Collateral flow was present in 100% of 29 occluded arteries in patients without Q wave infarction compared with only 76% of 45 occluded arteries with Q wave infarction (p less than .005). Clinical variables did not correlate with collateral flow. Collateral flow did not prevent ischemia on exercise thallium imaging in patients without Q wave infarction: 30 of 33 (91%) with collateral flow had reversible thallium defects compared with 24 of 24 (100%) without collateral flow (p = NS). In patients with Q wave infarction, partially reversible exercise thallium defects (peri-infarctional ischemia) were more common with flow to the area from either subtotal obstruction (73%) or collateral flow (45%) than with no flow from total occlusion (27%; p = .05). In patients with severe single-vessel disease the presence of collateral flow is principally determined by coronary occlusion. Collateral flow may protect from Q wave infarction but does not prevent exercise ischemia on thallium imaging.