Tricyclic farnesyl protein transferase inhibitors: crystallographic and calorimetric studies of structure-activity relationships.

Crystallographic and thermodynamic studies of farnesyl protein transferase (FPT) complexed with novel tricyclic inhibitors provide insights into the observed SAR for this unique class of nonpeptidic FPT inhibitors. The crystallographic structures reveal a binding pattern conserved across the mono-, di-, and trihalogen series. In the complexes, the tricycle spans the FPT active site cavity and interacts with both protein atoms and the isoprenoid portion of bound farnesyl diphosphate. An amide carbonyl, common to the tricyclic compounds described here, participates in a water-mediated hydrogen bond to the protein backbone. Ten high-resolution crystal structures of inhibitors complexed with FPT are reported. Included are crystallographic data for FPT complexed with SCH 66336, a compound currently undergoing clinical trials as an anticancer agent (SCH 66336, 4-[2-[4-(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5, 6]cyclohepta[1, 2-b]pyridin-11-yl)-1-piperidinyl]-2-oxoethyl]-1-piperidinecarbo xamide ). Thermodynamic binding parameters show favorable enthalpies of complex formation and small net entropic contributions as observed for 4-[2-[4-(3,10-dibromo-8-chloro-6,11-dihydro-11H-benzo[5, 6]cyclohepta[1, 2-b]pyridin-11-ylidene)-1-piperidinyl]-2-oxoethyl]pyridine N-oxide where DeltaH degrees bind = -12.5 kcal/mol and TDeltaS degrees bind = -1.5 kcal/mol.     

Enterococcal endocarditis: clinical and microbiological features of our series

Of 81 cases of infectious endocarditis seen at our institution from 1988 to 1995, 61 had positive culture (75%) and, of these, 10 (16%) were caused by enterococcal strains (9 by Enterococcus faecalis, 1 by Enterococcus faecium). The 10 cases consisted of 5 native valve endocarditis and 5 late prosthetic valve endocarditis. Median age of patients was 50 years (range 21-58); 6, were males. Diagnostic or surgical procedures on the abdomen, genito-urinary tract, or chest preceded the onset of fever in almost all cases. Nine enterococcal strains showed low-level resistance to aminoglycosides and one was highly resistant. Seven patients were treated with ampicillin and gentamicin and 2 with teicoplanin and gentamicin. The patient, whose infection was caused by an high gentamicin-resistant E. faecalis, was treated with the combination of ciprofloxacin and cotrimoxazole chosen on the basis of the in vitro susceptibility tests. Congestive heart failure occurred in 4 patients and major embolic events in 3. All patients were cured; 4, with medical therapy alone and 6, with antimicrobials associated with surgical substitution of the valve. The data indicate that enterococcal endocarditis, when treated with appropriate antimicrobial regimens, associated with surgical treatment when necessary, has a very low mortality rate. The conventional treatment, -lactams plus gentamicin is usually effective. However, for high-level gentamicin-resistant strains alternative treatments must be selected on the basis of the in vitro susceptibility tests.     

Alkamides from Cissampelos glaberrima

Two alkamides, deca-2E,4E-dienoic acid isobutylamide (1) and octa-2E,4E-dienoic acid isobutylamide (2), were isolated from the roots of Cissampelos glaberrima (Menispermaceae). Their structures were established by spectral and physical methods. Traces of two new alkamides, decen-2-oic acid isobutylamide (3) and decanoic acid isobutylamide (4), were identified by mass spectrometry.     

The epidemiology of endometrial cancer in young women

A case-control study was conducted in Los Angeles County, California, of 127 endometrial cancer cases aged 45 years or less at diagnosis, to investigate the role of fertility, obesity and exogenous oestrogens in the development of the disease in young women. Use of sequential oral contraceptive (SOCs) or oestrogen replacement therapy (ERT) for greater than or equal to 2 years was strongly associated with increased risk of endometrial cancer. After excluding these cases, since the SOC or ERT use was probably the cause of their disease, we were left with 110 case-control pairs for further study. Among these remaining case-control pairs increasing parity was strongly associated with decreased risk (relative risk of 0.12 for women of parity 3 compared to nulliparous women, P less than 0.001). Current weight was associated with increased risk (relative risk of 17.7 for women weighing greater than or equal to 190 lbs compared to women weighing less than 130 lbs, P less than 0.001). Combination oral contraceptive (COC) use was associated with a decreased risk, which decreased with duration of COC use (relative risk of approximately 0.28 at 5 years of use, P less than 0.001), but the estimate of the protective effect was reduced and became statistically non-significant when allowance was made for weight and parity. The protective effect of COC use was only clearly evident in women who had less than 3 live-births and weighed less than 170 lbs. These results provide further support for the "unopposed" oestrogen hypothesis of the aetiology of endometrial cancer.     

Spatial and Temporal Patterns of Neurogenesis in the Chick Retina

Chick embryo retinas were labelled in ovo by single injections of [3H]thymidine at selected times between days 2 and 12 of incubation. Embryos were later removed, at different stages of development, and the retinas processed for autoradiography of either serial sections or dissociated cell preparations. Analysis of unlabelled cells shows that neurogenesis starts, on day 2 of incubation, in a dorsotemporal area of the central retina, close to the posterior pole and to the optic nerve head. A gradient of neurogenesis spreads from this central area to the periphery, where neurogenesis ends, shortly after day 12, when the last few bipolar cells withdraw from the cell cycle. Additional dorsal-to-ventral and temporal-to-nasal gradients can be discerned in our autoradiographs. In all retinal sectors, ganglion cells start first to withdraw from the cell cycle, followed, with substantial overlapping, by amacrine, horizontal, photoreceptor plus Müller, and bipolar neuroblasts. Ganglion cells are also the first to reach the 50% level of unlabelled cells, followed this time by horizontal, photoreceptor, amacrine, Müller and bipolar cells. Finally, 100% levels of unlabelled cell populations are attained simultaneously by ganglion, horizontal and photoreceptor cells, followed by amacrine, then by Müller, and last by bipolar cells. Although all classes of neurons, in varying proportions, are being produced most of the time, our results also demonstrate that, in any given retinal area, the first cells leaving the cycle are determined to become ganglion cells, and the last ones bipolar cells, and not other types.     

Colorectal cancer screening knowledge, attitudes, and beliefs among veterans: does literacy make a difference?

PURPOSE: To evaluate whether lower literacy is associated with poorer knowledge and more negative attitudes and beliefs toward colorectal cancer screening among veterans without recent colorectal cancer screening. PATIENTS AND METHODS: Three hundred seventy-seven male veterans, age 50 years and older, who had not undergone recent colorectal cancer screening, were surveyed about their knowledge, attitudes, and beliefs regarding colorectal cancer screening. Patients' literacy was assessed with the Rapid Estimate of Adult Literacy in Medicine, an individually administered screening test for reading. RESULTS: Thirty-six percent of the 377 men had an eighth grade literacy level or higher. Men with lower literacy were 3.5 times as likely not to have heard about colorectal cancer (8.8% v 2.5%; P =.006), 1.5 times as likely not to know about screening tests (58.4% v 40.9%; P =.0001), and were more likely to have negative attitudes about fecal occult blood testing (FOBT), but not about flexible sigmoidoscopy. Specifically, men with lower literacy skills were two times as likely to be worried that FOBT was messy (26.7% v 13.3%; P =.008), 1.5 times as likely to feel that FOBT was inconvenient (28.7% v 18%; P =.05), and four times as likely to state they would not use an FOBT kit even if their physician recommended it (17.9% v 4.0%; P =.02). CONCLUSION: Limited literacy may be an overlooked barrier in colorectal cancer screening among veterans.     

Prognostic value of CD40 in adult soft tissue sarcomas.

PURPOSE: The purpose is to evaluate the expression of CD40, a membrane protein predominantly expressed on B cells, dendritic cells, and macrophages, in a series of adult soft tissue sarcomas and to test its possible prognostic value. EXPERIMENTAL DESIGN: CD40 expression was studied by immunohistochemistry. Correlations with other baseline characteristics of patients and tumors were analyzed with chi(2) test. The prognostic value was studied with univariable and multivariable analysis adjusted by age, sex, tumor size, grade, location, and distant metastases. RESULTS: Eighty-two patients, between January 1994 and May 2001, were analyzed. Membrane or cytoplasmic staining for CD40 protein was absent in 30% of the tumors but present in <10% of cells in 22 (27%), in 10% to 50% in 23 (28%), and in >50% of cells in 12 (15%) tumors. There was no correlation between CD40 expression and age, sex, size, grade, and location of the primary tumor and distant metastases. With 61 patients (74.4%) progressed and 31 (37.8%) dead, CD40 expression was a significant prognostic factor for disease-free and overall survival at univariable and multivariable analysis. Patients with tumors expressing CD40 in >50% of cells had a dramatically unfavorable prognosis with median disease-free and overall survival of 7 and 17 months, respectively, and hazard ratios of relapse and death as compared with patients with CD40-negative tumors of 2.89 (95% confidence interval: 1.26-6.60) and 6.92 (95% confidence interval: 2.18-22.0), respectively. CONCLUSIONS: These data suggest that expression of CD40 protein in >50% of cells might indicate an unfavorable prognosis in adult soft tissue sarcomas.     

Use of technetium-tagged white blood cells in patients with Crohn's disease and ulcerative colitis: is differential diagnosis possible?

Background. Studies have suggested that scans with technetium-tagged white blood cells (WBC-Tc^99m) may be equal to endoscopy in the assessment of extent and activity of inflammatory bowel disease (IBD). Objective. We have retrospectively examined the accuracy of WBC-Tc^99m scans in differentiating continuous from discontinuous colitis in pediatric IBD. Materials and methods. There were 207 children in the study (96 boys, 111 girls, median age 13 years). This included 29 controls – children with no gastrointestinal disease (NL) who underwent WBC-Tc^99m scans for other medical problems. Scans were obtained at 30 minutes and 2–4 hours following injection. Scans were interpreted as showing continuous colitis, discontinuous colitis, or no colitis. Results. In the 77 children with active Crohn's disease (CD) of the colon, the scans revealed discontinuous uptake in 63 children and continuous uptake in 14. In the 29 children with ulcerative colitis (UC), 23 scans showed continuous uptake and 6 revealed discontinuous uptake. Two of these 6 showed focal activity near the appendix, and subclinical appendicitis could not be excluded. Another child was bleeding and the scan could have been misinterpreted as showing small- bowel inflammation. In the last three patients, skip areas were clearly identifiable. In none of these last three patients were the biopsies typical of CD (i. e., no granuloma was identified) nor was inflammation patchy. In summary, of the 106 scans showing inflammation, 6 were classified into the wrong group. Conclusion. These data show that WBC-Tc^99m scanning can be useful in distinguishing discontinuous from continuous colitis. Received: 20 November 1997 Accepted: 29 May 1998     

Urodynamic assessment of the bashful bladder

PURPOSE: We prospectively studied the potential contribution of ambulatory urodynamic monitoring in men with urinary symptoms unable to initiate a void on conventional video cystometrography. MATERIALS AND METHODS: A total of 40 consecutive symptomatic men with a median International Prostate Symptom Score of 19 (range 1 to 29) and median age of 51.9 years (range 30 to 75) who were unable to void during video cystometrography underwent ambulatory urodynamic monitoring. Solid-state transducers mounted on silicone coated catheters were inserted urethrally and rectally, and connected to a portable recorder. Subjects voided in private into a specially designed flow meter, which they connected to the recording device. RESULTS: Of the patients 2 (5%) failed to attend ambulatory urodynamic monitoring, despite multiple reminders, and in 1 (2.5%) the trace was uninterpretable. Pressure flow data were available for the remaining 37 patients with mean plus or minus standard deviation 2.72+/-0.1 storage void cycles recorded per patient. All 6 patients (15%) with obstruction were older than 40 years. In 6 cases (15%) obstruction was equivocal and the remainder were unobstructed. Transurethral prostatic resection in 2 and urethrotomy in 1 of 6 patients with obstruction resulted in subjective and objective improvement. CONCLUSIONS: The bashful bladder syndrome was not associated with any specific urodynamic diagnosis. Ambulatory urodynamic monitoring will yield a urodynamic diagnosis in more than 90% of cases after failure to record void data on video cystometrography. A surgically correctable cause of symptoms can be found in about 20% of men older than 40 years. The contribution of ambulatory urodynamic monitoring compared to more conventional evaluation in men younger than 40 years is negligible.