Regulation of natural antibiotic expression by inflammatory mediators and mimics of infection in human endometrial epithelial cells

The natural antibiotic molecules, beta-defensins 1 and 2 (HBD1/2) and secretory leukocyte protease inhibitor (SLPI), have an important role in mucosal defence and are present in the uterus. This study details their regulation in primary endometrial epithelial cells and in two endometrial cell lines (MFE/HES). Cells were treated with proinflammatory molecules and mimics of infection [lipopolysaccharide (LPS) and lipoteichoic acid (LTA)]. mRNA for HBD1, HBD2 and SLPI was detected in primary endometrial epithelial cells using real-time quantitative PCR. HBD1 mRNA was present at very low levels preventing conclusive study of its regulation. However, HBD2 mRNA expression was increased by interferon-gamma, interleukin (IL)-1beta alone and IL-1beta+tumour necrosis factor (TNF)-alpha. SLPI mRNA was not affected by proinflammatory mediators, although protein levels fell in the presence of IL-1beta+TNFalpha. LPS had little effect on antimicrobial expression. However, there was a trend towards increased expression with LTA treatment for 4-8 h. Antimicrobial expression in endometrial cell lines was similar to that in primary cells, although SLPI was increased by IL-1beta+TNFalpha treatment. These results suggest that in endometrium some natural antibiotics (e.g. SLPI) may be constitutively expressed providing a basal level of protection, while others (e.g. HBD2) are inducible allowing maximal antimicrobial activity during infection. Natural antimicrobials will have an important role in endometrium in protecting against infection.     

Phase II evaluation of esorubicin (4′ deoxydoxorubicin) in pancreatic adenocarcinoma: A Southwest Oncology Group study

Summary Esorubicin (4 deoxydoxorubicin) is a new analogue of the anthracycline, doxorubicin. This compound lacks the hydroxyl group at 4 position on the amino sugar of the anthracycline. Phase II study was designed to determine the clinical response rate and to define the qualitative and quantitative toxicities of esorubicin in patients with adenocarcinoma of the pancreas. Fifty-eight patients with inoperable adenocarcinoma of the pancreas were entered on the study, 47 were evaluable for response, and 57 were evaluable for toxicity. The dose of esorubicin was 30 mg/m² for good risk patients and 25 mg/m² for poor risk patients every 21 days and administered IV push through a side arm of a running IV. Diphenhydramine, 50 mg is administered IM prior to the administration of the drug to block local venous reaction. Subsequent doses of esorubicin were modified according to granulocyte and platelet nadirs and the drug was not administered until recovery of platelets (> 100,000/ul) and wbc (> 3000/ul). Three partial responses, 20 stable, and 31 with increased disease were observed. Forty-seven had severe granulocytopenia (< 250), and two patients had severe thrombocytopenia (< 25,000). One patient experienced a decrease in left ventricular ejection fraction with a total dose of 180 mg/m². The dose of esorubicin in this study demonstrated that the drug has minimal activity in adenocarcinoma of the pancreas but the toxicity is tolerable. Search should continue for single agents with activity in this disease.     

Orbital trauma and reconstruction

This article reviews the most recent topics of investigation concerning orbital trauma and reconstruction. During the past year there have been many articles of interest regarding management of the sequelae to orbital trauma, pathophysiologic process in orbital injury, diagnostic techniques, as well as operative methods, materials, and complications. Recent research has focused on the pathophysiology of traumatic optic neuropathy and visual compromise in orbital hemorrhage. Theories regarding the etiology of atraumatic spontaneous enophthalmos are described. In the realm of orbital reconstruction, rigid fixation systems have ben extensively investigated for use in orbital and facial trauma. Investigators have begun to address the question of potential complications from rigid fixation in children.     

Prevalence of gambling disorders in a primary care setting

BACKGROUND: Pathologic gambling prevalence seems to be increasing as opportunities for gambling increase. Prevalence may be different in a primary care setting compared with population-based studies. OBJECTIVES: To determine the gambling disorder prevalence in a primary care setting and to investigate associations between gambling disorders and proximity to a casino, substance abuse, health ratings, age, sex, and socioeconomic status. DESIGN: Cross-sectional survey of 1394 patients presenting to their primary care physicians between November 1, 1997, and April 1, 1998. SETTING: Three primary care clinics in Wisconsin. PATIENTS: Adults aged 18 years and older. MAIN OUTCOME MEASURES: Gambling disorders, defined by scores of 3 or greater on the South Oaks Gambling Screen (SOGS), and information about drug use (alcohol, tobacco, and marijuana), overall health, specific health symptoms, age, sex, race, and socioeconomic status. RESULTS: A total of 1051 patients completed the survey. More than 80.0% of the patients had gambled, and 6.2% met the criteria for gambling disorders. Gambling disorders were more prevalent in men, nonwhites, and patients from lower socioeconomic groups. Patients with gambling disorders were more likely to use tobacco and abuse alcohol compared with nonproblem gamblers. No relation was seen between marijuana use and gambling disorders. Patients with gambling disorders rated their health more poorly and reported more severe symptoms of heartburn and backache. CONCLUSIONS: A considerable percentage of patients presenting to primary care clinics are affected by their need to gamble. There is significant comorbidity with tobacco use and alcohol abuse. Primary care physicians should consider asking about gambling habits in high-risk patients.     

Mortality in a cohort of licensed pesticide applicators in Florida

OBJECTIVES: Although the primary hazard to humans associated with pesticide exposure is acute poisoning, there has been considerable concern surrounding the possibility of cancer and other chronic health effects in humans. Given the huge volume of pesticides now used throughout the world, as well as environmental and food residue contamination leading to chronic low level exposure, the study of possible chronic human health effects is important. METHODS: This was a retrospective cohort study, analysed by general standardised mortality ratio (SMR) of licensed pesticide applicators in Florida compared with the general population of Florida. A cohort of 33,658 (10% female) licensed pesticide applicators assembled through extensive data linkages yielded 1874 deaths with 320,250 person-years from 1 January 1975 to 31 December 1993. RESULTS: The pesticide applicators were consistently and significantly healthier than the general population of Florida. As with many occupational cohorts, the risks of cardiovascular disease and of diseases associated with alcohol and tobacco use were significantly lower, even in the subpopulations--for example, men, women, and licence subcategories. Among male applicators, prostate cancer mortality (SMR 2.38 (95% confidence interval (95% CI) 1.83 to 3.04) was significantly increased. No cases of soft tissue sarcoma were confirmed in this cohort, and non-Hodgkin's lymphoma was not increased. The number of female applicators was small, as were the numbers of deaths. Mortality from cervical cancer and breast cancer was not increased. Additional subcohort and exposure analyses were performed. CONCLUSIONS: Consistent with previous publications on farmers but at odds with current theories about the protective effects of vitamin D, prostate cancer was increased in these pesticide applicators. Female breast cancer was not increased despite theories linking risk of breast cancer with exposure to oestrogen disruptors--such as the organochlorines. The lack of cases of soft tissue sarcoma is at odds with previous publications associating the use of the phenoxy herbicides with an increased risk of these cancers.

 

     

Intraoperative radiofrequency ablation or cryoablation for hepatic malignancies

BACKGROUND: The majority of patients with primary or metastatic malignancies confined to the liver are not candidates for resection because of tumor size, location, multifocality, or inadequate functional hepatic reserve. Cryoablation has become a common treatment in select groups of these patients with unresectable liver tumors. However, hepatic cryoablation is associated with significant morbidity. Radiofrequency ablation (RFA) is a technique that destroys liver tumors in situ by localized application of heat to produce coagulative necrosis. In this study, we compared the complication and early local recurrence rates in patients with unresectable malignant liver tumors treated with either cryoablation or RFA. PATIENTS AND METHODS: Patients with hepatic malignancies were entered into two consecutive prospective, nonrandomized trials. The liver tumors were treated intraoperatively with cryoablation or RFA; intraoperative ultrasonography was used to guide placement of cryoprobes or RFA needles. All patients were followed up postoperatively to assess complications, treatment response, and local recurrence of malignant disease. RESULTS: Cryoablation was performed on 88 tumors in 54 patients, and RFA was used to treat 138 tumors in 92 patients. Treatment-related complications, including 1 postoperative death, occurred in 22 of the 54 patients treated with cryoablation (40.7% complication rate). In contrast, there were no treatment-related deaths and only 3 complications after RFA (3.3% complication rate, P<0.001). With a median follow-up of 15 months in both patient groups, tumor has recurred in 3 of 138 lesions treated with RFA (2.2%), versus 12 of 88 tumors treated with cryoablation (13.6%, P<0.01). CONCLUSIONS: RFA is a safe, well-tolerated treatment for patients with unresectable hepatic malignancies. This study indicates that (1) complications occur much less frequently following RFA of liver tumors compared with cryoablation of liver tumors, and (2) early local tumor recurrence is infrequent following RFA.     

Patient-centeredness and its correlates among first year medical students

OBJECTIVE: This research was performed to study the attitudes that medical students hold concerning their relationships with patients, and whether such attitudes are gender-related, affect career plans, and influence their evaluation of psycho-social and biomedical issues. METHODS: One hundred fifty-three first year students at the Boston University School of Medicine completed the Patient-Practitioner Orientation Scale (PPOS), a scale that differentiates between a patient-centered vs. doctor-centered orientation toward medical practice, indicated their interest in community and primary care practice, and rank ordered psycho-social and biomedical clinical issues in terms of their perceived relative importance. RESULTS: The data revealed that female medical students were more patient-centered, and that (across sexes) patient centeredness was positively associated with an interest in community and primary care practice and the ranking of psycho-social issues. CONCLUSIONS: These findings indicate that differences in the practice attitudes of males and females exist very early on in medical training, and that these differences are associated with anticipated career choices. They also suggest that the PPOS may prove useful in measuring the attitudes of practicing physicians toward their clinical roles and might predict physicians' behavioral strategies and patient medical outcomes.     

Genetic mapping of modifier loci affecting malignant hypertension in TGRmRen2 rats.

BACKGROUND: Genetic background has a major influence on the manifestation of multifactorial diseases such as hypertension in which severe complications may be caused through an interaction with additional factors, which may be genetically determined. We have previously described a genetic model of malignant hypertension (MH) in rats carrying the mouse Ren2 gene (TGRmRen2-27), in which the phenotype is dependent on the genetic background. METHODS: Using a single homozygous TGRmRen2-27 male as transgene donor, we produced two F1 populations with (a) 100% penetrance of MH in progeny heterozygous for the Fischer F344 genetic background and (b) 58.5% penetrance in progeny heterozygous for the Lewis genetic background. To identify the modifier loci affecting the phenotype, a cohort of 252 males was produced by breeding the same single male with Fischer-Lewis F1 females. The progeny were phenotyped for clinical and pathological features of MH. RESULTS: Genome-wide screening and quantitative trait loci (QTL) analysis identified two loci, on chromosome 10 (LOD 4.4) and on chromosome 17 (LOD 3.9) close to the Ace and At1 genes, respectively, which contribute to the lethal MH phenotype. Their influence on mortality was consistent with a multiplicative effect of the two loci. In addition, we found higher plasma angiotensin-converting enzyme activity in progeny receiving the Fischer allele than in progeny receiving the Lewis allele (123.5 +/- 9.5 vs. 91.8 +/- 4.9 U/liter, P < 0.01), suggesting the association of angiotensin-converting enzyme and MH. CONCLUSIONS: Our study demonstrates the application of a transgene as a "major gene" to facilitate the identification of modifier loci, which can affect the phenotype of MH, and reveals Ace and At1 as candidate genes involved in the manifestation of the MH phenotype.