The role of TNF-alpha in fever: opposing actions of human and murine TNF-alpha and interactions with IL-beta in the rat.

1. The role of tumour necrosis factor-alpha (TNF-alpha) in fever is controversial. Some studies have indicated that TNF-alpha acts as a cryogen to inhibit fever, while others suggest that TNF-alpha is an endogenous pyrogen which mediates fever. The majority of studies in experimental animals supporting a cryogenic action have been conducted using human (h)TNF-alpha, which has been shown to bind only to one (p55) of the two TNF-alpha receptors in rodents. 2. The aim of the present investigation was to study the role of TNF-alpha in fever by comparing effects of hTNF-alpha, which binds only to the p55 receptor, with those of murine (m) TNF-alpha, which binds to both p55 and p75 TNF-alpha receptors, and to investigate the relationship between TNF-alpha and interleukin-1 (IL-1), an important endogenous pyrogen. 3. Injection of hTNF-alpha (0.3-10 micrograms kg-1, i.p.) had no effect on core temperature in conscious rats (measured by remote radiotelemetry), whereas mTNF-alpha (3 micrograms kg-1) induced fever which was maximal 1 h after the injection (38.2 +/- 0.2 degrees C compared to 37.3 +/- 0.1 degrees C in controls). Intracerebroventricular (i.c.v.) administration of either form of TNF-alpha elicited dose-dependent fever at doses higher than 0.12 microgram kg-1. 4. Peripheral injection of hIL-1 beta (1 microgram kg-1) resulted in fever (38.3 +/- 0.2 degree C compared to 37.2 +/- 0.1 degrees C in controls at 2 h), which was significantly attenuated (P < 0.01) by co-administration of a sub-pyrogenic dose of hTNF-alpha (1 microgram kg-1), but was unaffected by co-administration of mTNF-alpha (0.1 or 0.3 microgram kg-1, i.p.). In contrast, intracerebroventricular (i.c.v.) co-administration of a sub-pyrogenic dose (0.12 microgram kg-1) of hTNF-alpha did not attenuate fever induced by intraperitoneal (i.p.) injection of IL-1 beta, and sub-pyrogenic dose (0.12 microgram kg-1, i.c.v.) of mTNF-alpha significantly prolonged the febrile response to IL-1 beta. Pretreatment of animals with anti-TNF-alpha antiserum (i.c.v.) did not affect the febrile response to systemic IL-1 beta. 5. Animals injected i.p. with a pyrogenic dose of mTNF-alpha developed fever (38.2 +/- 0.2 degrees C compared to 37.3 +/- 0.1 degrees C in controls 2 h after the injection) that was completely abolished by peripheral administration of IL-1ra (2 mg kg-1, P < 0.001), while i.c.v. administration of IL-1ra (400 micrograms/rat) did not affect mTNF-alpha-induced fever. 6. These data indicate that endogenous TNF-alpha is probably a pyrogen and that previous results suggesting cryogenic actions of TNF-alpha resulted from the use of a heterologous protein in the rat. The markedly contrasting effects of mTNF-alpha and TNF-alpha could result from different interactions with the two TNF-alpha receptor subtypes. The data also suggest that fever induced by exogenous TNF-alpha is mediated via release of IL-1 beta in peripheral tissues, but not in the brain.     

Structure and culture of schools of public health to support academic public health practice.

Schools of public health have been cautioned about producing graduates and research that were disconnected from public interest. Although institutions may implement a variety of strategies to rectify the situation, institutional structural and cultural barriers impede progress. Public health practice coordinators in accredited schools of public health were surveyed to describe the presence of structural and cultural barriers to academic public health practice using the Stevens model. Administrative leadership and faculty reward systems are described as critical to advance academic public health practice.     

Human papillomavirus detection: verification with cervical cytology.

OBJECTIVE: Thirteen specific types of human papillomavirus (HPV), classified as high-risk for the development of cervical cancer, have been reported in 99.7% of all cervical cancers. For this reason, and because of the reported lack of sensitivity of the Papanicolaou (Pap) smear for detecting HPV, some experts believe that the use of papillomavirus DNA testing may replace cytology for routine gynecological screening. Our goal was to validate a commercial assay, the Digene Hybrid Capture-2 for the detection of human papillomavirus by comparing the results to cytological detection of cervical abnormalities. DESIGN: Cytology results of concurrent liquid-based Papanicolaou smears were compared to the Hybrid Capture-2 results. Correlation was assessed and discordant cytology results were reviewed. SETTING: Louisiana State University Health Sciences Center at Shreveport, Department of Pathology, HPV Diagnostic Laboratory. PATIENTS: All liquid cytology specimens submitted for HPV testing between November 1, 2000 and April 1, 2001. RESULTS: Of the 291 cases tested by Hybrid Capture-2, 12% and 28% were positive with the low-risk and high-risk probes, respectively, and 265 had concurrent cytology results. Fourteen specimens testing positive only with the low-risk probe were not included in this comparison. Thus, the results for 251 of the 291 (86%) specimens tested for human papillomavirus DNA were compared to the original cytology report. Overall concordance between Hybrid Capture-2 and the original smear cytology result was 78%. Slide review reduced the number of discordant specimens from 22% to 12%. CONCLUSION: Based upon these data, we find the HPV assay to be useful as a routine screen for Human papillomavirus.     

How we do it: Dispensing with drains in hemithyroidectomy – a feasibility study

? The NHS plan states that 75% of all elective surgery should be carried out as day cases, but reports confirm that we are falling well below such targets. ? The use of the harmonic scalpel in thyroidectomy in our department has facilitated faster surgery, minimal intra‐operative haemorrhage, and reduced postoperative blood loss into the drain. ? We propose that patients with small solitary nodules (<25 cm³ on preoperative ultrasound) undergoing hemithyroidectomy for diagnostic purposes are candidates for selective use of drains, or where used, early removal of the drain and same day discharge.     

Development of Activity Assays for High-Volume Evaluation of Human Immunodeficiency Virus (HIV) Protease Inhibitors in Rat Serum: Results with Ditekiren

We showed previously that a commercially available synthetic tetradecapeptide, Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Leu-Val-Tyr-Ser, produces authentic angiotensin I (Ang I) upon incubation with the HIV-1 protease (S. K. Sharma et al., Anal. Biochem. 198:363, 1991). Therefore, we developed an Ang-I based activity assay for HIV protease inhibitors based on the technology developed earlier (M. J. Ruwart et al., Pharm. Res. 7:407, 1990; S. K. Sharma et al., Anal. Biochem. 186:24, 1990) for tracking renin inhibitors in rat sera. Ditekiren was either extracted from sera with ethyl acetate or assayed after the interfering substances in sera were precipitated with acetonitrile. Purified recombinant HIV-1 protease was added to extracted rat serum and the enzymatic reaction was initiated in the presence of the tetradecapeptide substrate. The inhibition of Ang I production was measured by a commercially available RIA kit. The cleanup methodology also enabled a commercially available Proteinase Scintillation Proximity Assay (SPA, Amersham) to quantify ditekiren in rat serum through the addition of recombinant HIV-1 protease and cleavage of substrate from SPA beads. Results were confirmed by HPLC or by the renin assay for ditekiren, which inhibits both aspartyl proteases. These technologies should prove useful for assessing serum levels of HIV protease inhibitors in rat.     

Familial dyslipidemic hypertension. Evidence from 58 Utah families for a syndrome present in approximately 12% of patients with essential hypertension

Population-based sibships with essential hypertension diagnosed before the age of 60 years are being screened in Utah to find two or more hypertensive siblings with the same biochemical abnormality as a clue to an inherited cause for their specific type of hypertension. Among 131 hypertensive subjects in 58 sibships, concordant abnormalities in fasting serum lipid concentrations were observed in two or more siblings in 48% of the sibships. After adjusting for effects of antihypertensive medications, abnormal values reported in only 10% of the Lipid Research Clinics data were observed in 30% of patients for serum triglycerides, 19% for serum low-density lipoprotein cholesterol, and 39% for high-density lipoprotein cholesterol. More than one lipid level was abnormal in almost all concordant sibships, suggesting an association between hypertension and a syndrome of mixed lipid abnormalities, probably familial combined hyperlipidemia (renamed "familial combined dyslipidemia" because of common low high-density lipoprotein cholesterol levels). We conclude that familial dyslipidemic hypertension may be a specific syndrome with lipid abnormalities more severe than blood pressure elevations.     

The meaning of “physical fitness”

The understanding of the term "physical fitness" was determined for a randomly selected sample (n = 94) of a population using a self-administered mailed questionnaire. Subjects were asked to state and give a reason for their perceived level of physical fitness, to state their perceived performance level in a number of physical fitness tests (muscular strength, daily physical work capacity, fatness, level of regular physical exercise, exercise speed, and body flexibility), and to rate how well these tests measure physical fitness. The reason most frequently stated for perceived level of physical fitness was the level of habitual physical activity (43%); significantly less frequently (P less than 0.01-0.0001) cited were reasons related to health (23%), physical performance (12%), and obesity (3%). The variation in perceived level of physical fitness was best explained by the variation in imagined regular exercise and fatness (r2 = 0.66, P less than 0.0001) with no significant additional contribution from imagined performance in remaining fitness tests. The measurement of regular exercise was most favored as a test of physical fitness. These results, taken together with evidence of the physical and psychological health benefits of regular exercise, imply that the most appropriate measure of physical fitness for the average person is an assessment of the habitual physical activity level.     

The effect of a church-based breast cancer screening education program on mammography rates among African-American women

This study examines the effectiveness of breast cancer screening education programs on mammography rates among African-American women 40 years of age and over. We conducted two types of educational programs in community settings, primarily in African-American churches. Three-month follow-up interviews were used to determine whether women who participated in programming were more likely to get a mammogram if they had not had a mammogram in the last year. Our results demonstrate that the educational programs significantly increased the likelihood of getting a mammogram when compared to a control group that received no educational programming. Further, we found that the programs were effective for motivating breast cancer screening in housing projects as well as in the churches, and that the effectiveness of the programs remained even when we controlled for socioeconomic status, depression, and age.     

Assessment of the epidemic potential of a new strain of rotavirus associated with the novel G9 serotype which caused an outbreak in the United States for the first time in the 1995-1996 season

Rotavirus causes severe morbidity in developed countries and frequent deaths (> or = 500,000 per year) in less-developed countries. Historically, four serotypes--G1, G2, G3, and G4-have predominated; they are distinguished by one of two surface neutralization antigens (VP7). However, in 1983 and 1984 we described a new rotavirus serotype, designated G9, in five children hospitalized for diarrhea in Philadelphia, Pa. G9 rotavirus was not identified again in the Western Hemisphere until it caused ca. 50% of the rotavirus disease detected in Philadelphia in the 1995-1996 season. This outbreak allowed us to question whether a rotavirus strain completely new to a well-studied community would target either very young infants or older children, cause especially severe disease, or completely displace previously extant serotypes. We observed a significant excess of G9 infections in younger infants (especially in those < 6 months old) that might be attributed to the lack of G9-specific antibodies in mothers. Of further note, six of the seven oldest patients with rotavirus diarrhea were infected with the G9 strains (not significant). However, the age distribution of children with rotavirus did not differ over a 5-year study period regardless of the infecting serotype. Patients with diarrhea associated with G9 strains did not have disease more severe than that caused by the G1, G2, or G3 serotype. G9 strains did not displace the other serotypes but were virtually completely replaced by G1 or G2 serotypes in the three subsequent rotavirus seasons. We conclude that the abrupt appearance of this novel rotavirus serotype did not present a special threat to public health in the community.