Lack of late-phase airway responses in conscious guinea pigs after a variety of antigen challenges

Guinea pigs were actively sensitized by parenteral injections of ovalbumin (OA), house dust extract (HD) orAscaris suum extract (As) in a variety of multidose regimens. At least 3 weeks after the initial sensitization injection, aerosols of the appropriate antigen were administered to conscious guinea pigs in a double-chamber body plethysmograph. OA elicited the most consistent and intense bronchoconstriction (BC) as measured by decreases in specific airway conductance (sGAW). The airway responses to As were clearly separable into responders and nonresponders. HD produced essentially no BC. However, intense lacrimation and rhinorrhea occurred in all HD-sensitized, but not unsensitized, animals. No late-phase changes in sGAW or increased reactivity to other spasmogens were seen up to 8h after any antigen challenge. Eosinophil influx of magnitude similar to that measured by 24h post-antigen bronchoalveolar lavage (BAL) occurred with all the three antigens. Animals which did not bronchoconstrict to As experienced an equal or greater pulmonary eosinophilia as airway responders. The present data with HD and As suggest that acute BC in response to antigen provocation is not a prerequisite for the eventual pulmonary eosinophilia. The lack of late-phase airway reactions in these models raises a doubt in the direct extrapolation to airway responses in allergic human asthma. The acute lacrimation and rhinorrhea to HD may suggest utility as a model of allergic rhinitis.     

The importance of self-examination in the earliest diagnosis of multiple primary cutaneous melanomas: a report of 47 cases

BACKGROUND: Development of more than one primary melanoma in a patient is a relatively uncommon but well-recognized phenomenon. Its frequency has ranged from 1.2% to 8.2% in several series. This subgroup of patients with multiple primary lesions has not been characterized sufficiently. We report the experience of the Melanoma Unit of University Hospital Spedali Civili of Brescia, Italy. METHOD: Study subjects were drawn from 1240 patients with histologically confirmed melanoma, including melanoma in situ. From this group, multiple melanomas developed in 47 patients (3.79%). Every one of our patients has been taught to perform self-examination of the skin to detect suspicious pigmented lesions. RESULTS: Of the 47 patients described in this study, 38 had two primary melanomas, 7 had three melanomas and 2 had 5 and 10 melanomas, respectively. Mean age at first diagnosis was 46.2 years. The majority of subsequent melanomas (74.5%) were removed within 5 years of the initial operation. Synchronous lesions were found in 10 patients. In male patients, the lesion appeared most frequently on the trunk; in female patients, melanoma appeared mostly on the lower extremities. The second primary melanomas developed in the same anatomic region from the first in 53.2% of our patients. The proportion of in situ to invasive melanomas was greater for the second melanomas compared with the first melanomas. Regarding invasive melanomas, the mean thickness of the first melanomas was 1.31 mm compared with 0.66 mm for the second ones. Dividing patients into two groups, of more and less than 50, it is highlighted that in older patients synchronous lesions appear more frequently (36.4% vs. 8.0%); the median time interval between sequential melanomas is longer (84 vs. 63.7 months); and the ratio between the primary and secondary melanoma mean thickness is lower (1.21 : 1.08 vs. 1.43 : 0.63 mm). CONCLUSIONS: The study confirms that second primary melanoma is usually thinner than the first lesion, and it is more common in the same region of the body as the initial melanoma. The highest risk for a second melanoma is during the first 5 years, but a much longer time interval of 28 years is possible. Continued medical follow-up with complete skin examinations seems prudent, but it is very important to promote self-skin evaluation in patients to detect not only metastases but also subsequent primary melanomas in their earliest phases.     

Specifically designed thiosteroids as active-site-directed probes for functional dissection of rat liver cytochrome P450 3A isozymes.

Testosterone (T) 6 beta-hydroxylase (6 beta-OHase) is a well-recognized functional marker of rat liver cytochrome P450 3A (P450 3A) isozymes. Pretreatment of rats with inducers or specific or nonspecific inhibitors of P450 3A isozymes is associated not only with stimulation or inhibition of hepatic microsomal T 6 beta-OHase activity but also with parallel changes in the corresponding T 2 beta-, 15 beta-, and 18-OHase activities and T 4,6-diene formation. At the time these studies were conducted, no fully functionally active rat hepatic P450 3A isozymes had been isolated. To determine whether each of these activities was due to a single P450 3A isozyme, or whether multiple isozymes contributed to these activities, we specifically synthesized two thiotestosterone (6 beta- and 2 beta-SHT) analogues as potential mechanism-based inactivators of rat liver T 6 beta- and 2 beta-OHases. In addition, to assess their relative stereoselectivity, 2 alpha-SHT was also included as a control. Our studies revealed that although all three thiosteroids were excellent suicide substrates of P450 3A isozymes, they inactivated these T OHases differentially. Such differential inactivation and determination of the kinetic parameters of inactivation allowed the functional classification of rat hepatic P450 3A isozymes into at least two and possibly three categories: (i) forms (catalyzing 4,6-diene and 6 beta-OHT formation but with characteristically low 6 beta/2 beta-OHase ratios) highly susceptible to inactivation by SHTs; (ii) forms (catalyzing T 6 beta-, 2 beta-, 15 beta-, and 18-hydroxylations with high 6 beta-/2 beta-OHase ratios) moderately susceptible to the SHTs; and (iii) forms somewhat resistant to inactivation, at least at the SHT concentrations tested. Although no specific T OHase could be ascribed to a single P450 3A isozyme, it appears that each of these P450s catalyzed such T regiohydroxylations, albeit at considerably different extents. Furthermore, our studies also revealed that 2 alpha-SHT preferentially inactivated P450 3A forms but surprisingly failed to inactivate rat hepatic P450 2C11, thereby confirming the rather high substrate promiscuity of the P450 3A family of isozymes.     

Presentation of abdominal tuberculosis to general surgeons.

Abdominal tuberculosis (TB) continues to give rise to diagnostic and therapeutic challenges. A total of 24 patients with abdominal TB who presented to general surgeons over a 9-year period have been reviewed. Most (92 per cent) of these patients were Asian; only one had a past history of pulmonary TB. The most common presenting complaint was abdominal pain in 21 patients (88 per cent) with the associated symptoms of weight loss in 18 (75 per cent), anorexia in 15 (62 per cent) and night sweats in 13 (54 per cent). A tissue diagnosis was obtained in 18 patients (75 per cent) and 17 patients (71 per cent) underwent laparotomy. These results show that the diagnosis of abdominal TB is still difficult to establish, and that many patients undergo laparotomy despite the existence of less invasive diagnostic procedures.     

Molecular approach to the epidemiology of swine vesicular disease: correlation of variation in the virus structural polypeptides with serological properties.

Variation has been observed in the structural polypeptides of swine vesicular disease viruses isolated from the United Kingdom and Hong Kong. Despite the limited number of isolates examined, several distinct polypeptide patterns were obtained when the virus structural proteins were examined by polyacrylamide gel electrophoresis. Isolates from outbreaks in the United Kingdom which were known to be connected gave the same polypeptide pattern, whereas viruses with different polypeptide patterns could not be traced to a common source. The different polypeptide patterns were obtained consistently and were not altered by passage of the virus in tissue culture. In general, isolates with identical polypeptide patterns could not be distinguished by neutralization or antibody blocking tests or by competition radioimmunoassays. However, isolates with different polypeptide patterns could be differentiated by antibody blocking tests or radioimmunoassay. The correlation between the serological tests and the polyacrylamide gel electrophoresis analyses illustrates the value of analyzing structural polypeptides in the epidemiological study of swine vesicular disease.