Pharmacological activities of trimetoquinol and 1-benzyl halogen-substituted analogues on rat beta-adrenoceptor subtypes

The beta-adrenoceptor activity profile of trimetoquinol and its 1-benzyl halogen-substituted analogues was studied in rat tissues containing primarily beta 1 (atria)-, beta 2 (trachea)- and atypical beta/beta 3 (distal colon and brown adipose tissue)-adrenoceptors. Functional biological activity resided in the (-)-isomer of trimetoquinol which was 112-, 275-, 372- and 513-fold more potent than (+)-trimetoquinol in trachea, right atria, distal colon and brown adipose tissue, respectively. (+/-)-Trimetoquinol was equally or slightly less active than (-)-trimetoquinol. The 1-benzyl halogen-substituted analogues of trimetoquinol exhibited differential activation of beta-adrenoceptor subtypes. In functional assays, 3'-iodotrimetoquinol was a potent activator of all beta-adrenoceptor subtypes. 3',5'-Diiodotrimetoquinol was 10-fold more potent as an agonist in tissues containing atypical beta/beta 3-adrenoceptors than those tissues containing beta 1- and beta 2-adrenoceptor sites. Furthermore, this drug was a partial agonist as compared to (+/-)-trimetoquinol and 3'-iodotrimetoquinol on beta 1-adrenoceptors. Pharmacological properties of the compounds on rat beta 3-adrenoceptors expressed in Chinese hamster ovary (CHO) cells were consistent with results observed in functional assays. 3',5'-Diiodotrimetoquinol possessed the greatest potency for activation of adenylyl cyclase. Rank order of affinity for rat beta 3-adrenoceptor was 3'-iodotrimetoquinol = 3',5'-diiodotrimetoquinol > (+/-)-trimetoquinol > (-)-isoprenaline. These results suggest that 3',5'-diiodotrimetoquinol is a promising drug for further chemical modification in the development of selective beta 3-adrenoceptor ligands.     

Pediatric thyroid cancer after the Chernobyl disaster. Pathomorphologic study of 84 cases (1991-1992) from the Republic of Belarus

BACKGROUND: During the initial period after the Chernobyl accident, large amounts of radioactive iodine were released in fallout, resulting in serious exposure to the thyroid gland in the residents of areas around the nuclear power station. Beginning in 1990, a definite increase in the incidence of thyroid cancer was noted in children of the Republic of Belarus. METHODS: Morphologic and clinical features of 84 cases of post-Chernobyl thyroid carcinoma in Belarussian children from 5 to 14 years of age are reported. The latent period for tumor development was 4-6 years, with a mean of 5.8 years. RESULTS: Papillary carcinoma was found in 83 patients and medullary carcinoma in one. Besides typical papillary carcinoma (14%), solid (34%), follicular (33%), mixed (10%), and diffuse sclerosing (9%) variants were observed. The follow-up period ranged from 8 months to 2.5 years. One patient died, local recurrence developed in 2, and cervical lymph node metastases developed in 10. To date, the incidence of local recurrence or metastatic disease after surgery was significantly higher in patients 5-8 years of age and in residents of areas nearest to the Chernobyl station. CONCLUSIONS: Post-Chernobyl pediatric thyroid carcinoma is characterized by a short latency, a higher proportion of tumors arising in young children, and an almost equal sex ratio. Microscopically, these tumors were usually aggressive, often demonstrating intraglandular tumor dissemination (92%), thyroid capsular and adjacent soft tissue invasion (89%), and cervical lymph node metastases (88%). Papillary carcinoma was diagnosed in 99% of cases, with an unusually high frequency of solid growth patterns. Morphologic changes in nonneoplastic thyroid tissue were present in 90% of the glands, and the most specific findings were vascular changes and perifollicular fibrosis.     

Prevalence of Cyclospora species and other enteric pathogens among children less than 5 years of age in Nepal

Stools from 124 Nepalese children aged 6 to 60 months with diarrhea were examined for organisms of the coccidian genus Cyclospora and for other enteric pathogens. Enterotoxigenic Escherichia coli, Giardia Lamblia, Campylobacter species, Cyclospora species, and Cryptosporidium species were the most common pathogens identified. Cyclospora species were detected in none of 74 children < 18 months of age compared with 6 (12%) of 50 children > or = 18 months of age (P = 0.004).     

Protein-protein and protein-DNA interactions in the type I restriction endonuclease R.EcoR124I

The type I restriction-modification system EcoR124I recognizes and binds to the split DNA recognition sequence 5'-GAAN(6)RTCG-3'. The methyltransferase, consisting of HsdM and HsdS subunits with the composition M2S, can interact with one or more subunits of the HsdR subunit to form the endonuclease. The interaction of the methyltransferase with HsdR has been investigated by surface plasmon resonance, showing that there are two non-equivalent binding sites for HsdR which differ in binding affinity by at least two orders of magnitude. DNA footprinting experiments using Exonuclease III suggest that the addition of HsdR to the methyltransferase (at a stoichiometry of either 1:1 or 2:1) increases the stability of the resulting DNA-protein complex but does not increase the size of the footprint. More extensive in situ footprinting experiments using copper-phenanthroline on the DNA-protein complexes formed by M2S, R1M2S and R2M2S also show no difference in the detailed cleavage pattern, with approximately 18 nucleotides protected on both strands in each complex. Thus the HsdR subunit(s) of the endonuclease stabilise the interaction of the M2S complex with DNA, but do not directly contribute to DNA binding. In addition, the thymidine nucleotide in the tetranucleotide recognition sequence GTCG is hyper-reactive to cleavage in each case, suggesting that the DNA structure in this region is altered in these complexes.     

The acupuncture of biologically active points in the treatment of primary corneal stromal dystrophies

New trends in surgical treatment of purulent tendovaginitis of the hand are described on the basis of clinical data of 295 patients with purulent tendovaginitis and its complications. A sparing operation technique was used as well as the fractional bathing of the purulent focus and regional antibacterial therapy at the postoperative period. This method of surgical treatment resulted in a shorter first stage of inflammation, less risk of complications (dermatogenic contracture, limited mobility in the joints of the fingers and toes, trophoneurotic disturbances) and less influence of injurious factors on the tendon in the process of treatment.     

Relevance of the antibody response against human immunodeficiency virus type 1 envelope to vaccine design

Understanding the antibody response in HIV-1 infection is important to vaccine design. We have studied the antibody response to HIV-1 envelope at the molecular level and determined the characteristics of neutralizing and non-neutralizing antibodies. These antibodies were isolated from phage display libraries prepared from long-term seropositive asymptomatic individuals. The HIV-1 envelope is presented to the immune system in several antigenically distinct configurations: unprocessed gp160, gp120 and gp41 subunits and native envelope, each of which may be important in eliciting an antibody response in HIV-1 infection. The antibodies tested characteristically had poor affinities for native envelope as expressed on the surface of virions or infected cells, but had high affinities against non-native forms of HIV-1 envelope (viral debris). An exceptionally potent neutralizing antibody in contrast, bound native envelope with equivalent or somewhat higher affinity than this. This indicates that the antibody response in HIV-1 infection is principally elicited by viral debris rather than virions, and that these antibodies bind and neutralize viruses sub-optimally. Potential vaccines should be designed to elicit responses against native envelope.     

Characterization of GaN and In x Ga1−x N films grown by MOCVD and MBE on free-standing GaN templates and quantum well structures

Structural and optical studies have been performed on GaN, InGaN layers, In_0.08Ga_0.92N/GaN heterostructures, In_0.08Ga_0.92N/In_0.02Ga_0.98N single and multiquantum wells grown by metal organic chemical vapor deposition (MOCVD) and GaN by molecular beam epitaxy (MBE) on GaN templates by using transmission electron microscopy (TEM), X-ray diffraction (XRD), and photoluminescence (PL). The layers are found to be high quality with low defect density, on the order of 10⁶ cm^?2, which are mainly related to the threading dislocations originating/propagating from the hydride vapor phase epitaxy (HVPE) GaN template. The interface between the layers and substrate could not be detected by TEM and was therefore deemed to be of high quality. Convergent beam electron diffraction studies revealed that the polarity of the films is Ga-polarity, which is the same as that of the substrate. A dual structure with different compositions and having thicknesses of 10 and 25 nm was observed in InGaN layers grown on GaN in one of the heterostructure samples. The full width at half maximum (FWHM) of the XRD rocking curves of (0 0 0 2) for heterostructures and quantum wells were found to be in the range of 15–28 arcmin for a slit width of 2 mm. PL studies on GaN layers grown by MBE and MOCVD on GaN templates are reasonably similar. The PL spectra from all the MBE and MOCVD epilayers and the substrate contain a plethora of sharp peaks related to excitonic transitions. With the presence of donor-bound exciton peaks and their associated two-electron satellites, the binding energies of two distinct shallow donors (28.8 and 32.6 meV), which are attributed to Si and O, respectively, were determined. PL measurements revealed that the FWHM of the main donor bound exciton peak increased from 0.6 to 2.9 meV but no change in peak position (3.472 eV) was observed in GaN when doping with Si (5×10¹⁷ cm^?3). However, the intensities of the yellow band and the shallow donor–acceptor pair band increased 10 times as compared to that in the undoped GaN samples. In the case of InGaN/GaN heterostructures, a similar trend was observed when compared to the doped samples. In the multiquantum well In_0.08Ga_0.92N/In_0.02Ga_0.98N heterostructures, the activation energy of the exciton emission, found to be 18 meV, was the lowest in the samples studied. The peak at 3.02 eV related to the InGaN was strongly pronounced in the In_0.08Ga_0.92N/In_0.02Ga_0.98N multiquantum well structure. In the In_0.08Ga_0.92N/In_0.02Ga_0.98N quantum well structures, the change in peak position with variation of temperature from 15 to 300 K in PL spectra is “S”-shaped. The cause for the “S” shape, i.e., a red–blue–red shift, is discussed.     

Effects of a long-term hypertension control program on stroke incidence and prevalence in a rural community in northeastern Japan

BACKGROUND AND PURPOSE: Although randomized clinical trials have demonstrated the benefit of antihypertensive treatment in preventing stroke, the effectiveness of community-based programs is largely unknown. We investigated long-term community-based prevention activities. METHODS: In rural northeastern Japan, people aged > or = 30 years numbered 3219 in the full intervention community and 1468 in the minimal intervention community in 1965. Systematic blood pressure screening and health education began in 1963. Stroke was registered through 1987. RESULTS: More than 80% of people aged 40 to 69 years were screened in both communities in the 1960s. One community charged for screening services after 1968, whereas the other community intensified intervention; subsequently, screening rates and the follow-up of hypertensive individuals declined in the minimal intervention community, especially in men. In men, stroke incidence declined more (P < 0.001) in the full intervention (42% in the period 1970 to 1975, 53% in the period 1976 to 1981, and 75% in the period 1982 to 1987) than in the minimal intervention community (5% increase, 20% decrease, and 29% decrease, respectively); in women, the stroke incidence declined about 45% to 65% in both communities. Changes in stroke prevalence paralleled those in stroke incidence. Trends in systolic blood pressure levels tend to explain the differential stroke rates in men. CONCLUSIONS: Delivery of hypertension control services through intensive, free, community-wide screening and health education was effective in prevention of stroke for men in a community.