Long-term exposure of HIV type 1-infected cell cultures to combinations of the novel quinoxaline GW420867X with lamivudine, abacavir, and a variety of nonnucleoside reverse transcriptase inhibitors.

The novel quinoxaline GW420867X has been combined with a variety of nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) in HIV-1(IIIB)-infected CEM cell cultures. Whereas the antiviral efficacy of combinations of GW420867X with the NRTIs lamivudine (3TC) and abacavir (ABC) proved additive when administered to HIV-1-infected cells in a short-term (4-day) infection experiment, combination of GW420867X with the NRTIs 3TC and ABC resulted in a marked delay of virus breakthrough compared with the single drugs alone in a long-term (2-month) infection experiment. Delay of virus breakthrough was less pronounced for combinations of GW420867X with the NNRTIs. Combination of GW420867X with the NRTIs and NNRTIs resulted in additive inhibitory effects on recombinant HIV-1 reverse transcriptase as evident from isobolograms. Lamivudine plus GW420867X selected for the 3TC-specific M184I mutation and a number of NNRTI-characteristic mutations (i.e., V106A, V108I, and Y188H). Abacavir plus GW420867X selected only for NNRTI-specific mutations (i.e., K101E, K103R, V106A, and Y181C), including the novel L100V mutation. Combination of GW420867X with five different NNRTIs selected solely for NNRTI-specific mutations, and also for the L100V mutation in the combined presence of efavirenz, nevirapine, or emivirine, respectively. Five single-, two double-, and two triple-mutated HIV-1 strains that emerged from this study were evaluated for their sensitivity/resistance to AZT, lamivudine, and seven different NNRTIs. In all cases, efavirenz, GW420867X, and UC-781 retained pronounced antiviral potency. Our data suggest that combinations of GW420867X with 3TC, ABC, and NNRTIs (e.g., efavirenz) would be worth pursuing as therapeutic modalities against HIV-1 infections.

Initiation of HAART in drug-naive HIV type 1 patients prevents viral breakthrough for a median period of 35.5 months in 60% of the patients.

The introduction of potent combinations of antiviral drugs is a major breakthrough in the treatment of HIV. We investigated the long-term virologic outcome and the development of resistance after initiating highly active antiretroviral therapy (HAART) in drug-naive patients in daily clinical practice. Twenty-five treatment-naive HIV-1 patients were started on HAART. Fifteen patients responded with a drop in viral load below the limit of detection during 35.5 (interquartile range: 7) months of therapy. In 6 of 10 patients with virologic failure, virus with resistance-related mutations against the received drugs emerged. Compared with responders (R), nonresponding (NR) patients were in a later disease stage at therapy start (p = 0.0089) with lower CD4 cell counts at baseline (p = 0.040), and a lower proportion of nonresponders showed protease inhibitor (PI) levels above C(min) (p = 0.049). More NR patients showed secondary PI mutations at baseline (p = 0.079), and the CCR2-64I coreceptor polymorphism was absent among NR patients, compared with 38.5% of R patients displaying CCR2-64I (p = 0.053), although the differences were not significant. In conclusion, starting HAART in antiretroviral drug-naive HIV-infected patients followed in daily clinical practice prevented viral breakthrough for up to 44 months in 60% of the patients. Virologic failure was associated with the development of resistance-related mutations, a later stage of disease at start of therapy and lower PI drug levels.

Dental age estimation and third molars: a preliminary study.

The aim of the present investigation was to reconstruct the chronological age based on the dental developmental stages of third molars evaluated on orthopantomograms. A total of 1175 orthopantomograms were assembled from patients of Caucasian origin between 16 and 22 years of age. Each third molar present was scored by two observers according to a 10-stage developmental scale. The kappa statistics measured the intra- and inter-observer reliability. The general statistical analysis was based on multiple regression analysis in order to obtain multiple regression formulas for dental age estimation based on the number of third molars present on the evaluated orthopantomogram. No regression models were statistically significant when there was only one-third molar present because of the relatively small number of orthopantomograms that fitted this criterion. A strong agreement was found between the intra- and inter-observer measurements. The statistical analysis revealed both for males and females high Pearson correlation coefficients between contralateral third molars and smaller coefficients between antimeres. The obtained multiple regression formulas are only applicable in certain specified conditions, for instance when four third molars are present the following formulas should be used in a Caucasian male "age=10.2000+0.5122UL+0.5273LL" (developmental stage of upper and lower left third molars) or in case of a female "age=13.6206+0.1933UR+0.5080LR" (developmental stage of upper and lower right third molars). This investigation revealed that the chronological age of a Caucasian individual may be estimated based on regression formulas with a S.D. of 1.52 or 1.56 years for males and females, respectively, when all four third molars are present.

Third molar root development in relation to chronological age: a large sample sized retrospective study.

The aim of the present investigation, which is a continuation and extension of a previous published pilot study [Forensic Sci. Int. 129 (2002) 110], was to calculate the chronological age of an individual based on the dental developmental stages of third molars (so-called wisdom teeth). The evaluated material consisted of 2513 orthopantomograms (OPG's) of patients all of Belgian Caucasian origin between 15.7 and 23.3 years. The sample of OPG's was scored by two observers who were calibrated for intra- and interobserver reliability by means of kappa statistics. The kappa statistics revealed a strong agreement between the intra- and interobserver measurements. Further statistical analysis was performed in order to obtain multiple regression formulae for dental age calculation with the chronological age as the independent variable and the third molar developmental stages as dependent variables. Both for males and females a significant Pearson correlation coefficient was noticed for contralateral third molars, a smaller less significant one for the antimeres. For the application of the regression formulae one has to take into consideration the gender, the location and number of wisdom teeth. Probabilities for an individual to be older than 18 years were also calculated in case of fully developed wisdom teeth.

Chronological age determination based on the root development of a single third molar: a retrospective study based on 2513 OPGs.

The aim of this survey was to correlate chronological age with the root development of only one third molar using a sample of 2513 subjects of Belgian Caucasian origin within the age range of late 15 to 22 years. Observations were performed by two observers, who were calibrated for intra- and inter-rater reliability by means of Kappa statistics and each third molar present was scored according to the modified method of Gleiser and Hunt. The method used in this study delivered linear regression formulae based on a sole wisdom tooth, divided according to gender. The results revealed standard deviations similar to those reported in comparable publications and even to those calculated with other skeletal age calculation techniques.

The relation between the localization of foot dermatitis and the causative allergens in shoes: a 13-year retrospective study.

The purpose of this retrospective study was to test whether the initial pattern of clinical presentation of shoe dermatitis could indicate the causative allergen(s) and to estimate the odds on foot dermatitis in patients with a positive patch test versus those with a negative patch-test result. Between 1990 and 2002, 8543 patients were patch tested with the standard series (and additional allergens, if appropriate). Of them, 1168 (14%) had been referred because of foot dermatitis and 474 of these patients (5.5% of the total group) presented a positive reaction to one or more substances related to shoes. We found that 6 standard allergens in the male group and 8 standard allergens in the female group were statistically significant for the shoe dermatitis group. The data showed a relationship between the distribution pattern of the foot lesions and most of the allergens. These results have clinical applications since the gender of the patients and the localization of the foot eruptions can, indeed, indicate what allergen is involved.

Third generation aromatase inhibitors may prevent endometrial growth and reverse tamoxifen-induced uterine changes in postmenopausal breast cancer patients.

BACKGROUND: Tamoxifen may induce uterine abnormalities of clinical concern. Our aim was to compare early uterine changes occurring in postmenopausal breast cancer patients treated in first-line with tamoxifen or third generation aromatase inhibitors. We also assessed the effect of aromatase inhibitors on tamoxifen-induced uterine changes. PATIENTS AND METHODS: Seventy-seven consecutive postmenopausal breast cancer patients scheduled to start endocrine treatment were included in this prospective study. Transvaginal ultrasonography (TVUS) was carried out before and after 3 months of therapy. No interventions were done on pre-existing asymptomatic uterine abnormalities seen on baseline sonography. RESULTS: After 3 months of therapy, tamoxifen significantly increased endometrial thickness and uterine volume. Additionally, tamoxifen induced endometrial cysts and polyps, and increased the size of pre-existing fibroids. In contrast, aromatase inhibitors did not stimulate endometrial growth and were not associated with endometrial pathologies seen under tamoxifen. Furthermore, aromatase inhibitors decreased endometrial thickness and uterine volume in patients previously treated with tamoxifen. CONCLUSIONS: Our study demonstrates that tamoxifen induces uterine abnormalities from as early as 3 months of therapy. In contrast, these abnormalities are not seen in patients on aromatase inhibitors. Furthermore, our data indicate that tamoxifen therapy followed by an aromatase inhibitor may lead to a reduction in endometrial pathologies associated with tamoxifen.