Ofloxacin as a reference marker in hair of various colors.
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It has been proposed that administration of a reliable marker substance to human subjects may enhance the ability to identify drug use and treatment compliance in drug treatment programs. The goal of this study was to determine if an oral dose of the antibiotic ofloxacin (OFLX) could be used as a "marker" substance to establish reference points with respect to time in hair of various colors. Male and female subjects (n = 32) between 18 and 40 years of age received 800 mg of OFLX as a divided oral dose on a single day. Subjects were restricted from cutting their hair or performing chemical treatments. Hair was collected (by cutting) before, and at weeks 4, 5, 6, and 7 after drug administration. Subjects were classified as having black (n = 5), brown (n = 13), blonde (n = 8), or red (n = 6) hair. Hair was segmented into 3.0-cm segments prior to digestion, extraction, and analysis by high-pressure liquid chromatography (HPLC). At 7 weeks, the mean OLFX concentrations (+/- 1 SD) in the first 3.0 cm of hair closest to the scalp were as follows: 30.6 +/- 8.5 ng/mg (black), 6.0 +/- 1.8 ng/mg (brown), 3.5 +/- 1.6 ng/mg (blonde), and 1.4 +/- 0.3 ng/mg (red). A similar pattern was found in hair collected at weeks 4-6. Quantitative eumelanin (EUM) hair concentrations for each subject were also determined for each subject via HPLC. A strong relationship between OFLX concentration at 7 weeks and EUM was noted (r2 adjusted = 0.728; p < 0.001). In six subjects, we also determined the intrasubject variability of OFLX incorporation into individual hair strands. Four strands from each subject were segmented into 2-mm segments and analyzed. OFLX appeared in segments #1-#10 at week 5 (the first centimeter of hair). OFLX appeared in segments #2-#20 at week 7 (the first and second centimeter of hair). The maximum OFLX concentration (the "band" of drug) and location was then determined for each strand. The maximum OFLX concentration was measured in segments #2-#5 at week 5 for all subjects (within the first centimeter of hair length). The maximum OFLX concentration was measured in segments #3-#8 at week 7 (within the first and second centimeter of hair). This was consistent with a growth rate of less than 1.0 cm/month, although considerable intersubject variability was found. No significant axial diffusion of OFLX along the hair shaft beyond the first 3.0 cm of hair was noted. Despite a strong effect of hair color, these data suggest that OFLX may be a suitable marker substance for hair, allowing a subject to serve as their own "control". Future studies will explore whether drug use, treatment compliance, or recidivism in clinical drug-abuse studies can be determined with the aid of OFLX. (+info)
Biophysical properties of the pelt of a diurnal marsupial, the numbat (Myrmecobius fasciatus), and its role in thermoregulation.
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Numbats are unusual marsupials in being exclusively diurnal and termitivorous. They have a sparse (1921 hairs cm(-2)) and shallow (1.19 mm) pelt compared with other marsupials. Coat reflectivity is low (19%) for numbats compared with nocturnal marsupials, but absorptivity is similar to that of diurnal North American ground squirrels (72%), indicating that the coat of the numbat may be adapted for acquisition of solar heat. Numbat coat thermal resistance decreases significantly with wind speed from 45.9 s m(-1) (at 0.5 m s(-1)) to 29.8 s m(-1) (at 3 m s(-1)). Erecting the fur significantly increases pelt depth (6.5 mm) and coat resistance (79.2-64.2 s m(-1)) at wind speeds between 0.5 m s(-1) and 3 m s(-1). Numbat coat resistance is much lower than that of other marsupials, and wind speed has a greater influence on coat resistance for numbats than for other mammals, reflecting the low pelt density and thickness. Solar heat gain by numbats through the pelt to the level of the skin (60-63%) is similar to the highest value measured for any mammal. However the numbat's high solar heat gain is not associated with the same degree of reduction in coat resistance as seen for other mammals, suggesting that its pelt has structural and spectral characteristics that enhance both solar heat acquisition and endogenous heat conservation. Maximum solar heat gain is estimated to be 0.5-3.6 times resting metabolic heat production for the numbat at ambient temperatures of 15-32.5 degrees C, so radiative heat gain is probably an important aspect of thermoregulation for wild numbats. (+info)
Biogenesis of lysosome-related organelles complex 3 (BLOC-3): a complex containing the Hermansky-Pudlak syndrome (HPS) proteins HPS1 and HPS4.
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Hermansky-Pudlak syndrome (HPS) defines a group of autosomal recessive disorders characterized by deficiencies in lysosome-related organelles such as melanosomes and platelet-dense granules. Several HPS genes encode proteins of unknown function including HPS1, HPS3, and HPS4. Here we have identified and characterized endogenous HPS3 and HPS4 proteins from HeLa cells. Both proteins were found in soluble and membrane-associated forms. Sedimentation-velocity and coimmunoprecipitation experiments revealed that HPS4 but not HPS3 associates with HPS1 in a complex, which we term biogenesis of lysosome-related organelles complex 3 (BLOC-3). Mutant fibroblasts deficient in either HPS1 or HPS4 displayed abnormal localization of lysosomes and late endosomes, which were less concentrated at the juxtanuclear region in mutant cells than in control fibroblasts. The coat-color phenotype of young homozygous double-mutant mice deficient in subunits of BLOC-3 (HPS1) and BLOC-1 (pallidin) was indistinguishable from that of BLOC-1 single mutants. Taken together, these observations suggest that HPS1 and HPS4 are components of a protein complex that regulates the intracellular localization of lysosomes and late endosomes and may function in a BLOC-1-dependent pathway for melanosome biogenesis. (+info)
MC1R mutations modify the classic phenotype of oculocutaneous albinism type 2 (OCA2).
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The heterogeneous group of disorders known as oculocutaneous albinism (OCA) shares cutaneous and ocular hypopigmentation associated with common developmental abnormalities of the eye. Mutations of at least 11 loci produce this phenotype. The majority of affected individuals develop some cutaneous melanin; this is predominantly seen as yellow/blond hair, whereas fewer have brown hair. The OCA phenotype is dependent on the constitutional pigmentation background of the family, with more OCA pigmentation found in families with darker constitutional pigmentation, which indicates that other genes may modify the OCA phenotype. Sequence variation in the melanocortin-1 receptor (MC1R) gene is associated with red hair in the normal population, but red hair is unusual in OCA. We identified eight probands with OCA who had red hair at birth. Mutations in the P gene were responsible for classic phenotype of oculocutaneous albinism type 2 (OCA2) in all eight, and mutations in the MC1R gene were responsible for the red (rather than yellow/blond) hair in the six of eight who continued to have red hair after birth. This is the first demonstration of a gene modifying the OCA phenotype in humans. (+info)
A sensitive method for detecting variation in copy numbers of duplicated genes.
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Gene duplications are common in the vertebrate genome, and duplicated loci often show a variation in copy number that may have important phenotypic effects. Here we describe a powerful method for quantification of duplicated copies based on pyrosequencing. A reliable quantification was obtained by amplification of the duplication break-point and a corresponding nonduplicated sequence in a competitive PCR assay. A comparison with an independent method for quantification based on the Invader technology revealed an excellent correlation between the two methods. The pyrosequencing-based method was evaluated by analyzing variation in copy number at the duplicated KIT/Dominant white locus in pigs. We were able to distinguish haplotypes at this locus by combining the duplication breakpoint test with a diagnostic test for a functionally important splice mutation in the duplicated gene. An extensive allelic variation, including the presence of a new allele carrying a single KIT copy expected to encode a truncated KIT receptor, was revealed when analyzing white pigs from commercial lines. (+info)
Hair depigmentation is a biological readout for pharmacological inhibition of KIT in mice and humans.
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Deregulated activation of the KIT receptor tyrosine kinase has been implicated in several human cancers and in inflammation, making it an attractive target for therapeutic intervention. Conversely, deficiencies in KIT signaling have been implicated in human and animal hair pigmentation disorders, reflecting a role for KIT in the development and function of melanocytes. The goal of this study was to explore the potential utility of hair depigmentation as a biological readout for systemic inhibition of KIT by SU11248 5-[5-fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3- carboxylic acid (2-diethylaminoethyl)amide), an oral multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activity through targeting platelet-derived growth factor receptors, vascular endothelial growth factor receptors, KIT, and FLT3. Oral SU11248 treatment induced dose-dependent depigmentation of newly regrown hair in depilated C57BL/6 mice. Similar effects were seen after administration of a KIT-neutralizing antibody. SU11248-induced hair depigmentation was reversible with cessation of treatment. Histological and immunohistochemical evaluation of mouse skin samples supported these observations and revealed that SU11248 has no effect on levels of KIT-positive melanocytes associated with hair follicles, indicating that the inhibitory effect is at the level of melanocyte function rather than their development/survival. Similar hair depigmentation has been noted in several cancer patients receiving SU11248 in phase I trials. Strikingly, patient scalp hair exhibits bands of depigmentation and pigmentation that correspond, respectively, to periods of treatment and dosing rest periods. These data demonstrate that hair pigmentation can serve as a dose-dependent, dynamic, biological readout for KIT inhibition in mice, and, apparently, in humans. (+info)
Traits that influence longevity in mice: a second look.
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Analysis of genetic interactions in the F2 of an intercross of (C57BL/6 x DBA/2) F1J revealed influences of genetic factors on life span. Females lived longer than males. Dilute brown females died sooner than females of other colors. H-2b/H-2b males died sooner than H-2b/H-2d or H-2d/H-2d males, except that among dilute brown males those of typeH-2b/H-2d died sooner. Cluster analysis suggested that male and female genotypes each fall into two groups, with female dilute brown mice having shorter lives than other females, and male H-2b/H-2b mice except dilute brown and dilute brown H-2b/H-2d mice having shorter lives than other males. The association of heterozygosity with life span was clearer in females than in males, yet the longest-lived female genotype was homozygous H-2d/H-2d, of dominant Black phenotype at the Brown locus of chromosome 4, and homozygous dd at the Dilute locus of chromosome 9. The shortest-lived females were dilute brown H-2b/H-2b. The longest-lived and shortest-lived male genotypes were dilute brown H-2d/H-2d and dilute brown H-2b/H-2d, respectively. Although histological findings at postmortem differed between the sexes, there was no association of particular disorders with other genetic markers. The importance of H-2 in males was confirmed, but the allelic effects were perturbed, possibly by the absence of Sendai infection in this experiment. Overall our studies suggest that genetic influences on life span involve interactions between loci, and allelic interactions may change with viral infections or other environmental factors. (+info)
A prospective study of pigmentation, sun exposure, and risk of cutaneous malignant melanoma in women.
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BACKGROUND: Although sun exposure is an established cause of cutaneous malignant melanoma, possible interactions with host factors remain incompletely understood. Here we report the first results from a large prospective cohort study of pigmentation factors and sun exposure in relation to melanoma risk. METHODS: The Women's Lifestyle and Health Cohort Study included 106 379 women from Norway and Sweden who were aged 30-50 years in 1991 or 1992 when they completed an extensive questionnaire on personal characteristics and exposures. Linkages to national registries ensured complete follow-up through December 31, 1999. Poisson regression models were used to estimate relative risks (RRs). All statistical tests were two-sided. RESULTS: During an average follow-up of 8.1 years, 187 cases of melanoma were diagnosed. Risk of melanoma was statistically significantly associated with increasing body surface area (RR for > or =1.79 m2 versus < or =1.61 m2 = 1.60, 95% confidence interval [CI] = 1.03 to 2.48; P(trend) =.02), number of large asymmetric nevi on the legs (RR for > or =7 nevi versus 0 nevi = 5.29, 95% CI = 2.33 to 12.01; P(trend)<.001), hair color (RR for red versus dark brown or black = 4.05, 95% CI = 2.11 to 7.76; P(trend)<.001), sunburns per year at ages 10-19, 20-29, and 30-39 years (P(trend)<.001, P(trend) =.03, and P(trend) =.05, respectively), and use of a device that emits artificial light (solarium) one or more times per month (P =.04). CONCLUSIONS: Our results confirm previous findings that hair color, number of nevi on the legs, and history of sunburn are risk factors for melanoma and suggest that use of a solarium is also associated with melanoma risk. Adolescence and early adulthood appear to be among the most sensitive age periods for the effects of sunburn and solarium use on melanoma risk. However, it may be too early to see the full effect of adult exposures in this cohort. (+info)