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Myelin-deficiency in the cochlear nerve of the 'bt' mutant hamster.

In a previous report, we showed abnormal auditory evoked potentials in the mutant hamster, 'black tremor (bt)', with significantly prolonged wave latencies of auditory brainstem responses and prolonged N1 latencies of compound action potentials, but normal cochlear microphonics. In this report, we present the results of morphological studies supporting the results of our electrophysiological studies of the auditory pathway in bt. Observation by transmission electron microscopy revealed an abnormal myelin sheath surrounding the spiral ganglion cells, and a thinner compact myelin sheath surrounding the axons in bt than in normal hamsters. The bt hamster has a myelin deficiency not only in the brainstem, but also in the cochlear nerve.

Animals↗

Sequence polymorphism in the human melanocortin 1 receptor gene as an indicator of the red hair phenotype.

We describe a minisequencing protocol for screening DNA samples for the presence of 12 mutations in the human melanocortin 1 receptor gene (MC1R), eight of which are associated with the red hair phenotype. A minisequencing profile which shows homozygosity for one of these mutations or the presence of two different mutations would strongly indicate that the sample donor is red haired. The absence of any red hair causing mutations would indicate that the sample donor does not have red hair. We report the frequencies of MC1R variants in the British red haired population.

Forensic Medicine↗

Effect of pigmentation on the drug deposition in hair of grey-haired subjects.

The hair samples of 15 grizzled patients with a permanent medical treatment by amitriptyline, carbamazepine, chlorprothixene, diclofenac, doxepine, indomethacine, maprotiline or metoclopramide, or with a chronic heroin and cocaine abuse were separated into white and pigmented fibers and both fractions were independently investigated by GC-MS. The drugs were found in pigmented fibers as well as in white fibers, but the concentrations in the white fibers were smaller than in the pigmented ones for the most of the samples investigated. The concentration ratio of the drugs or their metabolites in both hair fractions (white/pigmented) was found to be between 0.09 and 1.57 (mean 0.70, 30 concentration pairs). There are large differences in this ratio between different subjects with the same drug, whereas for different drugs in the same subject in many cases similar ratios were measured. As a reason a different grade of pigmentation of the hair and the influence of the drug structure are discussed. From these results it follows that the natural hair colour is an important parameter in the evaluation of drug concentration in hair.

Anti-Inflammatory Agents, Non-Steroidal↗

Hair concentrations and self-reported abuse history of 20 amphetamine and ecstasy users.

Hair samples of 20 volunteers of the techno-music scene, who more or less regularly consumed ecstasy tablets and speed and anonymously reported their abuse history, were analyzed in one to seven 3 cm segments for amphetamine (A), methamphetamine (MA), methylenedioxyamphetamine (MDA), methylenedioxymethamphetamine (MDMA), methylenedioxyethamphetamine (MDE) and N-methyl-1-(1,3-benzodioxol-5-yl)-2-butylamine (MBDB) by digestion in 1 M NaOH, subsequent extraction with C18 Bond Elut columns, derivatization with pentafluoropropionyl anhydride and GC/MS-SIM measurements using deuterated standards of A, MA, MDA and MDMA. The concentrations were in the regions 0.1 to 4.8 ng/mg for A (17 samples), 0.05 to 0.89 ng/mg for MDA (16 samples), 0.1 to 8.3 ng/mg for MDMA (16 samples), 0.12 to 15 ng/mg for MDE (13 samples) and 0.21 to 1.3 ng/mg for MBDB (2 samples). MA was not detected. For comparison the frequency and the concentration of these drugs in 124 different ecstasy tablets were determined by HPLC. The drug concentration in the hair segments were compared with the volunteers' reports. Despite the enormous interindividual differences qualitatively an increase of the total concentration of MDA, MDMA and MDE in the proximate 3 cm segments with increasing ecstasy abuse frequency during the last three month before sampling is recognized. In the individual comparison with the chronological consumer reports in most cases a longer interruption or a change of the abuse intensity is not clearly seen at the segment concentrations. As a reason the incorporation of the drugs from sweat into elder hair regions and the slow removal by washing are discussed.

Adolescent↗

Transient quinonimines and 1,4-benzothiazines of pheomelanogenesis: new pulse radiolytic and spectrophotometric evidence.

Biosynthetic and model in vitro studies have shown that pheomelanins, the distinctive pigments of red human hair, arise by oxidative cyclization of cysteinyldopas mainly 5-S-cysteinyldopa (1) via a critical o-quinonimine intermediate, which rearranges to unstable 1,4-benzothiazines. To get new evidence for these labile species, fast time resolution pulse radiolytic oxidation by dibromide radical anion of a suitable precursor, the dihydro-1,4-benzothiazine-3-carboxylic acid 7 was performed in comparison with that of 1. In the case of 7, dibromide radical anion oxidation leads over a few microseconds (k = 2.1 x 10(9) M(-1) s(-1)) to a phenoxyl radical (lambda(max) 330 nm, epsilon = 6300 M(-1) cm(-1)) which within tens of milliseconds gives rise with second-order kinetics (2k = 2.7 x 10(7) M(-1) s(-1)) to a species exhibiting an absorption maximum at 540 nm (epsilon = 2200 M(-1) cm(-1)). This was formulated as the o-quinonimine 3 arising from disproportionation of the initial radical. The quinonimine chromophore is converted over hundreds of milliseconds (k = 6.0 s(-1)) to a broad maximum at around 330 nm interpreted as due to a 1,4-benzothiazine or a mixture of 1,4-benzothiazines, which as expected are unstable and subsequently decay over a few seconds (k = 0.5 s(-1)). Interestingly, the quinonimine is observed as a labile intermediate also in the alternative reaction route examined, involving cyclization of the o-quinone (lambda(max) 390 nm, epsilon = 6900 M(-1) cm(-1)) arising by disproportionation (2k = 1.7 x 10(8) M(-1) s(-1)) of an o-semiquinone (lambda(max) 320 nm, epsilon = 4700 M(-1) cm(-1)) directly generated by dibromide radical anion oxidation of 1. Structural formulation of the 540 nm species as an o-quinonimine was further supported by rapid scanning diode array spectrophotometric monitoring of the ferricyanide oxidation of a series of model dihydrobenzothiazines.

Dermatitis, Phototoxic↗

Sun exposure and number of nevi in 5- to 6-year-old European children.

The occurrence and number of melanocytic nevi are among the most important known risk factors for the development of malignant melanoma. Studying the causes of nevi should lead to successful strategies in the prevention of melanoma. Among 11,478 white German children of preschool age the association between benign melanocytic nevi and a number of risk factors for skin cancer was examined. We found that subjects with a reported history of increased sun exposure, for example, painful sunburns, and an increased number of holidays in foreign countries with a sunny climate had significantly higher nevus counts than individuals without these characteristics. Our results provide further evidence that nevus counts may not only be part of a genetic predisposition but also a result of increased exposure to ultraviolet radiation. Together with the fact that a high nevus count is the most relevant risk factor for malignant melanoma, the results strongly indicate a connection between UV-radiation and the development of melanocytic skin cancer. In conclusion, strategies to reduce the incidence of melanoma should begin with young children.

Child↗

Diagnostic utility of the history and physical examination for peripheral vascular disease among patients with diabetes mellitus.

BACKGROUND: We assessed the value of the medical history and physical examination in the diagnosis of peripheral vascular disease in diabetic subjects. METHODS: We performed a cross-sectional study in 631 diabetic veteran enrollees of a general internal medicine clinic that compared data obtained from a history and clinical evaluation with the presence of severe peripheral vascular disease defined as an ankle-arm index (AAI) < or = 0.5 derived from Doppler blood pressure measurement. RESULTS: We identified 90 limbs with an AAI < or = 0.5. Results presented below apply to the right leg, but do not differ from the left. Diminished or absent foot peripheral pulses (sensitivity 65%, specificity 78%), venous filling time > 20 sec (sensitivity 22%, specificity 93.9%), age > 65 years (sensitivity 83%, specificity 54%), claudication symptoms in < 1 block (sensitivity 50%, specificity 87%), and patient reported history of physician diagnosed peripheral vascular disease (PVD) (sensitivity 80%, specificity 70%) had the largest positive (or smallest negative) likelihood ratios. Capillary refill time > 5 sec or foot characteristics (absent hair, blue/purple color, skin coolness, or atrophy) conveyed little diagnostic information. Individual factors did not change disease probability to a clinically important degree. A stepwise logistic regression model identified four factors significantly (p < 0.05) associated with low AAI: absent or diminished peripheral pulses, patient reported history of PVD, age, and venous filling time. Substitution of < 1 block claudication for PVD history in this model resulted in a small reduction in model accuracy. CONCLUSIONS: Many purportedly useful historical and exam findings need not be elicited in diabetic patients suspected of having severe peripheral vascular disease, since most information related to probability of this disorder may be obtained from patient age, self-reported history of physician diagnosed PVD (or < 1 block claudication), peripheral pulse palpation, and venous filling time.

Aged↗

Detection of a point mutation (A to G) in exon 5 of the murine Mgf gene defines a novel allele at the Steel locus with a weak phenotype.

A new mutation at the locus encoding the mast cell growth factor (Mgf) is described and designated as MgfSl-3Neu. Homozygous mutants have a light grey fur, sometimes with white patches. Homozygotes are fertile, but with reduced litter size, when mated inter se. Analysis of haematological parameters indicated no difference between mutant and wild-type mice. Sequence analysis of the cDNA obtained from the brain of homozygous mutants revealed an A-->G exchange at position 400 leading to a predicted amino acid exchange from Asn-->Leu at position 122. As a consequence of the predicted amino acid exchange an extension of the alpha-helical context and a decreased hydropathicity of the region at positions 101-125 can be deduced. This single amino acid exchange is outside of the known important domains of MGF and explains the weak phenotype of MgfSl-3Neu.

Alleles↗

On the structure of human hair melanins from an infrared spectroscopy analysis of their interactions with Cu2+ ions.

Melanins were isolated from dark and red human hair and complexed with copper ions at various pH values in a complexing medium. IR spectra of melanins and their Cu2+-complexes for pellets with KBr were obtained. The IR spectra indicate that Cu2+ ions bound to melanins are fixed by different carboxyl and hydroxyl (phenolic and/or alcoholic) groups in the macromolecule. From these results it is concluded that, generally, melanin carboxyl groups are responsible for interactions of metal ions with the melanin molecule. Complexes of melanins isolated from dark and red human hair show structural differences when analysed by IR spectroscopy. Conclusions from these investigations assist in the differentiation of structures of analysed hair melanins. IR spectral analysis of melanin samples and their complexes suggest that melanin samples obtained from red hair may contain eumelanin.

Copper↗

Degenerative disorders caused by Bcl-2 deficiency prevented by loss of its BH3-only antagonist Bim.

Apoptosis is triggered when proapoptotic members of the Bcl-2 protein family bearing only the BH3 association domain bind to Bcl-2 or its homologs and block their antiapoptotic activity. To test whether loss of the BH3-only protein Bim could prevent the cellular attrition caused by Bcl-2 deficiency, we generated mice lacking both genes. Mice without Bcl-2 have a fragile lymphoid system, become runted, turn gray, and succumb to polycystic kidney disease. Concomitant absence of Bim prevented all these disorders. Indeed, loss of even one bim allele restored normal kidney development, growth, and health. These results demonstrate that Bim levels set the threshold for initiation of apoptosis in several tissues and suggest that degenerative diseases might be alleviated by blocking BH3-only proteins.

Alleles↗

Intrapair differences of physical aging and longevity in identical twins.

The genetic and environmental contributions to physical aging (hair graying, balding, presbyopia) and longevity (age at death) were examined by within-pair comparison in monozygotic (MZ) and dizygotic (DZ) twins in later adulthood. Physical aging was investigated on 135 pairs of adult twins aged over 50. Hair graying and hair loss (baldness) showed significantly higher rates of concordance in the MZ twins than in the DZ twins. The intrapair difference of the degree of hair graying was negligible in 79%, slight in 15% and striking in 5% among the MZ pairs; while negligible in 40%, slight in 50% and striking in 10% among the DZ pairs. The intrapair difference of the degree of hair loss was negligible in 92%, slight in 8% (and striking in none) among the MZ pairs; while negligible in 69%, slight in 25% and striking in 6% among the DZ pairs. The age at onset of presbyopia showed a slightly higher rate of concordance in the MZ than in the DZ pairs. Longevity (age at death) was surveyed on 184 pairs of twins who died at over 40 years of age. The intrapair difference of longevity was 6.65 +/- 5.6 years (maximum 18.0; minimum 0.04) in the MZ pairs, and 8.66 +/- 7.2 years (maximum 18.6; minimum 2.9) in the DZ pairs. The MZ pairs showed a slightly smaller within-pair difference of longevity than the DZ pairs.

Aged↗