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PubMed2001

Use of hair analysis for confirmation of self-reported cocaine use in users with negative urine tests.

INTRODUCTION: Identification of cocaine use based on a urine test may miss many cases because of the short elimination half-life of the drug. Our objective was to verify the sensitivity of the cocaine hair test in admitted users. PATIENTS AND METHODS: Admitted cocaine users (38), that were 18-70 years of age and reported to have refrained from using cocaine in the few days to months prior to the test, were compared to 10 controls who claimed never to have used cocaine. All had negative urine tests for cocaine and benzoylecgonine by thin-layer chromatography. Cocaine and benzoylecgonine were extracted from unwashed hair and tested by established immunoassays. RESULTS: The hair test was positive in 37/38 cases (97%) and in none of the controls. There was significantly more cocaine in black hair than in brown or blonde hair per mg of cocaine dose reported to have been consumed, highlighting a potential bias when interpreting test results in individuals with dark hair. There was a statistically significant correlation between reported dose used and hair concentrations of cocaine. DISCUSSION: The cocaine hair test appears to be highly sensitive and specific in identifying past cocaine use in the setting of a negative urine test.

Adolescent↗
PubMedDate not supplied

Molecular and pharmacological characterisation of the MSH-R alleles in Swiss cattle breeds.

The coat colour in mammals is determined by the relative amounts of eumelanin (black/brown) and phaeomelanin (red/yellow), produced in melanocytes, which are controlled by melanocyte stimulating hormone receptor (MSH-R). Melanocyte stimulating hormone receptor is activated by alpha-melanocyte-stimulating hormone (alpha-MSH). Stimulated MSH-R activates adenylyl cyclase (AC), thereby increasing the amount of cyclic AMP in the cell, which activates the enzyme tyrosinase resulting in eumelanin synthesis. In this study the complete coding sequences of five alleles of the MSH-R gene found in Holstein, Red Holstein, Simmental, and Brown Swiss cattle were cloned into a mammalian expression vector and transfected into human embryonic kidney (HEK) 293 cells. The expressed receptors were analyzed for their ability to increase intracellular cAMP in response to stimulation by alpha-MSH. The recessive red allele (e) found in Red Holstein and Simmental and the dominant black allele (ED) found in Holstein were unresponsive to a wide range of alpha-MSH concentrations. Two alleles from Brown Swiss (E(d1), E(d2)) and one allele found in the Simmental breed (e(f)) responded to stimulation by alpha-MSH in a dose-dependent manner. When compared to E(d1) and E(d2), the cells transfected with the e(f) MSH-R allele, however, reached the corresponding intracellular cAMP concentrations at a 10-fold higher concentration of alpha-MSH. In conjunction with the mode of inheritance of coat colour, the results indicate that the e MSH-R allele is a non-functional receptor, E(D) is constitutively activated receptor, and E(d1) and E(d2) are hormonally activated receptors. The delay in e(f) MSH-R response may explain the similarity between the e and e(f) phenotypes.

Alleles↗
PubMed1998

Visualization of melanosome dynamics within wild-type and dilute melanocytes suggests a paradigm for myosin V function In vivo.

Unlike wild-type mouse melanocytes, where melanosomes are concentrated in dendrites and dendritic tips, melanosomes in dilute (myosin Va-) melanocytes are concentrated in the cell center. Here we sought to define the role that myosin Va plays in melanosome transport and distribution. Actin filaments that comprise a cortical shell running the length of the dendrite were found to exhibit a random orientation, suggesting that myosin Va could drive the outward spreading of melanosomes by catalyzing random walks. In contrast to this mechanism, time lapse video microscopy revealed that melanosomes undergo rapid ( approximately 1.5 microm/s) microtubule-dependent movements to the periphery and back again. This bidirectional traffic occurs in both wild-type and dilute melanocytes, but it is more obvious in dilute melanocytes because the only melanosomes in their periphery are those undergoing this movement. While providing an efficient means to transport melanosomes to the periphery, this component does not by itself result in their net accumulation there. These observations, together with previous studies showing extensive colocalization of myosin Va and melanosomes in the actin-rich periphery, suggest a mechanism in which a myosin Va-dependent interaction of melanosomes with F-actin in the periphery prevents these organelles from returning on microtubules to the cell center, causing their distal accumulation. This "capture" model is supported by the demonstration that (a) expression of the myosin Va tail domain within wild-type cells creates a dilute-like phenotype via a process involving initial colocalization of tail domains with melanosomes in the periphery, followed by an approximately 120-min, microtubule-based redistribution of melanosomes to the cell center; (b) microtubule-dependent melanosome movement appears to be damped by myosin Va; (c) intermittent, microtubule-independent, approximately 0.14 microm/s melanosome movements are seen only in wild-type melanocytes; and (d) these movements do not drive obvious spreading of melanosomes over 90 min. We conclude that long-range, bidirectional, microtubule-dependent melanosome movements, coupled with actomyosin Va-dependent capture of melanosomes in the periphery, is the predominant mechanism responsible for the centrifugal transport and peripheral accumulation of melanosomes in mouse melanocytes. This mechanism represents an alternative to straightforward transport models when interpreting other myosin V mutant phenotypes.

Actin Cytoskeleton↗
PubMed2006

Notch signaling via Hes1 transcription factor maintains survival of melanoblasts and melanocyte stem cells.

Melanoblasts (Mbs) are thought to be strictly regulated by cell-cell interactions with epidermal keratinocytes, although the precise molecular mechanism of the regulation has been elusive. Notch signaling, whose activation is mediated by cell-cell interactions, is implicated in a broad range of developmental processes. We demonstrate the vital role of Notch signaling in the maintenance of Mbs, as well as melanocyte stem cells (MSCs). Conditional ablation of Notch signaling in the melanocyte lineage leads to a severe defect in hair pigmentation, followed by intensive hair graying. The defect is caused by a dramatic elimination of Mbs and MSCs. Furthermore, targeted overexpression of Hes1 is sufficient to protect Mbs from the elimination by apoptosis. Thus, these data provide evidence that Notch signaling, acting through Hes1, plays a crucial role in the survival of immature Mbs by preventing initiation of apoptosis.

Animals↗
PubMed1999

Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation.

We examined the effectiveness of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade, alone or in combination with a granulocyte/macrophage colony-stimulating factor (GM-CSF)-expressing tumor cell vaccine, on rejection of the highly tumorigenic, poorly immunogenic murine melanoma B16-BL6. Recently established tumors could be eradicated in 80% (68/85) of the cases using combination treatment, whereas each treatment by itself showed little or no effect. Tumor rejection was dependent on CD8(+) and NK1.1(+) cells but occurred irrespective of the presence of CD4(+) T cells. Mice surviving a primary challenge rejected a secondary challenge with B16-BL6 or the parental B16-F0 line. The same treatment regimen was found to be therapeutically effective against outgrowth of preestablished B16-F10 lung metastases, inducing long-term survival. Of all mice surviving B16-BL6 or B16-F10 tumors after combination treatment, 56% (38/68) developed depigmentation, starting at the site of vaccination or challenge and in most cases progressing to distant locations. Depigmentation was found to occur in CD4-depleted mice, strongly suggesting that the effect was mediated by CTLs. This study shows that CTLA-4 blockade provides a powerful tool to enhance T cell activation and memory against a poorly immunogenic spontaneous murine tumor and that this may involve recruitment of autoreactive T cells.

Abatacept↗
PubMed2003

MC1R mutations modify the classic phenotype of oculocutaneous albinism type 2 (OCA2).

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.

Adolescent↗
PubMed1986

Protein deficiency in premature infants receiving parenteral nutrition.

A classical finding of protein deficiency is hair depigmentation, or the flag sign. To determine the clinical conditions that predispose ill premature infants to the development of protein deficiency, we compared the clinical courses and nutritional histories of premature infants receiving parenteral nutrition who developed the flag sign (group F), with those of a matched control group (Group C). Occurrences of necrotizing enterocolitis (NEC) and consequent surgery were significantly higher in group F than in group C (p less than 0.002 and p less than 0.005, respectively). No differences were found in the mean (+/- SD) administration of amino acids (group F, 2.5 +/- 0.2 g X kg X day vs group C, 2.4 +/- 0.4) and total energy (83.4 +/- 13.4 kcal X kg X day vs 83.6 +/- 11.1, respectively). Mean serum albumin levels (2.6 +/- 0.4 g/dL vs 2.6 +/- 0.5, respectively) also were similar. Because infants in both groups received recommended amounts of protein, results suggest that infants who have NEC, and surgery as a consequence of NEC, require more protein than is presently recommended.

Enteral Nutrition↗
PubMed1999

Induction of melanoma in TPras transgenic mice.

In order to study the oncogenesis of melanocytes, transgenic mouse lines were established that express a mutated human Ha-ras (TPras) gene in pigment producing cells. The ras transgenic mice exhibit an altered phenotype, including melanocytic hyperplasia and a muted agouti coat, indicative of hyperproliferative melanocytes. These mice and their wild-type littermates have been subjected to a variety of carcinogenesis protocols, including 7, 12-dimethylbenz-[a]anthracene (DMBA), 12-O-tetradecanoylphorbol-13-acetate (TPA) and UV radiation exposure. Topical DMBA treatment of TPras mice resulted in a high incidence of melanomas. Metastatic lesions were observed in skin, lungs and lymph nodes. TPA treatment of TPras mice induced a small number of papillomas but no nevi or melanomas. UV light exposures induced papillomas in negative littermate and melanomas in some albino TPras mice. These results show that melanocytes expressing an activated Ha-ras in the TPras transgenic mice are susceptible to induction of melanoma by DMBA.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1987

Genetic organization of the agouti region of the mouse.

The agouti locus on mouse chromosome 2 acts via the hair follicle to control the melanic type and distribution of hair pigments. The diverse phenotypes associated with various agouti mutations have led to speculation about the organization of the agouti locus. Earlier studies indicated that two presumed agouti alleles, lethal yellow (Ay) and lethal light-bellied nonagouti (ax), are pseudoallelic. We present genetic data showing probable recombination between Ay and three agouti mutations (at, a, and ax), which suggest that Ay is a pseudoallele of the agouti locus. The close linkage of an endogenous ecotropic murine leukemia provirus, Emv-15, to Ay provides a molecular access to genes at or near the agouti locus. However, previous studies suggested that the Emv-15 locus can recombine with some agouti alleles and therefore we analyzed mice from recombinant inbred strains and backcrosses to measure the genetic distance between various agouti alleles and the Emv-15 locus. Our data indicate that the Emv-15 locus is less than 0.3 cM from the agouti locus. These experiments provide a conceptual framework for initiating chromosome walking experiments designed to retrieve sequences from the agouti locus and give new insight into the genetic organization of the agouti region.

Animals↗
PubMed1990

The molecular basis of brown, an old mouse mutation, and of an induced revertant to wild type.

The murine b locus encodes the tyrosinase related protein, TRP-1, a putative membrane-bound, copper-containing enzyme having about 40% amino acid identity with tyrosinase. The protein is essential for production of black rather than brown hair pigment. We show that skin of mutant brown mice contains the same amount of TRP-1 mRNA as wild type. On sequencing the coding region of the mutant mRNA we find four nucleotide differences from the wild-type (Black) sequence. Two of these differences result in different amino acid residues encoded by the brown allele. By sequencing the TRP-1 gene from a mouse in which a reversion from brown to Black has been induced by ethylnitrosourea we are able to show that only one of these amino acid changes, which substitutes a tyrosine for a conserved cysteine, is the cause of the brown phenotype. This mutation is adjacent to another cysteine at which, in the analogous position in tyrosinase a mutation results in the albino phenotype. The sequence of the revertant is the first report of DNA sequence of an ethylnitrosourea-induced genetic change in mouse.

Amino Acid Sequence↗
PubMed1994

Fine structure mapping and deletion analysis of the murine piebald locus.

piebald (s) is a recessive mutation that affects the development of two cell types of neural crest origin: the melanocytes, responsible for pigment synthesis in the skin, and enteric ganglia, which innervate the lower bowel. As a result, mice carrying piebald mutations exhibit white spotting in the coat and aganglionic megacolon. Previously the gene had been localized to the distal half of mouse chromosome 14. To determine its precise location relative to molecular markers, an intersubspecific backcross was generated. Two anchor loci of chromosome 14, slaty and hypogonadal, in addition to simple sequence length repeat markers, were used to localize s to a 2-cM interval defined by the markers D14Mit38 and D14Mit42. The molecular markers were also used to characterize nine induced s alleles. Three of these mutations exhibited no deletions or rearrangements of the flanking markers, whereas the other six had two or more of these markers deleted. The extent of the deletions was found to be consistent with the severity of the homozygous phenotype. The location of deletion breakpoints in the induced alleles, coupled with the recombination breakpoints in the backcross progeny, provide useful molecular landmarks to define the location of the piebald gene.

Animals↗
PubMed1994

Molecular genetics of the brown (b)-locus region of mouse chromosome 4. II. Complementation analyses of lethal brown deletions.

Numerous new mutations at the brown (b) locus in mouse chromosome 4 have been recovered over the years in germ-cell mutagenesis experiments performed at the Oak Ridge National Laboratory. A large series of radiation- and chemical-induced b mutations known to be chromosomal deletions, and also known to be prenatally lethal when homozygous, were analyzed by pairwise complementation crosses as well as by pseudodominance tests involving flanking loci defined by externally visible phenotypes. These crosses were designed to determine the extent of each deletion on the genetic and phenotype map of the chromosomal region surrounding the b locus; the crosses also provided basic data that assigned deletions to complementation groups and defined four new loci associated with aberrancies in normal development. Specifically, the pseudodominance tests identified deletions that include the proximally mapping whirler (wi) and the distally mapping depilated (dep) genes, thereby bracketing these loci defined by visible developmental abnormalities with landmarks (deletion breakpoints) that are easily identified on the physical map. Furthermore, the complementation crosses, which were supplemented with additional crosses that allowed determination of the gross time of lethality of selected deletions, defined four new loci required for normal development. Homozygous deletion of one of these loci (b-associated fitness, baf) results in a runting syndrome evident during postnatal development; deletion of one locus [l(4)2Rn] causes death in the late gestation/neonatal period; and deletion of either of two loci [l(4)1Rn or l(4)3Rn] results in embryonic death, most likely in pre-, peri- or postimplantation stages. The placement of these new functionally defined loci on the evolving molecular map of the b region should be useful for continuing the analysis of the roles played in development by genes in this segment of chromosome 4.

Animals↗
PubMed1995

A transgenic mouse assay for agouti protein activity.

The mouse agouti gene encodes an 131 amino acid paracrine signaling molecule that instructs hair follicle melanocytes to switch from making black to yellow pigment. Expression of agouti during the middle part of the hair growth cycle in wild-type mice produces a yellow band on an otherwise black hair. The ubiquitous unregulated expression of agouti in mice carrying dominant yellow alleles is associated with pleiotropic effects including increased yellow pigment in the coat, obesity, diabetes and increased tumor susceptibility. Agouti shows no significant homology to known genes, and the molecular analysis of agouti alleles has shed little new light on the important functional elements of the agouti protein. In this paper, we show that agouti expression driven by the human beta-ACTIN promoter produces obese yellow transgenic mice and that this can be used as an assay for agouti activity. We used this assay to evaluate a point mutation associated with the a16H allele within the region encoding agouti's putative signal sequence and our results suggest that this mutation is sufficient to cause the a16H phenotype. Thus, in vitro mutagenesis followed by the generation of transgenic mice should allow us to identify important functional elements of the agouti protein.

Actins↗
PubMed1996

Molecular basis of the pleiotropic phenotype of mice carrying the hypervariable yellow (Ahvy) mutation at the agouti locus.

The murine agouti locus regulates a switch in pigment synthesis between eumelanin (black/brown pigment) and phaeomelanin (yellow/red pigment) by hair bulb melanocytes. We recently described a spontaneous mutation, hypervariable yellow (Ahvy) and demonstrated that Ahvy is responsible for the largest range of phenotypes yet identified at the agouti locus, producing mice that are obese with yellow coats to mice that are of normal weight with black coats. Here, we show that agouti expression is altered both temporally and spatially in Ahvy mutants. Agouti expression levels are positively correlated with the degree of yellow pigmentation in individual Ahvy mice, consistent with results from other dominant yellow agouti mutations. Sequencing of 5' RACE and genomic PCR products revealed that Ahvy resulted from the integration of an intracisternal A particle (IAP) in an antisense orientation within the 5' untranslated agouti exon 1C. This retrovirus-like element is responsible for deregulating agouti expression in Ahvy mice; agouti expression is correlated with the methylation state of CpG residues in the IAP long terminal repeat as well as in host genomic DNA. In addition, the data suggest that the variable phenotype of Ahvy offspring is influenced in part by the phenotype of their Ahvy female parent.

Agouti Signaling Protein↗
PubMed2000

Cats as an aid to teaching genetics.

I have used an exercise involving domestic cats in the General Genetics course at the University of Nebraska-Lincoln for the past 5 years. Using a coherent set of traits in an organism familiar to the students makes it easy to illustrate principles of transmission and population genetics. The one-semester course consists primarily of sophomores and juniors who have either taken a one-semester introductory biology course, a one-semester cell biology course, or have a strong high school biology background. The students are given a handout and asked to determine the genotype at seven unlinked loci of at least one cat. To fill out the form, the students have to grasp such concepts as dominance, incomplete dominance, temperature-sensitive mutations, epistatic interactions, sex linkage, and variable expressivity. Completing the form reinforces these concepts as they observe the cat's phenotype and fill in the genotype. I then analyze the collected data and use it in my lectures on population genetics to illustrate the Hardy-Weinberg equilibrium, calculate allele frequencies, and use statistics. This allows the students to look at population genetics in a very positive light and provides concrete examples of some often misunderstood principles.

Alleles↗
PubMed1998

Longevity and gray hair, baldness, facial wrinkles, and arcus senilis in 13,000 men and women: the Copenhagen City Heart Study.

BACKGROUND: We have previously reported that men who look older than their contemporaries have a significantly higher risk for myocardial infarction. The purpose of this study was to investigate whether persons with pronounced aging signs such as graying of hair, baldness, or facial wrinkles are prone to a shorter life span compared to their contemporaries. METHODS: In the Copenhagen City Heart Study comprising a random sample of 20,000 men and women, we also recorded, in addition to cardiovascular risk factors, data on signs of aging: extent of gray hair, baldness, facial wrinkles, and arcus senilis (corneal arcus). During 16 years of follow-up, 3,939 persons (1,656 women and 2,283 men) had died. The Cox regression model for proportional hazards, which included age as an explanatory variable, was used for descriptive analysis of the correlation between these aging signs and all-cause mortality. RESULTS: We found no correlation between the mortality and the extent of graying of the hair, or baldness or facial wrinkles in either of the sexes, irrespective of age. A single exception was observed in a small subgroup of men with no gray hair. They had a slightly, but significantly, lower mortality than the rest [relative risk (RR) = .81, 95% confidence interval (CI) .67-.98; p < .05]. The presence of arcus senilis was significantly correlated with a shorter life span in women (RR = 1.25, 95% CI 1.08-1.46; p < .01). For men the same tendency was found, but the correlation was not statistically significant. CONCLUSION: We conclude that the degrees of graying of the hair, baldness, and facial wrinkles are not predictive of a shorter life span in men and women in the Copenhagen City Heart Study.

Adult↗
PubMed2001

Functional variation of MC1R alleles from red-haired individuals.

Red hair in humans is associated with variant alleles of the alphaMSH receptor gene, MC1R. Loss of MC1R function in other mammals results in red or yellow hair pigmentation. We show that a mouse bacterial artificial chromosome (BAC) which contains Mc1r will efficiently rescue loss of Mc1r in transgenic mice, and that overexpression of the receptor suppresses the effect of the endogenous antagonist, agouti protein. We engineered the BAC to replace the mouse coding region with the human MC1R sequence and used this in the transgenic assay. The human receptor also efficiently rescued Mc1r deficiency, and in addition, appeared to be completely resistant to the effects of agouti, suggesting agouti protein may not play a role in human pigmentary variation. Three human variant alleles account for 60% of all cases of red hair. We engineered each of these in turn into the BAC and find that they have reduced, but not completely absent, function in transgenic mice. Comparison of the phenotypes of alphaMSH-deficient mice and humans in conjunction with this data suggests that red hair may not be the null phenotype of MC1R.

Alleles↗