Exome sequencing of early-onset patients supports genetic heterogeneity in colorectal cancer.

Colorectal cancer (CRC) is a complex disease that can be caused by a spectrum of genetic variants ranging from low to high penetrance changes, that interact with the environment to determine which individuals will develop the disease. In this study, we sequenced 20 early-onset CRC patients to discover novel genetic variants that could be linked to the prompt disease development. Eight genes, CHAD, CHD1L, ERCC6, IGTB7, PTPN13, SPATA20, TDG and TGS1, were selected and re-sequenced in a further 304 early onset CRC patients to search for rare, high-impact variants. Although we found a recurring truncating variant in the TDG gene shared by two independent patients, the results obtained did not help consolidate any of the candidates as promising CRC predisposing genes. However, we found that potential risk alleles in our extended list of candidate variants have a tendency to appear at higher numbers in younger cases. This supports the idea that CRC onset may be oligogenic in nature and may show molecular heterogeneity. Further, larger and robust studies are thus needed to unravel the genetics behind early-onset CRC development, coupled with novel functional analyses and omic approaches that may offer complementary insight.

Candidate predisposing germline copy number variants in early onset colorectal cancer patients

Purpose. A great proportion of the heritability of colorectal cancer (CRC) still remains unexplained, and rare variants, as well as copy number changes, have been proposed as potential candidates to explain the so-called ‘missing heritability’. We aimed to identify rare high-to-moderately penetrant copy number variants (CNVs) in patients suspected of having hereditary CRC due to an early onset. Methods/patients. We have selected for genome-wide copy number analysis, 27 MMR-proficient early onset CRC patients (<50 years) without identifiable germline mutations in Mendelian genes related to this phenotype. Rare CNVs were selected by removing all CNVs detected at MAF >1% in the in-house control CNV database (n = 629 healthy controls). Copy number assignment was checked by duplex real-time quantitative PCR or multiplex ligation probe amplification. Somatic mutation analysis in candidate genes included: loss of heterozygosity studies, point mutation screening, and methylation status of the promoter. Results. We have identified two rare germline deletions involving the AK3 and SLIT2 genes in two patients. The search for a second somatic mutational event in the corresponding CRC tumors showed loss of heterozygosity in AK3, and promoter hypermethylation in SLIT2. Both genes have been previously related to colorectal carcinogenesis. Conclusions. These findings suggest that AK3 and SLIT2 may be potential candidates involved in genetic susceptibility to CRC (AU)

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Candidate predisposing germline copy number variants in early onset colorectal cancer patients.

PURPOSE: A great proportion of the heritability of colorectal cancer (CRC) still remains unexplained, and rare variants, as well as copy number changes, have been proposed as potential candidates to explain the so-called 'missing heritability'. We aimed to identify rare high-to-moderately penetrant copy number variants (CNVs) in patients suspected of having hereditary CRC due to an early onset. METHODS/PATIENTS: We have selected for genome-wide copy number analysis, 27 MMR-proficient early onset CRC patients (<50 years) without identifiable germline mutations in Mendelian genes related to this phenotype. Rare CNVs were selected by removing all CNVs detected at MAF >1% in the in-house control CNV database (n = 629 healthy controls). Copy number assignment was checked by duplex real-time quantitative PCR or multiplex ligation probe amplification. Somatic mutation analysis in candidate genes included: loss of heterozygosity studies, point mutation screening, and methylation status of the promoter. RESULTS: We have identified two rare germline deletions involving the AK3 and SLIT2 genes in two patients. The search for a second somatic mutational event in the corresponding CRC tumors showed loss of heterozygosity in AK3, and promoter hypermethylation in SLIT2. Both genes have been previously related to colorectal carcinogenesis. CONCLUSIONS: These findings suggest that AK3 and SLIT2 may be potential candidates involved in genetic susceptibility to CRC.

Childhood psychopathology in children of women with eating disorders.

OBJECTIVE: We aimed to investigate the effect of maternal eating disorders (ED) on childhood psychopathology, early delays in cognitive, motor and language development, mother and child relationship, and child temperament in a community-based cohort: the Danish National Birth Cohort (DNBC). METHOD: Data were obtained prospectively on 48 403 children at 18 months and 46 156 children at 7 years. Data on cognitive, motor and language development, temperament and attachment were obtained at 18 months; data on child psychopathology were obtained at 7 years of age, using the Strengths and Difficulties Questionnaire (SDQ). Children of mothers with lifetime diagnosis of anorexia nervosa (AN, n = 931), lifetime diagnosis of bulimia nervosa (BN, n = 906) and both (AN & BN = 360) were compared to children of mothers without an ED (n = 46 206). RESULTS: Girls of women with lifetime AN had higher odds of having emotional problems, and girls of women with lifetime BN of having conduct problems compared with children of healthy women. Boys of women with lifetime AN had higher odds of total, emotional and conduct problems; boys of women with lifetime BN had higher odds of total, conduct, hyperactivity and peer difficulties compared to children of women without an ED. Boys of women with lifetime AN and BN had higher odds of total, emotional and peer problems compared to children of healthy women. CONCLUSION: Maternal ED is associated with childhood psychopathology in both boys and girls. Boys seemed at higher risk for psychopathology in this sample. Associations between emotional disorders across genders in children of mothers with lifetime AN, and hyperactivity and peer difficulties in boys of mothers with lifetime BN confirm and extend previous findings and point to possible shared risk between ED and other psychopathology.

Combined c-fos and 14C-2-deoxyglucose method to differentiate site-specific excitation from disinhibition: analysis of maternal behavior in the rat.

On the basis of evidence that 14C-2-deoxyglucose (2-DG) autoradiography indicates activity at axonal terminals, whereas c-fos immunocytochemistry indicates activity of neuronal cell bodies, we combined these techniques in adjacent histological brain sections to assess excitatory and disinhibitory synaptic relations in selected sites in female rats in which maternal behavior was elicited by natural parturition, sensitization (7- to 10-day cohabitation with foster pups), or hysterectomy. All individuals in these three groups expressed maternal behavior immediately before 2-DG injection. Controls were non-maternal virgins. Parturient and Hysterectomized groups: elevation (compared with controls) in both 2-DG and c-fos activity in medial preoptic area (MPOA) indicated an increase in its input and output activity, i.e., an excitatory interaction; the MPOA was previously shown to be critical for maternal behavior. Sensitized group: a decrease in 2-DG activity of vomeronasal nuclei (bed nucleus of the accessory olfactory tract, BAOT, and medial amygdala, ME, replicating our previous study) and an elevation in c-fos activity, jointly indicate disinhibition of these nuclei, that were previously shown to modulate pup-chemostimulation-induced sensitization. All other sites showed evidence of excitatory input-output relationships (i.e., joint increase in both 2-DG and c-fos activity), e.g., bed nucleus of the stria terminalis (BNST), lateral habenula (LHAB), central gray (CG), thalamus (THAL), septum (SEPT), and ventral tegmental area (VTA). The present study demonstrates the feasibility of measuring 2-DG and c-fos activity jointly in adjacent sections of the same brain, thereby providing evidence to distinguish between localized excitation and disinhibition.

Surgical combination therapy for vitiligo and piebaldism.

BACKGROUND: Refractory and stable defects of vitiligo and piebaldism may be unresponsive to medical therapy. Melanocyte transplantation can restore the normal pigmentation in some selected patients. OBJECTIVES: To evaluate the efficacy of additional mini-grafting with 1.0-1.2-mm punch grafts to complete the restoration of achromic defects when performing surgical correction of leukoderma. METHODS: Eight patients with refractory stable leukoderma were treated with melanocyte transplantation; three with segmental vitiligo had epidermal shave, by removing the hyperpigmented macules at the periphery of achromic lesions; two others received suction epidermal grafts; and three subjects were treated by in vitro cultured epidermal autografts. All patients received additional mini-grafts in areas of residual achromia. RESULTS: The depigmented defects were 100% restored in seven patients, and in one subject 80% improvement was observed. CONCLUSION: Surgical methods, followed by additional mini-grafting, may be helpful to restore completely the depigmented defects when residual achromia, after treatment with the methods described above, is still present.

An epidemiologic case-control study in a population with vitiligo.

BACKGROUND: Previous epidemiologic studies of vitiligo have not included a sex- and age-matched population. OBJECTIVE: Our purpose was to attempt to determine possible risk factors and clinical differences associated with unilateral and bilateral vitiligo. METHODS: Two hundred thirty-four patients and 234 normal control subjects were examined and questioned. RESULTS: Patients with unilateral vitiligo were younger and had an earlier age at onset. Koebner's phenomenon and halo nevus were infrequent in the total vitiligo group, but no difference between vitiligo types was observed. Subjects with bilateral vitiligo more frequently had light skin (types I, II, and III) and more commonly had an associated autoimmune disease. CONCLUSION: Unilateral and bilateral vitiligo differ substantially in several clinical aspects, which suggests a different pathogenic mechanism for each condition.

The minigrafting test for vitiligo: detection of stable lesions for melanocyte transplantation.

BACKGROUND: Selected patients with stable and refractory vitiligo may consider melanocyte transplantation as a therapeutic alternative. A method to anticipate the response to surgical repair is not available. OBJECTIVE: We evaluated the pigment spread of minigrafts when implanted within achromic lesions of stable vitiligo as a test to identify good candidates for surgical repigmentation. METHODS: Four to six minigrafts of 1.0 to 1.2 mm were implanted within lesions of patients with unilateral (localized) and bilateral (generalized) vitiligo. Pigment spread was assessed 3 months later. RESULTS: Forty-seven subjects were examined. In unilateral vitiligo 19 of 20 patients (95%) had a positive test result in comparison with only 13 of 27 patients (48%) with bilateral vitiligo (p = 0.002). CONCLUSION: The minigrafting test is a reliable tool to identify patients with stable vitiligo who may respond to melanocyte transplantation. Unilateral (localized) vitiligo is the best indication for surgical repigmentation.

On the pathogenesis of idiopathic guttate hypomelanosis.

Idiopathic guttate hypomelanosis is a common leukodermic dermatosis of obscure origin, consisting of small 2- to 5-mm achromic or hypopigmented macules, mainly affecting the exposed upper and lower extremities. In a group of 400 consecutive dermatologic patients, idiopathic guttate hypomelanosis was much more prevalent in women than in men. However, in both sexes this prevalence became more common with advancing age. In another group of fifteen patients with idiopathic guttate hypomelanosis and fifteen normal controls matched by age, sex, and skin type, the following was found: A cause-effect relationship between chronic actinic exposure and the development of idiopathic guttate hypomelanosis could not be established by statistical studies. A family aggregation survey disclosed a higher prevalence of idiopathic guttate hypomelanosis in the family of patients with idiopathic guttate hypomelanosis than in the control group. Epithelial atrophy, patchy absence of melanocytes and melanin, flattening of the rete pegs, and basket weave hyperkeratosis were the most prominent histologic findings of idiopathic guttate hypomelanosis. Minigrafts of normal skin implanted in idiopathic guttate hypomelanosis lesions did not modify the achromic defects, whereas intralesional triamcinolone with or without grafts improved the appearance of these lesions.

Inhalant users in drug abuse prevention programs.

Inhalant use and related background characteristics are examined for participants in state-funded drug abuse prevention programs in Texas. Inhalant use was found to be a significant problem among Mexican-American youth in low socioeconomic neighborhoods. Frequent users of inhalers were consistently distinguished from nonusers and less frequent inhalers on a number of dimensions and were found to have significantly more family, school, legal, and peer-related problems. Areas for future research and intervention are discussed.