Disruption of mouse Slx4, a regulator of structure-specific nucleases, phenocopies Fanconi anemia

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Error blindness and motivational significance: Shifts in networks centering on anterior insula co-vary with error awareness and pupil dilation

This investigation aims to further our understanding of the brain mechanisms underlying the awareness of one's erroneous actions. While all errors are registered as such in the rostral cingulate zone, errors enter awareness only when the anterior insula cortex is activated. Aware but not unaware errors elicit autonomic nervous system reactivity. Our aim is to investigate the hypothesis that activation in the insula during error awareness is related to autonomic arousal and to inter-regional interactions with other areas of the brain. To examine the role of the anterior insula in error awareness, we assessed its functional connectivity to other brain regions along with autonomic nervous system reactivity in young healthy participants who underwent simultaneous pupil-diameter and functional magnetic resonance imaging measurements while performing a complex and error-prone task. Error blindness was associated with failures to engage sufficient autonomic reactivity. During aware errors increased pupil-diameter along with increased task-related activation within, and increased connectivity between anterior insula and task-related networks suggested an increased capacity for action-control information transfer. Increased pupil-diameter during aware errors was furthermore associated with decreased activation of the default-mode network along with decreased insular connectivity with regions of the default mode system, possibly reflecting decreased task-irrelevant information processing. This shifting mechanism may be relevant to a better understanding of how the brain and the autonomic nervous system interact to enable efficient adaptive behavior during cognitive challenge

Upper cervical cord atrophy is independent of cervical cord lesion volume in early multiple sclerosis: A two-year longitudinal study

Background: Upper cervical cord atrophy and lesions have been shown to be associated with disease and disability progression already in early relapsing-remitting multiple sclerosis (RRMS). However, their longitudinal relationship remains unclear. Objective: To investigate the cross-sectional and longitudinal relation between focal T2 cervical cord lesion volume (CCLV) and regional and global mean upper cervical cord area (UCCA), and their relations with disability. Methods: Over a two-year interval, subjects with RRMS (n = 36) and healthy controls (HC, n = 16) underwent annual clinical and MRI examinations. UCCA and CCLV were obtained from C1 through C4 level. Linear mixed model analysis was performed to investigate the relation between UCCA, CCLV, and disability over time. Results: UCCA at baseline was significantly lower in RRMS subjects compared to HCs (p = 0.003), but did not decrease faster over time (p ≥ 0.144). UCCA and CCLV were independent of each other at any of the time points or cervical levels, and over time. Lower baseline UCCA, but not CCLV, was related to worsening of both upper and lower extremities function over time. Conclusion: UCCA and CCLV are independent from each other, both cross-sectionally and longitudinally, in early MS. Lower UCCA, but not CCLV, was related to increasing disability over time

Benign mesenteric lymphangioma presenting as acute pancreatitis: a case report

Benign mesenteric lymphangiomas are rare intra-abdominal cysts which may be asymptomatic or present with a variety of abdominal symptoms including an acute abdomen. We are however not aware of any reports in the literature linking mesenteric lymphangioma to acute pancreatitis. We present the case of a 62-year-old man who was admitted with signs and symptoms of acute pancreatitis and a palpable abdominal mass. Computerised tomography (CT) of his abdomen confirmed the presence of a mesenteric cystic mass. He underwent a laparotomy at which a large thin walled mass filled with a chylous fluid was resected. Histological analysis of this cyst showed it to be a benign mesenteric lymphangioma

Risk factors for comorbid oppositional defiant disorder in attention-deficit/hyperactivity disorder

Oppositional defiant disorder (ODD) is highly prevalent in attention-deficit/hyperactivity disorder (ADHD). Individuals with both ADHD and ODD (ADHD + ODD) show a considerably worse prognosis compared with individuals with either ADHD or ODD. Therefore, identification of risk factors for ADHD + ODD is essential and may contribute to the development of (early) preventive interventions. Participants were matched for age, gender, and ADHD-subtype (diagnostic groups), and did not differ in IQ. Predictors included pre- and perinatal risk factors (pregnancy duration, birth weight, maternal smoking during pregnancy), transgenerational factors (parental ADHD; parental warmth and criticism in diagnostic groups), and postnatal risk factors (parental socioeconomic status [SES], adverse life events, deviant peer affiliation). Three models were assessed, investigating risk factors for ADHD-only versus controls (N = 86), ADHD + ODD versus controls (N = 86), and ADHD + ODD versus ADHD-only (N = 90). Adverse life events and parental ADHD were risk factors for both ADHD + ODD and ADHD-only, and more adverse life events were an even stronger risk factor for comorbid ODD compared with ADHD-only. For ADHD + ODD, but not ADHD-only, parental criticism, deviant peer affiliation, and parental SES acted as risk factors. Maternal smoking during pregnancy acted as minor risk factor for ADHD-only, while higher birth weight acted as minor risk factor for ADHD + ODD. No effects of age were present. Findings emphasise the importance of these factors in the development of comorbid ODD. The identified risk factors may prove to be essential in preventive interventions for comorbid ODD in ADHD, highlighting the need for parent-focused interventions to take these factors into account

Clinical heterogeneity within xeroderma pigmentosum associated with mutations in the DNA repair and transcription gene ERCC3

The human DNA excision repair gene ERCC3 specifically corrects the nucleotide excision repair (NER) defect of xeroderma pigmentosum (XP) complementation group B. In addition to its function in NER, the ERCC3 DNA helicase was recently identified as one of the components of the human BTF2/TFIIH transcription factor complex, which is required for initiation of transcription of class II genes. To date, a single patient (XP11BE) has been assigned to this XP group B (XP-B), with the remarkable conjunction of two autosomal recessive DNA repair deficiency disorders: XP and Cockayne syndrome (CS). The intriguing involvement of the ERCC3 protein in the vital process of transcription may provide an explanation for the rarity, severity, and wide spectrum of clinical features in this complementation group. Here we report the identification of two new XP-B patients: XPCS1BA and XPCS2BA (siblings), by microneedle injection of the cloned ERCC3 repair gene as well as by cell hybridization. Molecular analysis of the ERCC3 gene in both patients revealed a single base substitution causing a missense mutation in a region that is completely conserved in yeast, Drosophila, mouse, and human ERCC3. As in patient XP11BE, the expression of only one allele (paternal) is detected. The mutation causes a virtually complete inactivation of the NER function of the protein. Despite this severe NER defect, both patients display a late onset of neurologic impairment, mild cutaneous symptoms, and a striking absence of skin tumors even at an age of &gt;40 years. Analysis of the frequency of hprt- mutant T-lymphocytes in blood samples suggests a relatively low in vivo mutation frequency in these patients. Factors in addition to NER deficiency may be required for the development of cutaneous tumors.</p

A new nucleotide-excision-repair gene associated with the disorder trichothiodystrophy

The sun-sensitive, cancer-prone genetic disorder xeroderma pigmentosum (XP) is associated in most cases with a defect in the ability to carry out excision repair of UV damage. Seven genetically distinct complementation groups (i.e., A-G) have been identified. A large proportion of patients with the unrelated disorder trichothiodystrophy (TTD), which is characterized by hair-shaft abnormalities, as well as by physical and mental retardation, are also deficient in excision repair of UV damage. In most of these cases the repair deficiency is in the same complementation group as is XP group D. We report here on cells from a patient, TTD1BR, in which the repair defect complements all known XP groups (including XP-D). Furthermore, microinjection of various cloned human repair genes fails to correct the repair defect in this cell strain. The defect in TTD1BR cells is therefore in a new gene involved in excision repair in human cells. The finding of a second DNA repair gene that is associated with the clinical features of TTD argues strongly for an involvement of repair proteins in hair-shaft development.</p

A new nucleotide-excision-repair gene associated with the disorder trichothiodystrophy

The sun-sensitive, cancer-prone genetic disorder xeroderma pigmentosum (XP) is associated in most cases with a defect in the ability to carry out excision repair of UV damage. Seven genetically distinct complementation groups (i.e., A-G) have been identified. A large proportion of patients with the unrelated disorder trichothiodystrophy (TTD), which is characterized by hair-shaft abnormalities, as well as by physical and mental retardation, are also deficient in excision repair of UV damage. In most of these cases the repair deficiency is in the same complementation group as is XP group D. We report here on cells from a patient, TTD1BR, in which the repair defect complements all known XP groups (including XP-D). Furthermore, microinjection of various cloned human repair genes fails to correct the repair defect in this cell strain. The defect in TTD1BR cells is therefore in a new gene involved in excision repair in human cells. The finding of a second DNA repair gene that is associated with the clinical features of TTD argues strongly for an involvement of repair proteins in hair-shaft development.</p

A new nucleotide-excision-repair gene associated with the disorder trichothiodystrophy

The sun-sensitive, cancer-prone genetic disorder xeroderma pigmentosum (XP) is associated in most cases with a defect in the ability to carry out excision repair of UV damage. Seven genetically distinct complementation groups (i.e., A-G) have been identified. A large proportion of patients with the unrelated disorder trichothiodystrophy (TTD), which is characterized by hair-shaft abnormalities, as well as by physical and mental retardation, are also deficient in excision repair of UV damage. In most of these cases the repair deficiency is in the same complementation group as is XP group D. We report here on cells from a patient, TTD1BR, in which the repair defect complements all known XP groups (including XP-D). Furthermore, microinjection of various cloned human repair genes fails to correct the repair defect in this cell strain. The defect in TTD1BR cells is therefore in a new gene involved in excision repair in human cells. The finding of a second DNA repair gene that is associated with the clinical features of TTD argues strongly for an involvement of repair proteins in hair-shaft development.</p