Symptom Phenotype Research Articles

Endometriosis in patients with irritable bowel syndrome: Specific symptomatic and demographic profile, and response to the low FODMAP diet

Women with endometriosis are frequently misdiagnosed with irritable bowel syndrome (IBS) for some time before a correct diagnosis is made. Visceral hypersensitivity is a key feature in both conditions. To determine if there are distinct symptom patterns in women with IBS and endometriosis, and to determine the response of these women to a low FODMAP diet in comparison to those with IBS alone. A retrospective analysis of prospectively collected data from women attending a specialist IBS service in Christchurch New Zealand. Data from those who met Rome III criteria for IBS were sorted into two groups: concurrent endometriosis and those with IBS alone. Demographics and symptom patterns were identified from a prospective questionnaire. A low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) diet was taught to all women as the primary therapeutic intervention. Responses to the diet were noted against their ultimate disposition. Of the 160 women who met Rome III criteria for IBS, 36% had concurrent endometriosis. The presence of dyspareunia (P>0.0001), referred pain (P=0.005), bowel symptoms exacerbated by menstruation (P=0.0004) and a family history of endometriosis (P=0.0003) were associated with concurrent endometriosis. Seventy two percent of these women reported a >50% improvement in bowel symptoms after four weeks of a low FODMAP diet compared with 49% in those with no known endometriosis (P=0.001, odds ratio 3.11, 95% CI, 1.5-6.2). Women with concurrent endometriosis and IBS report a unique symptom phenotype. The low FODMAP diet appears effective in women with gut symptoms and endometriosis.

Symptom heterogeneity in Huntington's disease correlates with neuronal degeneration in the cerebral cortex

BackgroundHuntington's disease (HD) is characterised by variable symptoms and neuropathology of the basal ganglia and cortex. Previously, we have shown that the pattern of pyramidal cell loss in 8 different cortical regions correlates with the phenotypic variability in HD. In the primary motor and anterior cingulate cortices, the pattern of interneuron degeneration correlates with pyramidal cell death and variable HD symptom profiles. ObjectivesThis study aimed to examine the pattern of interneuron degeneration in 3 further regions of the HD cortex (primary sensory, superior frontal, superior parietal cortices) to determine whether HD neuropathogenesis was characterised by a general fundamental pattern of cortical interneuron loss, and explore the relationship between cortical interneuron loss with previously determined pyramidal cell loss and clinical heterogeneity. MethodsStereological counting was used to quantify 3 sub-populations of calcium-binding protein containing interneurons in 3 cortical human brain regions of 14 HD and 13 control cases as used in our previous studies (Nana et al., 2014; Kim et al., 2014). The HD cases were grouped according to their predominant symptom profile (“motor”, “mood”, “mixed”). ResultsThe present results demonstrated a heterogeneous loss of interneurons across the 3 cortical regions which, when compared with our previous studies, mirrored the pattern of pyramidal cell loss in the same cortical areas. Most interestingly, the pattern of neuronal loss in these regions correlated with the variable HD symptom profiles. ConclusionThe overall findings in our present and previous cortical studies establish a clear correlative pattern of variable cortical neuronal degeneration in HD pathogenesis, which mirrors the heterogeneity of HD symptom phenotypes.

Precision assessment of heterogeneity of lymphedema phenotype, genotypes and risk prediction

Lymphedema following breast cancer surgery is considered to be mainly due to the mechanical injury from surgery. Recent research identified that inflammation-infection and obesity may be the important predictors for lymphedema. The purpose of this exploratory research was to prospectively examine phenotype of arm lymphedema defined by limb volume and lymphedema symptoms in relation to inflammatory genes in women treated for breast cancer. A prospective, descriptive and repeated-measure design using candidate gene association method was used to enroll 140 women at pre-surgery and followed at 4–8 weeks and 12 months post-surgery. Arm lymphedema was determined by a perometer measurement of ≥5% limb volume increase from baseline of pre-surgery. Lymphedema symptom phenotype was evaluated using a reliable and valid instrument. Saliva samples were collected for DNA extraction. Genes known for inflammation were evaluated, including lymphatic specific growth factors (VEGF-C & VEGF-D), cytokines (IL1-a, IL-4, IL6, IL8, IL10, & IL13), and tumor necrosis factor-a (TNF-a). No significant associations were found between arm lymphedema phenotype and any inflammatory genetic variations. IL1-a rs17561 was marginally associated with symptom count phenotype of ≥8 symptoms. IL-4 rs2070874 was significantly associated with phenotype of impaired limb mobility and fluid accumulation. Phenotype of fluid accumulation was significantly associated with IL6 rs1800795, IL4 rs2243250 and IL4 rs2070874. Phenotype of discomfort was significantly associated with VEGF-C rs3775203 and IL13 rs1800925. Precision assessment of heterogeneity of lymphedema phenotype and understanding the biological mechanism of each phenotype through the exploration of inherited genetic susceptibility is essential for finding a cure. Further exploration of investigative intervention in the context of genotype and gene expressions would advance our understanding of heterogeneity of lymphedema phenotype.

National Institutes of Health Symptom Science Model sheds light on patient symptoms

Since the establishment of the nursing profession, identifying and alleviating the subjective symptoms experienced by patients has been at the core of nursing practice. In supporting the scientific foundation for clinical practice, nursing science has maintained a consistent commitment to prevent, manage, and eliminate symptoms. Scientists from the intramural research program at the National Institute of Nursing Research (NINR), a component of the National Institutes of Health, developed a National Institutes of Health Symptom Science Model (NIH-SSM) to guide symptom science research programs engaged in the use of emerging “omic” methods such as the genotyping of symptom phenotypes. The NIH-SSM was developed based on the NINR intramural research program's success in designing and implementing methods for examining identified symptoms or symptom clusters. The NIH-SSM identifies the research process of characterizing symptom phenotypes, identifying and testing biomarkers, and ultimately developing clinical interventions in cancer-related fatigue, gastrointestinal disorders, and traumatic brain injuries. The purpose of this article was to demonstrate how scientists can apply the NIH-SSM, leading the broader scientific community in advancing personalized and precise clinical interventions.

Diagnostic criteria and predictive tools for asthma in preschool-aged children

Preschool-aged children are more likely to be diagnosed with asthma compared with elder children or adolescents.Diagnosis might be a great challenge for clinical physicians due to its specialties in symptom patterns, phenotype classifications and difficulties to apply measurements.For decades researches based on the diagnosis and prediction of asthma in preschool-aged children have never been stopped, meanwhile efforts should be made on the development of the diagnostic criteria for Chinese preschool-aged children.This article places spotlight on the development of diagnosis and prediction of asthma in early childhood throughout the world, thus provide references for the establishment of the diagnostic criteria for Chinese preschool-aged children. Key words: Preschool-aged children; Asthma; Diagnostic criteria; Predictive tool

The symptom phenotype of oncology outpatients remains relatively stable from prior to through 1week following chemotherapy.

Some oncology outpatients experience a higher number of and more severe symptoms during chemotherapy (CTX). However, little is known about whether this high risk phenotype persists over time. Latent transition analysis (LTA) was used to examine the probability that patients remained in the same symptom class when assessed prior to the administration of and following their next dose of CTX. For the patients whose class membership remained consistent, differences in demographic and clinical characteristics, and quality of life (QOL) were evaluated. The Memorial Symptom Assessment Scale (MSAS) was used to evaluate symptom burden. LTA was used to identify subgroups of patients with distinct symptom experiences based on the occurrence of the MSAS symptoms. Of the 906 patients evaluated, 83.9% were classified in the same symptom occurrence class at both assessments. Of these 760 patients, 25.0% were classified as Low-Low, 44.1% as Moderate-Moderate and 30.9% as High-High. Compared to the Low-Low class, the other two classes were younger, more likely to be women and to report child care responsibilities, and had a lower functional status and a higher comorbidity scores. The two higher classes reported lower QOL scores. The use of LTA could assist clinicians to identify higher risk patients and initiate more aggressive interventions.

Milk allergy is a minor cause of milk avoidance due to perceived hypersensitivity among schoolchildren in Northern Sweden.

We investigated phenotypes of milk hypersensitivity among schoolchildren aged 11-12 in Northern Sweden. In a population-based cohort, 1824 (98%) children aged 11-12 participated in a questionnaire survey, skin prick testing, interviews on food hypersensitivity and assessment of body mass index (BMI). Of the 265 children reporting milk hypersensitivity, milk avoidance and no coeliac disease, 236 (89%) participated in a structured interview and blood samples for analyses of milk-specific Immunoglobulin E. The children were then categorised into milk hypersensitivity phenotypes according to preset criteria. In all, 14.5% reported milk hypersensitivity. Of these, 3% were categorised as current milk allergy, 23% as outgrown milk allergy, 40% as probable lactose intolerance and 11% as nondefinable. Furthermore, 23% had discontinued their elimination diet. Milk allergy was associated with other atopic disorders and lower BMI, with an odds ratio of 0.82 and 95% confidence interval of 0.80-0.98. Only 2% had previously undergone an oral challenge. The most common symptom phenotypes among Swedish children aged 11-12 with self-reported milk hypersensitivity and milk avoidance were probable intolerance and outgrown milk allergy, while current milk allergy was uncommon. Children with milk allergy had a lower BMI and most lacked a challenge-proven diagnosis.

Diagnosis of a new variant of soybean yellow mottle mosaic virus with extended host-range in India.

Soybean yellow mottle mosaic virus (SYMMV, genus Carmovirus) was previously known to occur in South Korea and USA causing bright yellow mosaic in soybean. In this study, SYMMV (Car-Mb14 isolate) was isolated from mungbean (Vigna radiata) exhibiting mild mottling and puckering symptoms in the experimental field at Indian Agricultural Research Institute, New Delhi during 2012. The virus isolate, Car-Mb14 induced veinal mottling, mild mottling, chlorotic blotching, local and systemic necrosis in soybean, mungbean, blackgram, French bean and guar bean, respectively. The symptomatology of the present isolate of SYMMV was different from the previously reported South Korean isolate, as the later did not induce symptoms in any of the above legumes other than soybean. The present isolate was phylogenetically distinct and shared 90-93% sequence identity in coat protein (CP) of 52 SYMMV isolates reported from Korea and USA. In order to know the serological relationships, the CP gene of the present isolate was over expressed as a 39kDa protein in E. coli and an antiserum of 1:16,000titer against the recombinant CP was produced. Serological cross reactivity analysis revealed that SYMMV was serologically related to blackgram mottle virus but not to cowpea mottle virus, the other legume infecting carmoviruses. The antiserum was used to detect prevalence of SYMMV in legume crops by ELISA. Out of 145 field samples of legumes (mungbean, blackgram, French bean and soybean) collected from different places in India, SYMMV was detected only in 16 samples of mungbean and one sample of blackgram. The natural infection of SYMMV in mungbean and blackgram was further confirmed based on CP gene sequence. This study provides evidence of occurrence of a new variant of SYMMV with distinct symptom phenotype and extended host-range in India.

Pathological gamma oscillations, impaired dopamine release, synapse loss and reduced dynamic range of unitary glutamatergic synaptic transmission in the striatum of hypokinetic Q175 Huntington mice

Huntington’s disease (HD) is a severe genetically inherited neurodegenerative disorder. Patients present with three principal phenotypes of motor symptoms: choreatic, hypokinetic-rigid and mixed. The Q175 mouse model of disease offers an opportunity to investigate the cellular basis of the hypokinetic-rigid form of HD. At the age of 1year homozygote Q175 mice exhibited the following signs of hypokinesia: Reduced frequency of spontaneous movements on a precision balance at daytime (−55%), increased total time spent without movement in an open field (+42%), failures in the execution of unconditioned avoidance reactions (+32%), reduced ability for conditioned avoidance (−96%) and increased reaction times (+65%) in a shuttle box. Local field potential recordings revealed low-frequency gamma oscillations in the striatum as a characteristic feature of HD mice at rest. There was no significant loss of DARPP-32 immunolabeled striatal projection neurons (SPNs) although the level of DARPP-32 immunoreactivity was lower in HD. As a potential cause of hypokinesia, HD mice revealed a strong reduction in striatal KCl-induced dopamine release, accompanied by a decrease in the number of tyrosine hydroxylase-(TH)- and VMAT2-positive synaptic varicosities. The presynaptic TH fluorescence level was also reduced. Patch-clamp experiments were performed in slices from 1-year-old mice to record unitary EPSCs (uEPSCs) of presumed cortical origin in the absence of G-protein-mediated modulation. In HD mice, the maximal amplitudes of uEPSCs amounted to 69% of the WT level which matches the loss of VGluT1+/SYP+ synaptic terminals in immunostained sections. These results identify impairment of cortico-striatal synaptic transmission and dopamine release as a potential basis of hypokinesia in HD.

Erratum to: A severe symptom phenotype in pepper cultivars carrying the Tsw resistance gene is caused by a mixed infection between resistance-breaking and non-resistance-breaking isolates of Tomato spotted wilt virus

Erratum to: A severe symptom phenotype in pepper cultivars carrying the Tsw resistance gene is caused by a mixed infection between resistance-breaking and non-resistance-breaking isolates of Tomato spotted wilt virus

A severe symptom phenotype in pepper cultivars carrying the Tsw resistance gene is caused by a mixed infection between resistance-breaking and non-resistance-breaking isolates of Tomato spotted wilt virus

Pepper (Capsicum annuum) plants with the Tsw resistance gene showing unusually severe symptoms consisting of local lesions, chlorosis, stunting and systemic necrosis on the apical leaves were found in a commercial field in north eastern Spain in 2009. The presence of Tomato spotted wilt virus (TSWV) was confirmed in all diseased plants. After mechanical inoculation of Nicotiana glutinosa with infected field samples, biological clones of the virus were isolated from individual local lesions. These biological clones produced two different types of symptoms after inoculation on Tsw resistant pepper plants: (i) typical symptoms caused by resistance-breaking (RB) isolates characterized by chlorosis and stunting, and (ii) severe symptoms as observed in the field plants. Similar symptoms in pepper plants carrying the Tsw resistance gene were reproduced under controlled conditions, after simultaneous inoculation of RB and non-resistance-breaking (NRB) isolates. The NRB isolate was detected in a low proportion in the apical uninoculated leaves, whereas NRB isolates could not infect resistant pepper when inoculated alone. Co-infection by NRB and RB isolates induced disease synergism with systemic necrosis on the apical leaves. To our knowledge, this is the first case in which a synergic interaction between isolates of the same virus has been described, which has the ability to overcome a natural genetic resistance. This finding could have epidemiological implications for the management of TSWV.

Autism phenotype versus registered diagnosis in Swedish children: prevalence trends over 10 years in general population samples

Objective To compare the annual prevalence of the autism symptom phenotype and of registered diagnoses for autism spectrum disorder during a 10 year period in children.Design Population based study.Setting Child...

Inherited and environmental influences on a childhood co-occurring symptom phenotype: Evidence from an adoption study

Risk factors for the childhood development of co-occurring internalizing and externalizing symptoms are not well understood, despite a high prevalence and poor clinical outcomes associated with this co-occurring phenotype. We examined inherited and environmental risk factors for co-occurring symptoms in a sample of children adopted at birth and their birth mothers and adoptive mothers (N = 293). Inherited risk factors (i.e., birth mothers' processing speed and internalizing symptoms) and environmental risk factors (i.e., adoptive mothers' processing speed, internalizing symptoms, and uninvolved parenting) were examined as predictors for the development of internalizing-only, externalizing-only, or co-occurring symptoms using structural equation modeling. Results suggested a unique pattern of predictive factors for the co-occurring phenotype, with risk conferred by adoptive mothers' uninvolved parenting, birth mothers' slower processing speed, and the birth mothers' slower processing speed in tandem with adoptive mothers' higher internalizing symptoms. Additional analyses indicated that when co-occurring-symptom children were incorporated into internalizing and externalizing symptom groups, differential risk factors for externalizing and internalizing symptoms emerged. The findings suggest that spurious results may be found when children with co-occurring symptoms are not examined as a unique phenotypic group.

A meta-analysis of immunogenetic Case-Control Association Studies in irritable bowel syndrome.

To date, genetic-association studies of single nucleotide polymorphisms (SNP) in selected candidate genes with the symptom phenotype of irritable bowel syndrome (IBS) have typically involved hundreds to 2000 patients. SNPs in immune-related genes, such as cytokine and cytokine receptor encoding genes, have been reported to associate with IBS risk. We conducted two independent case-control studies on 16 SNPs in IL1R1, IL4, IL6, IL8, IL10, IL23R, TNFA, and TNFSF15, one from the UK (194 patients and 92 healthy volunteers) and one from the USA (137 patients and 96 healthy volunteers). The main aim was to examine the relationship between inherited immunological diversity and IBS risk in a meta-analysis which included 12 additional, earlier studies. The meta-analysis comprised a total of 2894 patients (839 IBS-C, 1073 IBS-D, 502 IBS-M), and 3138 healthy volunteers with self-reported Caucasian ancestry. The association of SNP rs4263839 (TNFSF15) was investigated in four studies and confirmed in the meta-analysis: IBS (OR 1.19, 95% CI 1.08-1.31), and IBS-C (OR 1.24, 95% CI 1.08-1.42). No additional SNPs residing in immunogenes associated with IBS symptom phenotypes. Our meta-analysis could not confirm a major role of most investigated SNPs, but a moderate association between rs4263839 TNFSF15 and IBS, in particular IBS-C. The analysis emphasizes the importance of definition and phenotype homogeneity, adequate study size and representativeness of the patient and control collective.

Factors associated with severe human Rift Valley fever in Sangailu, Garissa County, Kenya.

BackgroundMosquito-borne Rift Valley fever virus (RVFV) causes acute, often severe, disease in livestock and humans. To determine the exposure factors and range of symptoms associated with human RVF, we performed a population-based cross-sectional survey in six villages across a 40 km transect in northeastern Kenya.Methodology/Principal Findings:A systematic survey of the total populations of six Northeastern Kenyan villages was performed. Among 1082 residents tested via anti-RVFV IgG ELISA, seroprevalence was 15% (CI95%, 13–17%). Prevalence did not vary significantly among villages. Subject age was a significant factor, with 31% (154/498) of adults seropositive vs. only 2% of children ≤15 years (12/583). Seroprevalence was higher among men (18%) than women (13%). Factors associated with seropositivity included a history of animal exposure, non-focal fever symptoms, symptoms related to meningoencephalitis, and eye symptoms. Using cluster analysis in RVFV positive participants, a more severe symptom phenotype was empirically defined as having somatic symptoms of acute fever plus eye symptoms, and possibly one or more meningoencephalitic or hemorrhagic symptoms. Associated with this more severe disease phenotype were older age, village, recent illness, and loss of a family member during the last outbreak. In multivariate analysis, sheltering livestock (aOR = 3.5 CI95% 0.93–13.61, P = 0.065), disposing of livestock abortus (aOR = 4.11, CI95% 0.63–26.79, P = 0.14), and village location (P = 0.009) were independently associated with the severe disease phenotype.Conclusions/SignificanceOur results demonstrate that a significant proportion of the population in northeastern Kenya has been infected with RVFV. Village and certain animal husbandry activities were associated with more severe disease. Older age, male gender, herder occupation, killing and butchering livestock, and poor visual acuity were useful markers for increased RVFV infection. Formal vision testing may therefore prove to be a helpful, low-technology tool for RVF screening during epidemics in high-risk rural settings.

Association of symptoms and severity of rift valley fever with genetic polymorphisms in human innate immune pathways.

BackgroundMultiple recent outbreaks of Rift Valley Fever (RVF) in Africa, Madagascar, and the Arabian Peninsula have resulted in significant morbidity, mortality, and financial loss due to related livestock epizootics. Presentation of human RVF varies from mild febrile illness to meningoencephalitis, hemorrhagic diathesis, and/or ophthalmitis with residual retinal scarring, but the determinants for severe disease are not understood. The aim of the present study was to identify human genes associated with RVF clinical disease in a high-risk population in Northeastern Province, Kenya.Methodology/Principal FindingsWe conducted a cross-sectional survey among residents (N = 1,080; 1–85 yrs) in 6 villages in the Sangailu Division of Ijara District. Participants completed questionnaires on past symptoms and exposures, physical exam, vision testing, and blood collection. Single nucleotide polymorphism (SNP) genotyping was performed on a subset of individuals who reported past clinical symptoms consistent with RVF and unrelated subjects. Four symptom clusters were defined: meningoencephalitis, hemorrhagic fever, eye disease, and RVF-not otherwise specified. SNPs in 46 viral sensing and response genes were investigated. Association was analyzed between SNP genotype, serology and RVF symptom clusters. The meningoencephalitis symptom phenotype cluster among seropositive patients was associated with polymorphisms in DDX58/RIG-I and TLR8. Having three or more RVF-related symptoms was significantly associated with polymorphisms in TICAM1/TRIF, MAVS, IFNAR1 and DDX58/RIG-I. SNPs significantly associated with eye disease included three different polymorphisms TLR8 and hemorrhagic fever symptoms associated with TLR3, TLR7, TLR8 and MyD88.Conclusions/SignificanceOf the 46 SNPs tested, TLR3, TLR7, TLR8, MyD88, TRIF, MAVS, and RIG-I were repeatedly associated with severe symptomatology, suggesting that these genes may have a robust association with RVFV-associated clinical outcomes. Studies of these and related genetic polymorphisms are warranted to advance understanding of RVF pathogenesis.

Heterologous replicase driven 3′ end repair of Cucumber mosaic virus satellite RNA

To investigate the extent of the 3′ end repair in a satellite RNA of Cucumber mosaic virus (CMV) strain Q (Qsat) by a heterologous Tomato aspermy virus (TAV), a set of biologically active agrotransformants corresponding to the three genomic RNAs of TAV was developed. Analysis of Nicotiana benthamiana plants agroinfiltrated with TAV and either wild type or each of the six 3′ deletion mutants of Qsat revealed that (i) heterologous replicase failed to generate Qsat multimers, a hallmark feature of homologous replicase dependent replication of Qsat; (ii) manifestation of severe symptom phenotypes and progeny analysis suggested that heterologous replicase was competent to repair Qsat deletion mutants lacking up to 3′13 nucleotides (nt) but not beyond and (iii) comparative in silico analysis indicated that the 3′ secondary structural features of the repaired Qsat progeny from heterologous vs homologous driven replicases are remarkably very similar. The significance of these observations is discussed.

Intermediate phenotypes and biomarkers of treatment outcome in major depressive disorder

Major depressive disorder (MDD) is a pleomorphic illness originating from gene x environment interactions. Patients with differing symptom phenotypes receive the same diagnosis and similar treatment recommendations without regard to genomics, brain structure or function, or other physiologic or psychosocial factors. Using this present approach, only one third of patients enter remission with the first medication prescribed, and patients may take longer than 1 year to enter remission with repeated trials. Research to improve treatment effectiveness recently has focused on identification of intermediate phenotypes (IPs) that could parse the heterogeneous population of patients with MDD into subgroups with more homogeneous responses to treatment. Such IPs could be used to develop biomarkers that could be applied clinically to match patients with the treatment that would be most likely to lead to remission. Putative biomarkers include genetic polymorphisms, RNA and protein expression (transcriptome and proteome), neurotransmitter levels (metabolome), additional measures of signaling cascades, oscillatory synchrony, neuronal circuits and neural pathways (connectome), along with other possible physiologic measures. All of these measures represent components of a continuum that extends from proximity to the genome to proximity to the clinical phenotype of depression, and there are many levels along this continuum at which useful IPs may be defined. Because of the highly integrative nature of brain systems and the complex neurobiology of depression, the most useful biomarkers are likely to be those with intermediate proximity both to the genome and the clinical phenotype of MDD. Translation of findings across the spectrum from genotype to phenotype promises to better characterize the complex disruptions in signaling and neuroplasticity that accompany MDD, and ultimately to lead to greater understanding of the causes of depressive illness.

Fear load: The psychophysiological over-expression of fear as an intermediate phenotype associated with trauma reactions

Psychophysiological measures of fear expression provide observable intermediate phenotypes of fear-related symptoms. Research Domain Criteria (RDoC) advocate using neurobiological intermediate phenotypes that provide dimensional correlates of psychopathology. Negative Valence Systems in the RDoC matrix include the construct of acute threat, which can be measured on a physiological level using potentiation of the acoustic startle reflex assessed via electromyography recordings of the orbicularis oculi muscle. Impairments in extinction of fear-potentiated startle due to high levels of fear (termed fear load) during the early phases of extinction have been observed in posttraumatic stress disorder (PTSD). The goals of the current work were to examine dimensional associations between fear-related symptoms of PTSD and fear load variables to test their validity as an intermediate phenotype. We examined extinction of fear-potentiated startle in a cohort (n=269) of individuals with a broad range of civilian trauma exposure (range 0–13 traumatic events per person, mean=3.5). Based on previously reported findings, we hypothesized that fear load would be significantly associated with intrusion and fear memories of an index traumatic event. The results indicated that early extinction was correlated with intrusive thoughts (p=0.0007) and intense physiological reactions to trauma reminders (p=0.036). Degree of adult or childhood trauma exposure, and depression severity were not associated with fear load. After controlling for age, sex, race, income, level of prior trauma, and level of fear conditioning, fear load during extinction was still significantly predictive of intrusive thoughts (p=0.004). The significance of these findings is that they support dimensional associations with symptom severity rather than diagnostic category and, as such, fear load may emerge as a transdiagnostic intermediate phenotype expressed across fear-related disorders (e.g., specific phobia, social phobia).

A novel mutation in the XPA gene results in two truncated protein variants and leads to a severe XP/neurological symptoms phenotype.

The nucleotide excision repair (NER) pathway repairs UV-induced DNA lesions in an accurate fashion and prevents UV-irradiated areas of the skin from tumour formation. The XPA protein plays a major role in DNA damage demarcation as well as stabilization of other NER factors and was found to be defective in xeroderma pigmentosum (XP) complementation group A patients. Characterization of four new XP-A patients. Genomic and cDNA sequencing, post-UV cell survival of living cells, host-cell reactivation of patients' fibroblasts and Western blotting. One of the four investigated patients shows a novel mutation leading to two different truncated protein variants. Three patients contain the already described p.R228X mutation. All patient cell lines exhibit a strong UVC sensitivity and reduced NER capability. In most of the cases stable protein expression was detected. We discovered four new XP-A patients and a novel XPA mutation resulting in two diverse patient alleles.