Genetic and epidemiological studies of Infantile Hypertrophic Pyloric Stenosis

Infantile Hypertrophic Pyloric Stenosis (IHPS) is a condition of early infancy characterized by thickening of the pyloric muscle resulting in obstruction of gastric outflow. It affects 1-3/1000 live births and is one of the most common causes of gastrointestinal obstruction in infants. IHPS is developed under influence of both genetic and environmental factors, but the exact pathogenesis is unknown. The aim of this thesis was to elucidate genetic and environmental factors contributing to development of IHPS. In study I and II we used a candidate gene approach to study association of two different genes with potential involvement in pathogenesis of IHPS. Since treatment with the motilin agonist erythromycin gives an increased risk for IHPS, we proposed the GI-hormon motilin as an IHPS candidate gene (study I). Sequencing of the MLN coding exons revealed three previously not reported sequence variants occurring in both cases and controls, though without obvious association to the disease. In addition, no significant association was found between the rs2281820 (p.Val15Ala) polymorphism and IHPS. Neuronal nitric oxide synthase encoded of NOS1 is key player in the pathway mediating pyloric relaxation, and is suggested as a IHPS susceptibility gene. A functional NOS1C promoter polymorphism (c.-84G>A; rs41279104) regulating expression of the gene was genotyped in cases and controls (study II). We could not confirm a previously reported association of the A-allele with IHPS in our material. In study III we used an unbiased strategy, genome wide linkage analysis, to search for chromosomal regions harboring candidate genes. 37 Swedish IHPS families were analysed in an initial genome wide scan revealing seven regions of interest for fine mapping. Fine mapping using a statistical model with equal weight to all families identified significant linkage to 2q24.3, and suggestive linkage to 7p22.2 and 12q24.23. The statistical model using a weighting scheme to compensate for different pedigree structures identified significant linkage to 2q24.3 and 7p21.3, and suggestive linkage to 6p21.31. Interestingly, these candidate regions harbor the previously suggested candidate genes MLN and NOS1. Two novel proposed candidate genes, NPY and GCG, were sequenced without obvious pathological findings. Extending the material with additional 31 British IHPS families in the fine mapped regions did not enhance the NPL score. In study IV we performed a nationwide register study based on all IHPS cases in Sweden 1973- 2008, yielding a study cohort of 3608 cases and 17588 matched controls. Incidence fell from 2.25 to 0.43/1000 between years 1988-1998 with a relatively constant sex ratio of 5:1 boys to girls. Study variables associated with an increased risk for IHPS in our material were caesarian delivery, prematurity, neonatal jaundice and being first born. Maternal smoking, low maternal age and Nordic ethnicity were also associated with increased IHPS risk. Maternal smoking and low birth rank were stronger risk factors during period with low incidence. Prematurity was a stronger risk factor when analysis was stratified for late onset of disease. In summary we have identified candidate gene regions on chromosome 2, 6, 7 and 12 and identified several epidemiological risk factors for IHP

Distinct Lysosomal Network Protein Profiles in Parkinsonian Syndrome Cerebrospinal Fluid.

BackgroundClinical diagnosis of parkinsonian syndromes like Parkinson's disease (PD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) is hampered by overlapping symptomatology and lack of diagnostic biomarkers, and definitive diagnosis is only possible post-mortem.ObjectiveSince impaired protein degradation plays an important role in many neurodegenerative disorders, we hypothesized that profiles of select lysosomal network proteins in cerebrospinal fluid could be differentially expressed in these parkinsonian syndromes.MethodsCerebrospinal fluid samples were collected from PD patients (n = 18), clinically diagnosed 4-repeat tauopathy patients; corticobasal syndrome (CBS) (n = 3) and PSP (n = 8); and pathologically diagnosed PSP (n = 8) and CBD patients (n = 7). Each patient set was compared to its appropriate control group consisting of age and gender matched individuals. Select lysosomal network protein levels were detected via Western blotting. Factor analysis was used to test the diagnostic sensitivity, specificity and accuracy of the select lysosomal network protein expression profiles.ResultsPD, CBD and PSP were markedly different in their cerebrospinal fluid lysosomal network protein profiles. Lysosomal-associated membrane proteins 1 and 2 were significantly decreased in PD; early endosomal antigen 1 was decreased and lysozyme increased in PSP; and lysosomal-associated membrane proteins 1 and 2, microtubule-associated protein 1 light chain 3 and lysozyme were increased in CBD. A panel of lysosomal-associated membrane protein 2, lysozyme and microtubule-associated protein 1 light chain discriminated between controls, PD and 4-repeat tauopathies.ConclusionsThis study offers proof of concept that select lysosomal network proteins are differentially expressed in cerebrospinal fluid of Parkinson's disease, corticobasal syndrome and progressive supranuclear palsy. Lysosomal network protein analysis could be further developed as a diagnostic fluid biomarker in parkinsonian syndromes

Determinants of cognitive and brain resilience to tau pathology: a longitudinal analysis

Mechanisms of resilience against tau pathology in individuals across the Alzheimer's disease spectrum are insufficiently understood. Longitudinal data are necessary to reveal which factors relate to preserved cognition (i.e. cognitive resilience) and brain structure (i.e. brain resilience) despite abundant tau pathology, and to clarify whether these associations are cross-sectional or longitudinal. We employed a longitudinal study design to investigate the role of several demographic, biological and brain structural factors in yielding cognitive and brain resilience to tau pathology as measured with PET. In this multicenter study, we included 366 amyloid-β-positive individuals with mild cognitive impairment or Alzheimer's disease-dementia with baseline [18F]flortaucipir-PET and longitudinal cognitive assessments. A subset (n = 200) additionally underwent longitudinal structural MRI. We used linear mixed-effects models with global cognition and cortical thickness as dependent variables to investigate determinants of cognitive resilience and brain resilience, respectively. Models assessed whether age, sex, years of education, APOE-ε4 status, intracranial volume (and cortical thickness for cognitive resilience models) modified the association of tau pathology with cognitive decline or cortical thinning. We found that the association between higher baseline tau-PET levels (quantified in a temporal meta-region of interest) and rate of cognitive decline (measured with repeated Mini-Mental State Examination) was adversely modified by older age (Stβinteraction = -0.062, P = 0.032), higher education level (Stβinteraction = -0.072, P = 0.011) and higher intracranial volume (Stβinteraction = -0.07, P = 0.016). Younger age, higher education and greater cortical thickness were associated with better cognitive performance at baseline. Greater cortical thickness was furthermore associated with slower cognitive decline independent of tau burden. Higher education also modified the negative impact of tau-PET on cortical thinning, while older age was associated with higher baseline cortical thickness and slower rate of cortical thinning independent of tau. Our analyses revealed no (cross-sectional or longitudinal) associations for sex and APOE-ε4 status on cognition and cortical thickness. In this longitudinal study of clinically impaired individuals with underlying Alzheimer's disease neuropathological changes, we identified education as the most robust determinant of both cognitive and brain resilience against tau pathology. The observed interaction with tau burden on cognitive decline suggests that education may be protective against cognitive decline and brain atrophy at lower levels of tau pathology, with a potential depletion of resilience resources with advancing pathology. Finally, we did not find major contributions of sex to brain nor cognitive resilience, suggesting that previous links between sex and resilience might be mainly driven by cross-sectional differences

Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy

Peer reviewe

Monoaminergic and histaminergic strategies and treatments in brain diseases

The monoaminergic systems are the target of several drugs for the treatment of mood, motor and cognitive disorders as well as neurological conditions. In most cases, advances have occurred through serendipity, except for Parkinson's disease where the pathophysiology led almost immediately to the introduction of dopamine restoring agents. Extensive neuropharmacological studies first showed that the primary target of antipsychotics, antidepressants, and anxiolytic drugs were specific components of the monoaminergic systems. Later, some dramatic side effects associated with older medicines were shown to disappear with new chemical compounds targeting the origin of the therapeutic benefit more specifically. The increased knowledge regarding the function and interaction of the monoaminergic systems in the brain resulting from in vivo neurochemical and neurophysiological studies indicated new monoaminergic targets that could achieve the efficacy of the older medicines with fewer side-effects. Yet, this accumulated knowledge regarding monoamines did not produce valuable strategies for diseases where no monoaminergic drug has been shown to be effective. Here, we emphasize the new therapeutic and monoaminergic-based strategies for the treatment of psychiatric diseases. We will consider three main groups of diseases, based on the evidence of monoamines involvement (schizophrenia, depression, obesity), the identification of monoamines in the diseases processes (Parkinson's disease, addiction) and the prospect of the involvement of monoaminergic mechanisms (epilepsy, Alzheimer's disease, stroke). In most cases, the clinically available monoaminergic drugs induce widespread modifications of amine tone or excitability through neurobiological networks and exemplify the overlap between therapeutic approaches to psychiatric and neurological conditions. More recent developments that have resulted in improved drug specificity and responses will be discussed in this review.peer-reviewe

En kvalitativ studie av kvinnors tankar om att avstå organiserad gynekologisk cellprovtagningskontroll

I ett samhällsperspektiv är organiserad Gynekologisk cellprovtagning (GCK) en kostnadseffektiv metod för att förebygga samt minska dödligheten i livmoderhalscancer, vilken är den näst vanligaste cancerformen hos kvinnor världen över. Genom GCK kan förstadium till livmodershalscancer upptäckas. Dödligheten i livmoderhalscancer har minskat i Sverige sedan organiserad GCK infördes och tidigare studier visar att denna cancerform förekommer oftare hos kvinnor som inte deltar i organiserad GCK. Många kvinnor väljer dock att avstå från att delta. Syftet med denna studie är att beskriva kvinnors tankar om organiserad gynekologisk cellprovtagningskontroll när de valt att avstå från deltagande i sådan. Informanter rekryterades genom två datainsamlingsmetoder. Fyra informanter rekryterades från kallelseregistret och sju via snöbollsmetoden. Intervjuer med tre kvinnor och telefonintervjuer med åtta kvinnor genomfördes. Intervjuerna analyserades enligt kvalitativ innehållsanalys. Resultatet åskådliggörs genom fyra kategorierna vilka är Att göra det sedan, Att det inte gäller mig, Att undvika en utlämnande situation samt Att inte bli bekräftad i mötet med barnmorskan vid provtagningstillfället. Kvinnornas tankar tyder på att de gjort ett aktivt ställningstagande att inte delta i organiserad GCK och att de sköt beslutet om deltagande till framtiden. Därutöver framkom att de avstått deltagande i organiserad GCK på grund av rädsla för att inte bli bekräftade i mötet med barnmorskan vid provtagningstillfället. Gemensamt för kvinnorna i studien var att de alla kunde tänka sig att delta i organiserad GCK i framtiden om förhållandena kring GCK vore annorlunda. Inom ramen för den organiserade cellprovtagningskontrollen bör utrymme finnas för att tillgodose kvinnors olika behov då vissa kvinnor behöver extra stöd och motivation för att hörsamma kallelsen.Program: Barnmorskeutbildnin

Betydelsen av vila och återhämtning för personer med medelsvår KOL som upplever fatigue

Kroniskt Obstruktiv Lungsjukdom (KOL) är en komplex sjukdom med flera symtom som tillsammans påverkar livskvaliteten. Fatigue är ett vanligt men ofta outtalat symtom som påverkar individen i olika livssammanhang, känsloliv och på djupare existentiell nivå. Trots detta är det ovanligt att trötthet och behovet att vila tas upp som ett problem både av personen själv, närstående eller av sjukvården. Vila är ett av människans grundläggande behov och har betydelse för välbefinnandet. Syftet med studien är att beskriva betydelsen av vila och återhämtning i det dagliga livet hos personer med medelsvår KOL som upplever fatigue. Studien har utförts som en kvalitativ intervjustudie med en fenomenologisk ansats och analyserats med en beskrivande innebördsanalys. Resultatet har strukturerats och presenteras med hjälp av van Manens livsvärldsexistentialer under fyra teman; vilan och kroppen, vilan och tiden, vilan och platsen och vilan och relationerna. Studien visar att för personer med medelsvår KOL som upplever fatigue har vila och återhämtning betydelse. Vilan har flera dimensioner, den kan vara tvingande men också frivillig och läkande vilket påverkar livsvärlden på olika sätt. Sjukdomen medför att kroppen kräver vila och det dagliga livet anpassas efter kroppens förmåga. Behovet av vila varierar och samsjuklighet har stor betydelse för hur stor trötthet personen upplever. Resultatet belyser att deltagarna använder olika sätt att vila eller hämta kraft. De vilar när kroppen känns trött, vid behov av avkoppling, värk eller då tiden är långsam. Att hämta kraft sker oftast i samband med något energigivande och lustfyllt som promenader, fritidsintressen och socialt umgänge. Att ha olika strategier för vila och återhämtning är effektivt och underlättar det dagliga livet. Distriktssköterskan kan bidra med verktyg om betydelsen av rytm och rutiner för vila och återhämtning för ett ökat välbefinnande

Attention deficit hyperactivity and autism spectrum disorders in patients with anorectal malformations

Aim To assess the risk of neurodevelopmental disorders in patients with anorectal malformations compared to controls. Methods This was a population-based cohort study including all patients born in Sweden 1997–2012 with anorectal malformation in the Swedish National Patient Register and five matched controls per patient. Anorectal malformation was the exposure. All individuals were evaluated for the outcomes, attention deficit hyperactivity disorder or autism spectrum disorder in the National Patient Register. Data on drugs for attention deficit hyperactivity disorder were retrieved from the Swedish Prescribed Drug Register and used as proxy for attention deficit hyperactivity disorder. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (95% CI). Analyses were adjusted for confounders. Results Five hundred and fifteen patients with anorectal malformations and 2560 controls were included. Patients with anorectal malformation had a higher risk of attention deficit hyperactivity disorder (OR 3.01 (95% CI, 1.83–4.95)) and autism spectrum disorders (OR 3.07 (95% CI, 1.62–5.79)) compared to the controls. Significantly more patients with anorectal malformation had been prescribed medication for attention deficit hyperactivity disorder compared to controls (OR 2.26 (95% CI 1.33–3.85)). Conclusion Patients with anorectal malformations have a higher risk of attention deficit hyperactivity disorder and autism spectrum disorders than controls

Controlled long term outcome of pyloromyotomy for pyloric stenosis : No long-term adverse effect

Purpose: Pyloromyotomy for pyloric stenosis is one of the more common surgical procedures performed on infants. The long-term effects of the procedure are however unclear. The purpose of this study was to study the effects into adult life, compare them with controls and to see if there is a need for structured follow up of patients. Methods: Of the 101 patients operated for pyloric stenosis between 1972 and 1974 at our tertiary referral center 91 could be traced. They were all invited to participate in the study and were sent validated ques-tionnaires (PAGI-SYM, GIQLI) as well as a study-specific questionnaire examining the use of antacid drugs, incidence of gastroscopy and abdominal surgery. Sixty patients responded (66%, mean age 45 years, 46 male) and were included. Thereafter, 600 age and sex-matched controls were sent the same question-naires. 132 responded (22%, 90 male) and were includes as controls. Results: No significant differences could be found in any of the examined parameters when looking at the whole material or the male patients. Female patients had higher PAGI-SYM-scores for post prandial fullness (mean 1.11 vs 0.43, P = 0.035) and heartburn (mean 0.59 vs 0.14, P = 0.043) when compared to controls. Conclusions: The present study shows that most patients operated for pyloric stenosis during infancy experience no negative effects into adulthood. The finding in the female patient group is interesting but is unlikely to have any clinical implications. The results from this study strongly implicate that there is no need for follow up of patients into adulthood.Level of evidence: Level III

Effect of Treatment with Natalizumab on Ability to Work in People with Multiple Sclerosis Productivity Gain Based on Direct Measurement of Work Capacity before and after 1 Year of Treatment

Background: Sweden is a high endemic region for multiple sclerosis (MS), a neurologic disorder characterized by repeated inflammatory episodes affecting the CNS. The disease has its peak age of onset at approximately 30 years and affects women twice as often as men. The young age of onset makes MS one of the major causes of reduced capacity to work due to neurologic disease in Western society. Natalizumab (Tysabri(R)) is among the new generation of biologic drugs for the treatment of MS. Clinical studies have demonstrated that natalizumab is an effective treatment for preventing relapses and inflammatory activity. Objective: The aim of the study was to estimate the monetary value of treatment with natalizumab on the ability to work in patients with MS in Sweden, based on a direct measurement of weekly hours worked before and after 1 year of treatment with natalizumab. Methods: A sample of patients, consisting of all patients who had started treatment with natalizumab during the period June 2007 May 2008, was identified through the Swedish Multiple Sclerosis Register (SMSreg). Data about sex, age, disease severity, and disease duration were collected from the register. Data about type of work and work capacity (number of hours worked per week) were collected retrospectively through a postal questionnaire. The average hours worked per week was estimated at baseline (2 weeks before treatment started) and at follow-up (50 weeks after treatment started), and the change was assigned an economic value using the human capital approach. Results: This study showed that after 50 weeks of treatment with natalizumab, people with MS increased their productivity by 3.3 hours per week on average (p<0.01), which corresponded to an economic value of 3216 per person per year (year 2007 values). A shorter duration of illness or being 25-35 years old was significantly associated with a greater productivity gain (p = 0.025 and p = 0.002, respectively). Conclusion: A shorter duration of illness and a lower age at the start of treatment were significantly associated with a greater productivity gain after 50 weeks of treatment with natalizumab, which indicates that it is more beneficial to initiate efficient therapy early in patients with MS