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Statins are widely used lipid-lowering drugs that are effective in reducing cardiovascular disease risk. Although they are generally well tolerated, they can cause muscle toxicity, which can lead to severe rhabdomyolysis. Research in this area has been hampered to some extent by the lack of standardized nomenclature and phenotypic definitions. We have used numerical and descriptive classifications and developed an algorithm to define statin-related myotoxicity phenotypes, including myalgia, myopathy, rhabdomyolysis, and necrotizing autoimmune myopathy.
BACKGROUND: Children with severe acute malnutrition (SAM) have increased requirements for phosphorus and magnesium during recovery. If requirements are not met, the children may develop refeeding hypophosphatemia and hypomagnesemia. However, little is known about the effect of current therapeutic diets (F-75 and F-100) on serum phosphate (S-phosphate) and magnesium (S-magnesium) in children with SAM. METHODS: Prospective observational study, with measurements of S-phosphate and S-magnesium at admission, prior to rehabilitation phase and at discharge in children aged 6-59 months admitted with SAM to Jimma Hospital, Ethiopia. Due to shortage of F-75, 25 (35 %) children were stabilized with diluted F-100 (75 kcal/100 ml). RESULTS: Of 72 children enrolled, the mean age was 32 ± 14 months, and edema was present in 50 (69 %). At admission, mean S-phosphate was 0.92 ± 0.34 mmol/L, which was low compared to normal values, but increased to 1.38 ± 0.28 mmol/L at discharge, after on average 16 days. Mean S-magnesium, at admission, was 0.95 ± 0.23 mmol/L, and increased to 1.13 ± 0.17 mmol/L at discharge. At discharge, 18 (51 %) children had S-phosphate below the normal range, and 3 (9 %) had S-phosphate above. Most children (83 %) had S-magnesium above normal range for children. Both S-phosphate and S-magnesium at admission were positively associated with serum albumin (S-albumin), but not with anthropometric characteristics or co-diagnoses. Using diluted F-100 for stabilization was not associated with lower S-phosphate or S-magnesium. CONCLUSION: Hypophosphatemia was common among children with SAM at admission, and still subnormal in about half of the children at discharge. This could be problematic for further recovery as phosphorus is needed for catch-up growth and local diets are likely to be low in bioavailable phosphorus. The high S-magnesium levels at discharge does not support that magnesium should be a limiting nutrient for growth in the F-100 diet. Although diluted F-100 (75 kcal/100 mL) is not designed for stabilizing children with SAM, it did not seem to cause lower S-phosphate than in children fed F-75.
Not enough is known about which patients suffering from major depressive disorder benefit from antidepressant drug treatment. Individual temperament is relatively stable over a person's lifespan and is thought to be largely biologically predefined. We assessed how temperament profiles are related to depression and predict the efficacy of antidepressant treatment. METHODS: We recruited one hundred Finnish outpatients (aged 19 to 72) suffering from major depressive disorder, of whom 86 completed the 6-week study. We assessed their temperament features with the Temperament and Character Inventory and used cluster analysis to determine the patient's temperament profile. We also categorized the patients according to the vegetative symptoms of major depressive disorder. RESULTS: There was an association between skewed temperament profile and severity of major depressive disorder, but the temperament profiles alone did not predict antidepressant treatment response. Those with higher baseline vegetative symptoms score had modest treatment response. Our model with baseline Montgomery Åsberg Depression Rating Scale (MADRS) vegetative symptoms, age and temperament clusters as explanatory variables explained 20% of the variance in the endpoint MADRS scores. CONCLUSION: The temperament clusters were associated both with severity of depression and antidepressive treatment response of depression. The effect of the temperament profile alone was modest but, combined with vegetative symptoms of depression, their explanatory power was more marked suggesting that there could be an association of these two in the biological basis of MDD.
BACKGROUND: Decreased arterial elasticity is a risk factor for several cardiovascular outcomes. Longitudinal data on the effect of physical activity in youth on adult arterial elasticity are limited. The aim of this study was to determine the long-term effects of physical activity in children and young adults on carotid artery elasticity after 21 years of follow-up. METHODS AND RESULTS: Participants were 1417 children (aged 9 to 15 years) and 999 young adults (aged 18 to 24 years) from the prospective Cardiovascular Risk in Young Finns Study. Participants had questionnaire measures of leisure-time physical activity available from 1986 and ultrasound-derived indices of carotid artery elasticity measured in 2007. Carotid artery elasticity indices were distensibility (%/10 mm Hg), Young's elastic modulus (kPa), and stiffness index (unitless). Physical activity at age 18 to 24 years was directly associated with distensibility (β=0.068, P=0.014) and inversely with Young's elastic modulus (β=-0.057, P=0.0037) and indirectly with stiffness index (β=-0.050, P=0.0028) 21 years later in males and females. The associations remained after adjustment for age, sex, body mass index, smoking, systolic blood pressure, serum lipids and insulin, and 21-year change in physical activity. At age 9 to 15 years, the favorable association, remaining after adjustment, was found in males (distensibility [β=0.097, P=0.010], Young's elastic modulus [β=-0.060, P=0.028], and stiffness index [β=-0.062, P=0.007]) but not in females (P=0.70, P=0.85, and P=0.91, respectively). CONCLUSIONS: Leisure-time physical activity in boys and young adults is associated with carotid artery elasticity later in life, suggesting that higher levels of physical activity in youth may benefit future cardiovascular health.
Infants have a natural tendency to look at adults' faces, possibly to help initiate vital interactions with caregivers during sensitive periods of development. Recent studies using eye-tracking technologies have identified the mechanisms that underlie infants' capacity to orient and hold attention on faces. These studies have shown that the bias for faces is weak in young infants, but becomes more robust and resistant to distraction during the second half of the 1st year. This development is apparently related to more general changes in infants' attention and control of eye movement. As a tractable and reproducible aspect of infant behavior, the attention bias for faces can be used to examine the neural correlates of attention and may be a way to monitor early neurodevelopment in infants.
Peroxisome proliferator-activated receptor (PPAR) agonists, fibrates and thiazolidinediones, are commonly used drugs in the treatment of dyslipidemia and diabetes. Their targets, PPARα and PPARγ, have also been shown to have a role in the regulation of inflammatory responses linking metabolism and inflammation. In the present study we investigated the effects of PPAR agonists on macrophage activation. In addition to the proinflammatory classical activation, we also focused on interleukin (IL) 4 and 13 -induced alternative activation which is a significant macrophage phenotype in tissue repairing processes and in fibrosing diseases. PPARα agonists GW7647 and fenofibrate as well as PPARγ agonist GW1929 inhibited lipopolysaccharide-induced classical macrophage activation and production of the characteristic biomarkers of this phenotype, i.e. IL-6 and nitric oxide, in murine J774 macrophages. Remarkably, the PPARα agonists also inhibited IL-4 and IL-13 –induced expression of alternative activation markers arginase-1, fizz1 and mannose receptor 1 whereas the PPARγ agonist GW1929 enhanced their expression in J774 macrophages. The PPARα agonists GW7647 and fenofibrate also attenuated the production of alternative activation markers chemokine (C-C motif) ligand 13 and plateletderived growth factor in human THP-1 macrophages. The present findings show that PPARα and PPARγ agonists differently regulate classical and alternative macrophage phenotypes. Furthermore, PPARα activation was introduced as a novel concept to down-regulate alternative macrophage activation indicating that PPARα agonists have therapeutic potential in conditions associated with aberrant alternative macrophage activation such as fibrosing diseases.
BACKGROUND: Alcohol use among emergency patients has been studied earlier, but the data regarding alcohol use especially among critically ill and injured patients treated in the prehospital setting is scarce. The aim of this study was to evaluate the incidence of alcohol use and the characteristics of cases attended by a physician staffed mobile intensive care unit (MICU). FINDINGS: During a 2 month period, exhaled air alcohol concentration-measured as a part of routine patient examination in all adolescent and adult patients treated by the MICU-was recorded. The MICU encountered 258 patients, of which 82 could be tested for alcohol use. Of the tested patients 43 % gave a positive breath test result. Proportion of male patients providing a positive result in the breath test did not differ significantly those of women. The primary reason for not to test the patient was a decreased level of consciousness in one-fifth of the initial 258 patients. CONCLUSIONS: A significant proportion (47 %) of the encountered patients could not be tested due to their critical condition. Alcohol use was observed in 43 % of those capable of providing a breath test sample. The rate of positive tests seemed to be higher than those reported from emergency departments. Novel diagnostic methods to detect alcohol consumption in non-cooperative patients are warranted.
Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.
Muistisairauksien itsenäisiä riskitekijöitä on paljon, ja ne yhdessä saattavat selittää jopa kolmanneksen muistisairauksien vallitsevuudesta. Riskitekijöiden yhteisvaihtelun huomiotta jättäminen johtaa virheelliseen käsitykseen muistisairauksien ennaltaehkäisyn hyödyistä ja niiden kasautumisen parempi tuntemus auttaisi kohdentamaan riskiarvioita ja ennaltaehkäiseviä toimenpiteitä. Riskin arviointiin voidaan käyttää riskipistejärjestelmiä, kuten suomalaisella aineistolla kehitetty CAIDE -riskipisteytys. Tutkimuksen tavoitteena oli selvittää, onko CAIDE -riskipisteytyksellä mitatun kohonneen riskin henkilöillä enemmän myös muita muistisairauksien riskitekijöitä, kuten mielenterveyden häiriöitä, päihteiden käyttöä, tai huonot ruokailutottumukset. Tutkimusaineisto koostuu Pirkanmaan 2011 2014 MEVA -hankkeen muistiviikoilla kerätyistä kyselylomakkeista, joihin sisältyi CAIDE -riskipisteytys ja muita riskitekijöitä tiedustelevia lisäkysymyksiä. Lomakkeet kerättiin pääosin Tampereen ja sen ympäryskuntien terveysasemien vastaanottoja edeltävästi. Tilastomenetelminä käytettiin ristiintaulukointia ja logistista regressioanalyysia. Miessukupuoli, positiivinen masennusseula ja tyydyttäväksi tai sitä huonommaksi todettu muisti olivat yhteydessä kohonneisiin CAIDE -riskipisteisiin eli aineistossa todettiin riskitekijöiden kasautumista. Valikoitumisharha voi selittää tulokset, eivätkä ne siten ole riittävällä varmuudella yleistettävissä tai siirrettävissä muihin otoksiin.
Autosomal recessive spastic ataxia of Charlevoix-Saguenay is a rare disorder outside Quebec causing childhood-onset cerebellar ataxia, peripheral neuropathy, and pyramidal tract signs. A Finnish family with milder form of ARSACS was found to harbor three mutations, p.E1100K, p.N1489S, and p.M1359T, in SACS gene. The mutations segregated with the disease.
Ethyl pyruvate (EP) is a simple derivative of pyruvic acid, which is an important endogenous metabolite that can scavenge reactive oxygen species (ROS). Treatment with EP is able to ameliorate systemic inflammation and multiple organ dysfunctions in multiple animal models, such as acute pancreatitis, alcoholic liver injury, acute respiratory distress syndrome (ARDS), acute viral myocarditis, acute kidney injury and sepsis. Recent studies have demonstrated that prolonged treatment with EP can ameliorate experimental ulcerative colitis and slow multiple tumor growth. It has become evident that EP has pharmacological anti-inflammatory effect to inhibit multiple early inflammatory cytokines and the late inflammatory cytokine HMGB1 release, and the anti-tumor activity is likely associated with its anti-inflammatory effect. EP has been tested in human volunteers and in a clinical trial of patients undergoing cardiac surgery in USA and shown to be safe at clinical relevant doses, even though EP fails to improve outcome of the heart surgery, EP is still a promising agent to treat patients with multiple inflammatory organ injuries and the other clinical trials are on the way. This review focuses on how EP is able to ameliorate multiple organ injuries and summarize recently published EP investigations. Graphical AbstractThe targets of the anti-inflammatory agent EP.
The role of R-Ras in retinal angiogenesis and vascular permeability was evaluated in an oxygen-induced retinopathy (OIR) model using R-Ras knockout (KO) mice and in human diabetic neovascular membranes. Methods: Mice deficient for R-Ras and their wild-type (WT) littermates were subjected to 75% oxygen from postnatal day 7 (P7) to P12 and then returned to room air. At P17 retinal vascularization was examined from whole mounts, and retinal vascular permeability was studied using Miles assay. Real-time RT-PCR, Western blotting, and immunohistochemistry were used to assess the expression of R-Ras in retina during development or in the OIR model. The degree of pericyte coverage and vascular endothelial (VE)-cadherin expression on WT and R-Ras KO retinal blood vessels was quantified using confocal microscopy. The correlation of R-Ras with vascular endothelial growth factor receptor 2 (VEGFR2) and human serum albumin on human proliferative diabetic retinopathy membranes was assessed using immunohistochemistry. Results: In retina, R-Ras expression was mostly restricted to the vasculature. Retinal vessels in the R-Ras KO mice were significantly more permeable than WT controls in the OIR model. A significant reduction in the direct physical contact between pericytes and blood vessel endothelium as well as reduced VE-cadherin immunostaining was found in R-Ras-deficient mice. In human proliferative diabetic retinopathy neovascular membranes, R-Ras expression negatively correlated with increased vascular leakage and expression of VEGFR2, a marker of blood vessel immaturity. Conclusions: Our results suggest that R-Ras has a role in controlling retinal vessel maturation and stabilization in ischemic retinopathy and provides a potential target for pharmacologic manipulation to treat diabetic retinopathy.
Liikunta on iäkkäille elintärkeää fyysisen toimintakyvyn säilyttämiseksi. Liikunnan lisäämiskeinoja on tutkittu paljon, mutta tutkimus on keskittynyt paljolti kotona asuviin. Tässä pilottitutkimuksessa selvitettiin, miten aikaisemmissa tutkimuksissa ”tarpeeksi hyväksi” todettu askelmittari soveltuu liikunnan lisäämiseen palvelutalossa asuvilla. Pilotti koostui seitsemän viikon kävelyohjelmasta, jossa tarkoituksena oli asteittain lisätä askelmääriä henkilökohtaisesta perustasosta. Tutkimukseen osallistui kahdeksan keski-iältään 81-vuotiasta palvelutalon asukasta. Huomiota kiinnitettiin erityisesti tutkittavien ja hoitajien kokemuksiin mittarin käytöstä, motivoinnin keinoihin sekä askelmäärien seurantaan. Alussa tutkittavien askeleiden perustasojen mediaani oli 800 askelta (päivittäinen keskiarvo 1369). Kävelyohjelman lopussa mitattuna tutkittavien askeleet eivät olleet tilastollisesti merkitsevällä tavalla lisääntyneet. Sekä tutkittavat että hoitajat raportoivat että osa iäkkäistä lisäsi liikunnallista aktiivisuuttaan askelmittarin käytön myötä. Samalla kuitenkin raportoitiin mittarin tarkkuuteen, kiinnitykseen sekä käyttöön liittyneistä ongelmista. Askelmittariin perustuvan kävelyohjelman toteuttaminen palveluasumisyksikössä todettiin mahdolliseksi, joskin haastavaksi. Tulevaisuuden interventioissa tulee kiinnittää huomiota avoimeen kommunikaatioon hoitohenkilökunnan ja tutkijaryhmän välillä. Askelmittarien tarkkuus ei vielä näytä riittävältä toimintarajoitteisten ikäihmisten liikkumisaktiviteetin seuraamiseen. Tarve erityisesti iäkkäille suunnitelluille askelmittareille on ilmeinen.
This study examines the association between thrombolysis and visuoperceptual functions in right hemisphere (RH) infarct patients. Fifty-six consecutive patients with first acute RH infarct were matched for age, years of education and stroke severity at the time of admission to the emergency department (baseline NIHSS; National Institute of Health Stroke Scale), compared according to whether (T+) or not (T−) they received thrombolysis. Neurological (NIHSS at hospital ward; Barthel index; BI) and neuropsychological examinations were conducted 4 days after onset. Visuoconstructive abilities were assessed with the block design and visual search and reasoning with the picture completion subtests of the Wechsler Adult Intelligence Scale revised. Visual neglect was assessed with the conventional subtests of the Behavioural Inattention test and visual memory with the visual reproduction subtest of the Wechsler Memory Scale Revised. T+ and T− patients did not differ in baseline NIHSS, age, years of education, hemianopia, hemiparesis, or in basic ADL (BI). T− patients had more severe strokes (NIHSS at hospital ward) and poorer visuoconstructive abilities than T+ patients. Our results indicate that thrombolysis has a favourable effect on visuoperceptual functions in acute stroke.
Background Milk is an important source of nutrients. The consumption of milk, however, may cause abdominal complaints in lactose intolerant individuals. The frequency of -13910C/C genotype is known to be high among Northern Russians, exceeding the prevalence in northern Europe. In our study we tested two hypotheses: 1) subjects with lactase non-persistent genotype (-13910C/C) have more gastrointestinal (GI) symptoms associated with milk 2) subjects with lactase non-persistence avoid using milk. Methods In total, 518 students aged 17 to 26 years were randomly selected from different departments in the Northern State Medical University (NSMU) for genotyping the lactase activity-defining -13910C/T variant. All subjects filled in a questionnaire covering their personal data, self-reported GI symptoms and milk consumption habits. Results Northern Russians consume very small amounts of milk daily. Among carriers of the lactase non-persistent (LNP) genotype there were 10 percentage units of milk-consumers fewer than among lactase-persistent (LP) subjects (p = 0.03). Complaints of GI disorders caused by milk were different between the genotypes (p = 0.02). Among all types of food analyzed only milk was associated with increased GI symptoms among subjects with the LNP genotype (OR =1.95, CI 1.03-3.69) Conclusions Subjects with -13910C/C have more GI symptoms from milk. Subjects with lactase non-persistent genotype avoid using milk. In the case of increasing milk consumption symptoms may increase the need for medical consultation. It is thus important either for people themselves or for health care staff to be aware of lactase persistence/non-persistence.
Background Acetaminophen (APAP) overdose induces massive hepatocyte necrosis. Liver regeneration is a vital process for survival after a toxic insult. Since hepatocytes are mostly in a quiescent state (G0), the regeneration process requires the priming of hepatocytes by cytokines such as TNF-α and IL-6. Ringer's lactate solution (RLS) has been shown to increase serum TNF-α and IL-6 in patients and experimental animals; in addition, RLS also provides lactate, which can be used as an alternative metabolic fuel to meet the higher energy demand by liver regeneration. Therefore, we tested whether RLS therapy improves liver recovery after APAP overdose. Methods C57BL/6 male mice were intraperitoneally injected with a single dose of APAP (300 mg/kg dissolved in 1 mL sterile saline). Following 2 hrs of APAP challenge, the mice were given 1 mL RLS or Saline treatment every 12 hours for a total of 72 hours. Results 72 hrs after APAP challenge, compared to saline-treated group, RLS treatment significantly lowered serum transaminases (ALT/AST) and improved liver recovery seen in histopathology. This beneficial effect was associated with increased hepatic tissue TNF-α concentration, enhanced hepatic NF-κB DNA binding and increased expression of cell cycle protein cyclin D1, three important factors in liver regeneration. Conclusion RLS improves liver recovery from APAP hepatotoxicity.
Background In the recently published meta-analysis of multiple sclerosis genome-wide association studies De Jager et al. identified three single nucleotide polymorphisms associated to MS: rs17824933 (CD6), rs1800693 (TNFRSF1A) and rs17445836 (61.5 kb from IRF8). To refine our understanding of these associations we sought to replicate these findings in a large more extensive independent sample set of 11 populations of European origin. Principal Findings We calculated individual and combined associations using a meta-analysis method by Kazeem and Farral (2005). We confirmed the association of rs1800693 in TNFRSF1A (p 4.19×10−7, OR 1.12, 7,665 cases, 8,051 controls) and rs17445836 near IRF8 (p 5.35×10−10, OR 0.84, 6,895 cases, 7,580 controls and 596 case-parent trios) The SNP rs17824933 in CD6 also showed nominally significant evidence for association (p 2.19×10−5, OR 1.11, 8,047 cases, 9,174 controls, 604 case-parent trios). Conclusions Variants in TNFRSF1A and in the vicinity of IRF8 were confirmed to be associated in these independent cohorts, which supports the role of these loci in etiology of multiple sclerosis. The variant in CD6 reached genome-wide significance after combining the data with the original meta-analysis. Fine mapping is required to identify the predisposing variants in the loci and future functional studies will refine their molecular role in MS pathogenesis.
Recent studies have suggested a bacterial role in the development of autoimmune disorders including type 1 diabetes (T1D). Over 30 billion nucleotide bases of Illumina shotgun metagenomic data were analyzed from stool samples collected from four pairs of matched T1D case-control subjects collected at the time of the development of T1D associated autoimmunity (i.e., autoantibodies). From these, approximately one million open reading frames were predicted and compared to the SEED protein database. Of the 3,849 functions identified in these samples, 144 and 797 were statistically more prevalent in cases and controls, respectively. Genes involved in carbohydrate metabolism, adhesions, motility, phages, prophages, sulfur metabolism, and stress responses were more abundant in cases while genes with roles in DNA and protein metabolism, aerobic respiration, and amino acid synthesis were more common in controls. These data suggest that increased adhesion and flagella synthesis in autoimmune subjects may be involved in triggering a T1D associated autoimmune response. Extensive differences in metabolic potential indicate that autoimmune subjects have a functionally aberrant microbiome. Mining 16S rRNA data from these datasets showed a higher proportion of butyrate-producing and mucin-degrading bacteria in controls compared to cases, while those bacteria that produce short chain fatty acids other than butyrate were higher in cases. Thus, a key rate-limiting step in butyrate synthesis is more abundant in controls. These data suggest that a consortium of lactate- and butyrate-producing bacteria in a healthy gut induce a sufficient amount of mucin synthesis to maintain gut integrity. In contrast, non-butyrate-producing lactate-utilizing bacteria prevent optimal mucin synthesis, as identified in autoimmune subjects.
Kajoamaton kaksoispaineventilaatiohoito on viimeisen vuosikymmenen aikana mahdollistanut hengityksen tukemisen tavallisella vuodeosastolla ja potilaan kotona. Kaksoispaineventilaattorilla voidaan usein välttää keinoilmatie ja respiraattorihoito, lyhentää potilaan sairaalassaoloaikaa ja säästää kustannuksia. Kaksoispaineventilaatiohoito vähentää kroonisesta hengitysvajauksesta kärsivän potilaan hengenahdistusta ja väsymystä, jolloin elämänlaatu paranee ja tietyissä tilanteissa myös elinikä pitenee. Hoito vaatii lääkäriltä perustietoja hengitysfysiologiasta ja perehtymistä kaksoispaineventilaattorin säätämiseen. Hoitohenkilökunnalta se edellyttää kokemusta hoidon toteutuksesta ja ohjauksesta.
Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8×10−106), PRMT6 (rs17496332, 1p13.3, p = 1.4×10−11), GCKR (rs780093, 2p23.3, p = 2.2×10−16), ZBTB10 (rs440837, 8q21.13, p = 3.4×10−09), JMJD1C (rs7910927, 10q21.3, p = 6.1×10−35), SLCO1B1 (rs4149056, 12p12.1, p = 1.9×10−08), NR2F2 (rs8023580, 15q26.2, p = 8.3×10−12), ZNF652 (rs2411984, 17q21.32, p = 3.5×10−14), TDGF3 (rs1573036, Xq22.3, p = 4.1×10−14), LHCGR (rs10454142, 2p16.3, p = 1.3×10−07), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7×10−08), and UGT2B15 (rs293428, 4q13.2, p = 5.5×10−06). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5×10−08, women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ~15.6% and ~8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.
Mykobakteerien aiheuttamat lasten kaulaimusolmukkeiden tulehdukset ovat odotetusti lisääntyneet sen jälkeen, kun kaikkien lasten BCG-rokotuksista siirryttiin vuonna 2006 riskiryhmien rokottamiseen. Koska nämä infektiot ovat olleet erittäin harvinaisia rokotetuilla lapsilla, nykyinen ongelma on uusi lääkäreille. Hyväkuntoisen lapsen kaulaan kasvaa vähitellen suureneva aristamaton patti. Iho alkaa kuukauden tai parin kuluttua sinertää. Kehittynyt paise puhkeaa, ja eritys jatkuu viikkoja. Viimeistään vuoden kuluttua paikalla on arpi. Parantava hoito on kokeneen korvalääkärin suorittama imusolmukkeen poisto. Mikäli poisto ei ole mahdollinen kasvohermon vaurioitumisen vaaran tai tulehtuneen alueen laajuuden vuoksi, voidaan tilannetta seurata ilman toimenpiteitä. Lääkehoidosta ei yleensä ole hyötyä. Tilanteen ja taudinkulun selittäminen vanhemmille on tärkeää.
Vanhusväestöstä 1 - 4 % kärsii vaikeasta masennuksesta. Vanhusten masennusoireet voivat olla erilaisia verrattuna nuorempien oireisiin. Vanhusikäisillä vaikeakin masennustila on alidiagnosoitu ja siten saattaa jäädä myös hoitamatta. Vaikean ja psykoottisen masennuksen vakavin komplikaatio on itsemurha, johon päätyi vuonna 2008 162 yli 65-vuotiasta. Vanhusten vaikeimpien masennustilojen hoito alkaa usein psykiatrisessa sairaalassa. Tässä potilasryhmässä masennuslääkkeillä saattaa olla tehoeroja. Sähköhoidon mahdollisuus tulisi muistaa myös vaikeasta ja psykoottisesta masennuksesta kärsiviä vanhuspotilaita hoidettaessa. Potilaita tulisi ohjata tähän tehokkaimpaan hoitoon nykyistä aiemmin. Sähköhoito on turvallinen myös vanhusikäiselle. Vaikeassa ja psykoottisessa masennustilassa sen teho on kiistaton.
Background The aim of the study was to evaluate the long-term outcome of patients successfully resuscitated from pre-hospital cardiac arrest with initial pulseless electrical activity (PEA), because the long-term outcome of these patients is unknown. Survival, neurological status one year after cardiac arrest and self-perceived quality of life after five years were assessed. Methods This retrospective study included adult patients resuscitated from PEA between August 2001 and March 2003 in three urban areas in southern Finland. A validated questionnaire was sent to patients while neurological status according to the Cerebral Performance Category (CPC) -classification was assessed based on medical database notes recorded during follow-up evaluations. Results Out of 99 included patients in whom resuscitation was attempted, 41 (41%) were successfully resuscitated and admitted to hospital. Ten (10%) patients were discharged from hospital. Seven were alive after one year and six after five years following cardiac arrest. Five of the seven patients alive one year after resuscitation presented with the same functional level as prior to cardiac arrest. Conclusions Patients with initial PEA have been considered to have poor prognosis, but in our material, half of those who survived to hospital discharge were still alive after 5 years. Their self-assessed quality of life seems to be good with only mild to moderate impairments in activities of daily life.
Lapsuuden poissolokohtausepilepsia kuuluu yleistyviin epilepsioihin, joiden syynä ovat toistaiseksi pääosin tunnistamattomat perintötekijät. Alle 15-vuotiaiden lasten epilepsioista poissaolokohtausepilepsian osuus on noin 30-60/1000 epilepsiaa sairastavaa lasta kohti. Tämä epilepsia ilmee hyvin lyhyinä, usein vaikeasti havaittavina, muutamien sekuntien kestoisina poissaoloina. Poissaolokohtausten aikana lapsen toiminta pysähtyy, eikä hän reagoi näkemäänsä tai kuulemaansa. Kohtauksen jälkeen hän jatkaa toimintaansa, eikä yleensä ole tietoinen kohtauksesta. Poissaolokohtausepilepsiaan sairastuvat lapset ovat muutoin tavallisesti kehittyneitä. Lapsuuden poissaoloepilepsiaa tarkasteltiin kolmesta eri näkökulmasta. Ensiksi tutkittiin juuri poissaolokohtausepilepsiaan sairastuneiden lapsien suoriutumista tietokonepohjaisin aivojen toimintaa tutkivin testein ja epilepsialääkityksen aloittamisen jälkeen poissaolokohtausten loppumisen vaikutusta heidän suoriutumiseensa. Tutkimusryhmän lisäksi samat testit tehtiin myös terveille kontrolleille. Toisena näkökulmana oli lapsuusiän poissaoloepilepsiaan sairastuneiden pitkäaikaisennuste. Pääosin taannehtivasti selvitettiin 52 lapsuusiän poissaolokohtausepilepsiaa sairastaneen henkilön pitkäaikaisennuste haastattelemalla. Kolmantena näkökulmana oli pyrkiä selvittämään lapsuusiän poissaoloepilepsian perinnöllistä taustaa. Kaksi sukua osallistui tutkimukseen, jossa geenimerkkien avulla pyrittiin paikantamaan kohtausalttiutta aiheuttavien perintötekijöiden sijainti. Suvuissa esiintyi lapsuuden poissaolokohtausepilepsiaa, kuumekouristuksia ja paikallisalkuisia epilepsioita. Tutkimuksessa todettiin, että poissaolokohtaukset vaikuttavat etenkin näönvaraiseen muistiin. Epilepsialääkityksen aloittamisen jälkeen ja kohtausten loppumisen myötä poissaolokohtausepilepsiaan sairastuneiden lasten näönvarainen muisti parani merkittävästi. Ryhmien välillä ei todettu eroa yleisessä suoriutumistasossa. Pitkäaikaisennuste tutkimusryhmässä oli hyvä. Keskimääräinen seuranta-aika oli 10 vuotta, (vaihteluväli 2-22 vuotta). 87% tutkimukseen osallistuneista epilepsialääkitys oli lopetettu ja he olivat kohtauksettomia. 27%:lla poissaolokohtausepilepsiapotilaista oli suvussaan muitakin henkilöitä, joilla oli ollut epilepsiadiagnoosi ja 17%:lla poissaolokohtausepilepsiapotilaista oli suvussa esiintynyt myös kuumekouristuksia. Molempien perheiden DNA näytteiden avulla tunnistettin kaksi perimän aluetta (kromsomeissa 16 ja 17), joissa kohtausalttiutta aiheuttava perimän muutos todennäköisesti sijaitsee. Näiltä alueilta tutkittiin tarkemmin 16 ehdokasgeeniä. CACNA1H-geenissä, joka on aiemmin liitetty lapsuuden poissaolokohtausepilepsiaan, todettin emäsjärjestyksen muutos toisen perheen yhdessä sukuhaarassa. Tämä muutos mahdollisesti altistaa epilepsialle. Poissaolokohtaukset vaikuttavat aivojen toimintaan, kuten tässä tukimuksessa havaittiin näönvaraisen muistin osalta. Lähes aina epilepsialääkkeet kuitenkin tehoavat hyvin ja tasaavat mahdollisia suoriutumiseroja verrattuna terveisiin lapsiin. Pitkällä tähtäimellä lääkitys voidaan useimmiten lopettaa ja suurin osa poissaolokohtausepilepsiaan sairastuneista pysyy kohtauksettomina. Perinnölliseltä taustaltaan lapsuuden poissaolokohtausepilepsia on monitekijäinen. Sellaiset suvut, joissa esiintyy lapsuuden poissaolokohtausepilepsiaa ja muita taustaltaan todennäköisesti perinnöllisiä epilepsioita, ovat hyviä tutkimuskohteita monitekijäisten epilepsioiden geneettisen taustan selvittämiseksi.
Sydämen vajaatoiminta johtaa huomattavaan sairastavuuteen ja kuolleisuuteen maailmanlaajuisesti. Länsimaissa se on yleisin sairaalahoidon syy yli 65- vuotiailla ja sen ilmaantuvuus jatkaa edelleen kasvuaan. Vanhusten määrä lisääntyy ja heillä laajan muun kuin sydänkirurgian on arvioitu lisääntyvän 25% seuraavan 10 - 20 vuoden aikana. Sydämen vajaatoimintaa sairastavien potilaiden kuolleisuus laajassa ei-sydänkirurgiassa on kaksinkertainen verrattuna potilaisiin yleensä tai sepelvaltimotautia sairastaviin potilaisiin. Lisäksi sairaalaan takaisin joutumisen riski on huomattavasti kohonnut. Yritykset vähentää näitä haittatapahtumia eivät ole olleet tuloksekkaita. Näin ollen tehokkaita sydämen vajaatoiminnan hoitoja tarvitaan. Sairaalahoidossa dobutamiini ja milrinoni ovat tavallisimmin käytettyjä suonensisäisesti annosteltavia lääkkeitä sydämen vajaatoimintaan. Näiden cAMP:n kautta vaikuttavien lääkkeiden perusvaikutusmekanismi eli solun sisäisen kalsiumvirran lisääntyminen saattaa altistaa rytmihäiriöille ja lisätä sydämen energiankulutusta. Levosimendaani on viimeisin kliiniseen käyttöön tullut, Suomessa kehitetty kalsiumherkistäjä, joka lisää sydämen supistusvireyttä lisäämättä solun sisäisen kalsiumin määrää tai sydämen energiakulutusta. Levosimendaanilla on lisäksi laskimoita ja valtimoita sekä sepelvaltimoita laajentava vaikutus. Suomessa levosimendaanilla on tällä hetkellä myyntilupa äkillisesti pahentuneen kroonisen sydämen vajaatoiminnan hoitoon. Levosimendaanin vaikutusmekanismin perusteella voi olettaa, että sen käyttöä muissakin sydämen pumppausvajausta aiheuttavissa tautitiloissa kannattaa tutkia. Väitöskirjatutkimusen tarkoituksena oli selvittää, olisiko levosimendaanista hyötyä seuraavissa tilanteissa: 1) potilailla, joilta leikataan vatsa-aortan aneurysma tai 2) korjataan aorttaläppä sepelvaltimoiden ohitusleikkauksen yhteydessä ja kokeellissa eläinkoetutkimuksessa, jossa aiheutetaan sioille 3) vaikea kalsiumestäjä- tai 4) beetasalpaajamyrkytys. Väitöskirjatyön päätelminä voidaan todeta, että levosimendaanilla voi olla positiivisia vaikutuksia mahalaukun seinämän verenkiertoon. Koko suoliston alueen verenkiertoa parantavaa vaikutusta ei havaittu. Vuorokautta ennen sydänleikkausta annosteltu levosimendaani parantaa sydämen pumppaustoimintaa neljän leikkauksen jälkeisen päivän ajan. Lisäksi havaittiin, että levosimendaani saattaa parantaa selviytymistä kokeellisessa kalsiumsalpaajamyrkytyksessä. Beetasalpaaja myrkytyksessä levosimendaani näytti parantavan sekä sydämen pumppausvoimaa että selviytymistä ja se voi olla uusi vaihtoehto vaikeiden myrkytysten hoidossa.