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Our patient material included families and sporadic patients of Finnish origin with the diagnosis of Charcot‐Marie‐Tooth (CMT) disease types 1 and 2, Déjérine‐Sottas syndrome (DSS), and hereditary neuropathy with liability to pressure palsies (HNPP). We screened for mutations in the peripheral myelin protein genes connexin 32 (Cx32), myelin protein zero (P0) and peripheral myelin protein 22 (PMP22) by direct sequencing. All patients chosen for mutation screening were negative for the 1.5 Mb duplication/deletion at 17p11.2‐p12. Eleven Cx32 mutations were found in 12 families, six with a CMT2 diagnosis, three with a CMT1 diagnosis and three with unclassified CMT. The total number of patients in these 12 CMTX families was 61, giving a minimum prevalence of 1.2/100,000 for CMTX in Finland. Four of the mutations, Pro58Arg, Pro172Leu, Asn175Asp and Leu204Phe, have not been previously reported. One male patient with an early onset CMT had a double Cx32 mutation, Arg22Gln and Val63Ile. The double de novo mutation was found to be of maternal grandpaternal origin. In the P0 gene a Ser78Leu mutation was found in one family with severe CMT1 and a de novo Tyr82Cys mutation was found in one DSS patient. Both mutations have been previously reported in other CMT1 families. A novel PMP22 mutation, deletion of Phe84, was found in one sporadic DSS patient. Our mutation screening results show the necessity of molecular diagnosis, in addition to clinical and electrophysiological evaluation, for proper subtyping of the disease and for accurate genetic counseling. Hum Mutat 12:59–68, 1998. © 1998 Wiley‐Liss, Inc.

A decline in stem cell function impairs tissue regeneration during ageing, but the role of the stem-cell-supporting niche in ageing is not well understood. The small intestine is maintained by actively cycling intestinal stem cells that are regulated by the Paneth cell niche 1 , 2 . Here we show that the regenerative potential of human and mouse intestinal epithelium diminishes with age owing to defects in both stem cells and their niche. The functional decline was caused by a decrease in stemness-maintaining Wnt signalling due to production of Notum, an extracellular Wnt inhibitor, in aged Paneth cells. Mechanistically, high activity of mammalian target of rapamycin complex 1 (mTORC1) in aged Paneth cells inhibits activity of peroxisome proliferator activated receptor α (PPAR-α) 3 , and lowered PPAR-α activity increased Notum expression. Genetic targeting of Notum or Wnt supplementation restored function of aged intestinal organoids. Moreover, pharmacological inhibition of Notum in mice enhanced the regenerative capacity of aged stem cells and promoted recovery from chemotherapy-induced damage. Our results reveal a role of the stem cell niche in ageing and demonstrate that targeting of Notum can promote regeneration of aged tissues. Ageing-associated decline in intestinal stem cell function is mediated by increased Notum, a protein inhibitor of stemness-maintaining Wnt signalling, which is secreted by Paneth cells.

Background All-cause mortality and cardiovascular disease are increased in subjects with metabolic syndrome (MetS). Risk scores are used to predict individual risk of heart disease. We performed a long-term follow-up study to investigate whether risk scores and cardiovascular risk factors such as arterial stiffness, high-sensitive C-reactive protein (hs-CRP) and oxidized LDL (OxLDL) can be used to predict cardiovascular events in Finnish men with MetS. Methods After baseline measurements we followed 105 Finnish men aged 30 to 65 years with MetS for a mean period of 16.4 years. The primary outcome of the study was a composite of myocardial infarction, stroke, symptomatic vascular disease diagnosed with invasive angiography, coronary or peripheral revascularization, amputation due to peripheral vascular disease, cardiovascular death and non-cardiovascular death. The endpoints were retrieved from electronic medical records. Results The number of acute myocardial infarctions and strokes during the first 10 years was lower than estimated by FINRISK score but SCORE predicted cardiovascular death correctly. During the whole follow-up period, 27 of 105 participants (25.8%) had 30 endpoint events. The incidence of the primary composite outcome was significantly lower in subjects with hs-CRP < 1.0 mg/L than in subjects with hs-CRP ≥ 1.0 mg/L (6 of 41 subjects [14.6%] vs. 21 of 64 subjects [32.8%]; p  = 0.036). The incidence of the primary composite outcome was higher among subjects with large artery elasticity classified as borderline compared to subjects with normal large artery elasticity (5 of 10 subjects [50%] vs. 22 of 93 subjects [24%]; p  = 0.05). There was no difference in the incidence of primary composite outcome in groups with different degrees of small artery elasticity or different level of oxLDL. Conclusions Men with MetS who had hs-CRP ≥ 1.0 mg/L had higher risk for CVD and all-cause mortality than those with hs-CRP of < 1.0 mg/L. This also applies to subjects with borderline decreased large artery elasticity. The amount of OxLDL had no predictive value on the incidence of CVD and all-cause mortality. Men with MetS participating in the Hämeenlinna Metabolic Syndrome Research Program without lifestyle or drug intervention had better outcome for myocardial infarction or stroke than estimated by the FINRISK score. Trial registration ClinicalTrials.gov NCT01119404 retrospectively registered 07/05/2010.

Pseudomyxoma peritonei (PMP) is a subtype of mucinous adenocarcinoma mainly restricted to the peritoneal cavity and most commonly originating from the appendix. The genetic background of PMP is poorly understood and no targeted treatments are currently available for this fatal disease. While RAS signaling pathway is affected in most if not all PMP cases and over half of them also have a mutation in the GNAS gene, other genetic alterations and affected pathways are, to a large degree, poorly known. In this study, we sequenced whole coding genome of nine PMP tumors and paired normal tissues in order to identify additional, commonly mutated genes and signaling pathways affected in PMP. These exome sequencing results were validated with an ultra-deep amplicon sequencing method, leading to 14 validated variants. The validated results contain seven genes that contribute to the protein kinase A (PKA) pathway. PKA pathway, which also contains GNAS, is a major player of overproduction of mucin, which is the characteristic feature of PMP. In addition to PKA pathway, we identified mutations in six genes that belong to the transforming growth factor beta (TGF-β) pathway, which is a key regulator of cell proliferation. Since either GNAS mutation or an alternative mutation in the PKA pathway was identified in 8/9 patients, inhibition of the PKA pathway might reduce mucin production in most of the PMP patients and potentially suppress disease progression.

BackgroundWe investigated whether stress-related exhaustion (chronic or short-term, and co-occurring with depression or not) is related to cognitive performance and whether polygenic cognitive potential modifies these associations.MethodsThe participants were from the Young Finns Study (N = 541–1273). Stress-related exhaustion was assessed using the Maastricht Questionnaire, depressive symptoms with the Beck Depression Inventory, and cognitive performance with subtests of the Cambridge Neuropsychological Test Automated Battery, measuring visuospatial learning, reaction time, sustained attention, and executive function. Cognitive performance and depression were assessed in 2011, and exhaustion in 2001, 2007, and 2011. A polygenic score for cognitive potential was calculated based on a GWAS on intelligence.ResultsHigh stress-related exhaustion, especially chronic, was associated with slower reaction time. Only clinical levels of depression were related to slower reaction time. Polygenic cognitive potential did not modify these associations. There were no differences in cognitive performance between individuals with co-occurring exhaustion and depression vs. those with only either condition.ConclusionStress-related exhaustion, especially if chronic, seems to relate to slower reactions. Co-occurring exhaustion and depression may not have additive effects on cognitive performance. High polygenic cognitive potential may not protect from or predispose to harmful effects of exhaustion or depression on reaction time.

Background Low education, low cognitive abilities, and certain cognitive styles are suggested to predispose to social intolerance and prejudices. Evidence is, however, restricted by comparatively small samples, neglect of confounding variables and genetic factors, and a narrow focus on a single sort of prejudice. We investigated the relationships of education, polygenic cognitive potential, cognitive performance, and cognitive styles with social intolerance in adulthood over a 15‐year follow‐up. Methods We used data from the prospective population‐based Young Finns Study (n = 960‒1679). Social intolerance was evaluated with the Social Intolerance Scale in 1997, 2001, and 2011; cognitive performance with the Cambridge Neuropsychological Test Automated Battery in 2011; cognitive styles in 1997; and socioeconomic factors in 1980 (childhood) and 2011 (adulthood); and polygenic cognitive potential was calculated based on genome‐wide association studies. Results We found that nonrational thinking, polygenic cognitive potential, cognitive performance, or socioeconomic factors were not related to social intolerance. Regarding cognitive styles, low flexibility (B = –0.759, p < .001), high perseverance (B = 1.245, p < .001), and low persistence (B = –0.329, p < .001) predicted higher social intolerance consistently in the analyses. Discussion When developing prejudice‐reduction interventions, it should be considered that educational level or cognitive performance may not be crucial for development of social intolerance. Adopting certain cognitive styles may play more important roles in development of social intolerance.

Strip-cutting management has been proposed as an alternative to clear-cuts in drained boreal peatland pine (Pinus sylvestris L.) forests. We explored the hydrological feasibility of strip cutting, that is, under which conditions the post-harvest water table (WT) in peat remains sufficiently deep (here, a WT of −0.35 m during the late growing season) to enable undisturbed tree growth. We approached the question by (1) measuring the WTs in a harvested strip and an adjacent unharvested stand in peatland forests in southern Finland and (2) by simulating the WTs in different strip cut layouts, unharvested peatland, and clear-cut cases using a process-based hydrological model. The measured WTs were, on average, 0.06–0.12 m closer to the peat surface in the harvested strips than in the unharvested stands. The hydrological feasibility of strip cutting increased along with increasing site productivity and improving climate conditions. Strip cutting resulted in the rise in the WTs of adjacent unharvested stands, which can have undesired consequences. Depending on the stand density and strip cut layout, the share of the well-drained area in the harvested strips was slightly larger or even two times larger compared to a complete clear-cut of the forest. Narrow strips (here, 13 m in width) indicated better drainage in the harvested area than wider (20–30 m in width) strips. Even though strip cutting has limited capacity to maintain efficient drainage in the harvested strip on low hydraulic conductivity peat, the increase in the WT was smaller than after clear-cut.

Background Acute abdominal pain is one of the most frequent complaints evaluated at emergency departments. Approximately 25 % of abdominal pain patients discharged from emergency departments are diagnosed with undifferentiated abdominal pain. One possible reason for acute abdominal pain is renal infarction. Diagnosis is difficult and often late. Case presentation A white, 33-year-old, previously healthy Finnish man came to our emergency department because of acute abdominal pain. After evaluation and follow-up he was discharged the next day with a diagnosis of undifferentiated abdominal pain. He returned a day later and was diagnosed with renal infarction. Appropriate therapy was initiated in the nephrology ward. Further tests confirmed a diagnosis of renal infarction as a result of fibromuscular dysplasia. He recovered well and was discharged on the tenth day of hospitalization. His renal function was normal. Conclusions Renal infarction is rare and should be considered if a patient with intense flank pain has no sign of urolithiasis or pyelonephritis. Contrast-enhanced computer tomography and assay of lactate dehydrogenase are recommended. The optimal treatment is still uncertain. Every patient discharged with undifferentiated abdominal pain should be given clear instructions as to when it is necessary to return to the emergency department.