Fibroblast growth factor 2 decreases bleomycin‐induced pulmonary fibrosis and inhibits fibroblast collagen production and myofibroblast differentiation

Fibroblast growth factor (FGF) signaling has been implicated in the pathogenesis of pulmonary fibrosis. Mice lacking FGF2 have increased mortality and impaired epithelial recovery after bleomycin exposure, supporting a protective or reparative function following lung injury. To determine whether FGF2 overexpression reduces bleomycin‐induced injury, we developed an inducible genetic system to express FGF2 in type II pneumocytes. Double‐transgenic (DTG) mice with doxycycline‐inducible overexpression of human FGF2 (SPC‐rtTA;TRE‐hFGF2) or single‐transgenic controls were administered intratracheal bleomycin and fed doxycycline chow, starting at either day 0 or day 7. In addition, wild‐type mice received intratracheal or intravenous recombinant FGF2, starting at the time of bleomycin treatment. Compared to controls, doxycycline‐induced DTG mice had decreased pulmonary fibrosis 21 days after bleomycin, as assessed by gene expression and histology. This beneficial effect was seen when FGF2 overexpression was induced at day 0 or day 7 after bleomycin. FGF2 overexpression did not alter epithelial gene expression, bronchoalveolar lavage cellularity or total protein. In vitro studies using primary mouse and human lung fibroblasts showed that FGF2 strongly inhibited baseline and TGFβ1‐induced expression of alpha smooth muscle actin (αSMA), collagen, and connective tissue growth factor. While FGF2 did not suppress phosphorylation of Smad2 or Smad‐dependent gene expression, FGF2 inhibited TGFβ1‐induced stress fiber formation and serum response factor‐dependent gene expression. FGF2 inhibition of stress fiber formation and αSMA requires FGF receptor 1 (FGFR1) and downstream MEK/ERK, but not AKT signaling. In summary, overexpression of FGF2 protects against bleomycin‐induced pulmonary fibrosis in vivo and reverses TGFβ1‐induced collagen and αSMA expression and stress fiber formation in lung fibroblasts in vitro, without affecting either inflammation or epithelial gene expression. Our results suggest that in the lung, FGF2 is antifibrotic in part through decreased collagen expression and fibroblast to myofibroblast differentiation. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

A case of back pain associated with neurology in a young man

Background  

We present the case of a 14-year-old with a 3-month history of back pain, who on presentation, was demonstrated to have neurological signs.     

Minor physical anomalies across ethnic groups in a first episode psychosis sample

Minor physical anomalies (MPAs) are more prevalent amongst individuals with psychosis, supporting a neurodevelopmental model for psychotic disorders. The aim of this study was to investigate the possibility that neurodevelopmental adversity contributes to the excess of psychosis found in some ethnic groups in the UK. Subjects with first onset psychosis and healthy neighbourhood controls were enrolled in the AESOP study in South East London and Nottingham between 1997 and 1999. MPA rates were estimated in four broad ethnic groupings (White, African Caribbean, Black African and Other). Patients (n=245) had a higher mean total MPA score than healthy controls (n=158). This held true across each of the four ethnic groupings. The results of this study suggest that neurodevelopmental factors play a role in the aetiology of psychosis across all ethnic groups.     

Sex hormone status may modulate rate of expansion of proximal femur diameter in older women alongside other skeletal regulators

CONTEXT: Little is known of associations between hip geometry and skeletal regulators. This is important because geometry is a determinant of both hip function and resistance to fracture. OBJECTIVE: We aimed to determine the effects of sex hormone status and other candidate regulators on hip geometry and strength. SUBJECTS AND METHODS: A random sample of 351 women aged 67-79 had two to four hip dual-energy x-ray absorptiometry scans performed over 8 yr of follow-up. Hip structural analysis software was used to measure subperiosteal diameter (PD) and the distance from the center of mass to the lateral cortical margin (d-lat) on three 5-mm-thick cross-sectional regions: narrow neck, intertrochanter, and shaft. Section modulus (Z), bone mineral density (grams per centimeter squared), and an index of bone mineral content (cross-sectional area) were calculated as estimators of bone strength. Serum analytes measured at baseline included SHBG, estradiol, PTH, creatinine, albumin, vitamin D metabolites, and glutamate- and gamma-carboxyglutamate-osteocalcin (OC). A linear mixed model was used to model associations with predictor variables, including testing whether the predictors significantly modified the effect of aging. RESULTS: Aging was associated with increasing PD and d-lat, and higher baseline SHBG significantly modified this effect, in the case of PD, increasing the rates of change at the narrow neck region by 19% for SHBG level 2 sd higher than population mean (P = 0.026). Higher baseline creatinine was independently associated with faster increases in PD and d-lat with aging (P < 0.041). Z declined faster with aging if baseline PTH was higher, and higher albumin had a contrary effect. Z was positively associated with free estradiol and inversely associated with SHBG and glutamate-OC. CONCLUSION: These results show large effects of SHBG on the regulation of proximal femur expansion and bending resistance, probably acting as a surrogate for low bioavailable estrogen. Potentially important effects for fracture resistance in old age were also revealed for PTH, markers related to renal function and the nutritional markers albumin and undercarboxylated OC.     

Is functional decline necessary for a diagnosis of Alzheimer's disease?

BACKGROUND: The purpose of this study is to examine baseline differences and annualized cognitive and functional change scores in mild Alzheimer's disease (AD) patients with and without impaired activities of daily living (ADL). METHODS: We recruited 267 mild probable AD patients with at least 1 year of follow-up (NINCDS-ADRDA criteria, MMSE>or=20). Based on initial ADL scores, they were divided into 2 groups: unimpaired (n=40) and impaired (n=227). We compared the differences in annualized change scores on MMSE, Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), ADL and Clinical Dementia Rating sum of box score (CDR-SB) for patients with and without functional impairment at baseline. RESULTS: The group with unimpaired ADL at baseline had a significantly shorter symptom duration (p=0.01) and better neuropsychological test scores at baseline (p<0.001) than those with impaired ADL. The annualized cognitive and functional change of each group from baseline to 1-year follow-up was not significantly different on the MMSE, ADAS-cog, CDR-SB, Physical Self-Maintenance Scale and Instrumental Activities of Daily Living. After 1 year, 56% of the initially unimpaired group and 6% of the initially impaired group reported no ADL impairment. CONCLUSIONS: Our study suggests that functional decline should not be required for the diagnosis of mild AD.     

Perceptions of disadvantage, ethnicity and psychosis

BACKGROUND: People from Black ethnic groups (African-Caribbean and Black African) are more prone to develop psychosis in Western countries. This excess might be explained by perceptions of disadvantage. AIMS: To investigate whether the higher incidence of psychosis in Black people is mediated by perceptions of disadvantage. METHOD: A population-based incidence and case-control study of first-episode psychosis (Aetiology and Ethnicity in Schizophrenia and Other Psychoses (AESOP)). A total of 482 participants answered questions about perceived disadvantage. RESULTS: Black ethnic groups had a higher incidence of psychosis (OR= 4.7, 95% CI 3.1-7.2). After controlling for religious affiliation, social class and unemployment, the association of ethnicity with psychosis was attenuated (OR=3.0, 95% CI 1.6-5.4) by perceptions of disadvantage. Participants in the Black non-psychosis group often attributed their disadvantage to racism, whereas Black people in the psychosis group attributed it to their own situation. CONCLUSIONS: Perceived disadvantage is partly associated with the excess of psychosis among Black people living in the UK. This may have implications for primary prevention.