Lifestyle choices influence 20–40 % of adult peak bone mass. Therefore, optimization of lifestyle factors known to influence peak bone mass and strength is an important strategy aimed at reducing ...risk of osteoporosis or low bone mass later in life. The National Osteoporosis Foundation has issued this scientific statement to provide evidence-based guidance and a national implementation strategy for the purpose of helping individuals achieve maximal peak bone mass early in life. In this scientific statement, we (1) report the results of an evidence-based review of the literature since 2000 on factors that influence achieving the full genetic potential for skeletal mass; (2) recommend lifestyle choices that promote maximal bone health throughout the lifespan; (3) outline a research agenda to address current gaps; and (4) identify implementation strategies. We conducted a systematic review of the role of individual nutrients, food patterns, special issues, contraceptives, and physical activity on bone mass and strength development in youth. An evidence grading system was applied to describe the strength of available evidence on these individual modifiable lifestyle factors that may (or may not) influence the development of peak bone mass (Table
1
). A summary of the grades for each of these factors is given below. We describe the underpinning biology of these relationships as well as other factors for which a systematic review approach was not possible. Articles published since 2000, all of which followed the report by Heaney et al.
1
published in that year, were considered for this scientific statement. This current review is a systematic update of the previous review conducted by the National Osteoporosis Foundation
1
.
Lifestyle Factor
Grade
Macronutrients
Fat
D
Protein
C
Micronutrients
Calcium
A
Vitamin D
B
Micronutrients other than calcium and vitamin D
D
Food Patterns
Dairy
B
Fiber
C
Fruits and vegetables
C
Detriment of cola and caffeinated beverages
C
Infant Nutrition
Duration of breastfeeding
D
Breastfeeding versus formula feeding
D
Enriched formula feeding
D
Adolescent Special Issues
Detriment of oral contraceptives
D
Detriment of DMPA injections
B
Detriment of alcohol
D
Detriment of smoking
C
Physical Activity and Exercise
Effect on bone mass and density
A
Effect on bone structural outcomes
B
Considering the evidence-based literature review, we recommend lifestyle choices that promote maximal bone health from childhood through young to late adolescence and outline a research agenda to address current gaps in knowledge. The best evidence (grade A) is available for positive effects of calcium intake and physical activity, especially during the late childhood and peripubertal years—a critical period for bone accretion. Good evidence is also available for a role of vitamin D and dairy consumption and a detriment of DMPA injections. However, more rigorous trial data on many other lifestyle choices are needed and this need is outlined in our research agenda. Implementation strategies for lifestyle modifications to promote development of peak bone mass and strength within one’s genetic potential require a multisectored (i.e., family, schools, healthcare systems) approach.
Correction of Fragile X Syndrome in Mice Dölen, Gül; Osterweil, Emily; Rao, B.S. Shankaranarayana ...
Neuron (Cambridge, Mass.),
12/2007, Letnik:
56, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Fragile X syndrome (FXS) is the most common form of heritable mental retardation and the leading identified cause of autism. FXS is caused by transcriptional silencing of the
FMR1 gene that encodes ...the fragile X mental retardation protein (FMRP), but the pathogenesis of the disease is unknown. According to one proposal, many psychiatric and neurological symptoms of FXS result from unchecked activation of mGluR5, a metabotropic glutamate receptor. To test this idea we generated
Fmr1 mutant mice with a 50% reduction in mGluR5 expression and studied a range of phenotypes with relevance to the human disorder. Our results demonstrate that mGluR5 contributes significantly to the pathogenesis of the disease, a finding that has significant therapeutic implications for fragile X and related developmental disorders.
Summary Background Anti-NMDA receptor (NMDAR) encephalitis is an autoimmune disorder in which the use of immunotherapy and the long-term outcome have not been defined. We aimed to assess the ...presentation of the disease, the spectrum of symptoms, immunotherapies used, timing of improvement, and long-term outcome. Methods In this multi-institutional observational study, we tested for the presence of NMDAR antibodies in serum or CSF samples of patients with encephalitis between Jan 1, 2007, and Jan 1, 2012. All patients who tested positive for NMDAR antibodies were included in the study; patients were assessed at symptom onset and at months 4, 8, 12, 18, and 24, by use of the modified Rankin scale (mRS). Treatment included first-line immunotherapy (steroids, intravenous immunoglobulin, plasmapheresis), second-line immunotherapy (rituximab, cyclophosphamide), and tumour removal. Predictors of outcome were determined at the Universities of Pennsylvania (PA, USA) and Barcelona (Spain) by use of a generalised linear mixed model with binary distribution. Results We enrolled 577 patients (median age 21 years, range 8 months to 85 years), 211 of whom were children (<18 years). Treatment effects and outcome were assessable in 501 (median follow-up 24 months, range 4–186): 472 (94%) underwent first-line immunotherapy or tumour removal, resulting in improvement within 4 weeks in 251 (53%). Of 221 patients who did not improve with first-line treatment, 125 (57%) received second-line immunotherapy that resulted in a better outcome (mRS 0–2) than those who did not (odds ratio OR 2·69, CI 1·24–5·80; p=0·012). During the first 24 months, 394 of 501 patients achieved a good outcome (mRS 0–2; median 6 months, IQR 2–12) and 30 died. At 24 months’ follow-up, 203 (81%) of 252 patients had good outcome. Outcomes continued to improve for up to 18 months after symptom onset. Predictors of good outcome were early treatment (0·62, 0·50–0·76; p<0·0001) and no admission to an intensive care unit (0·12, 0·06–0·22; p<0·0001). 45 patients had one or multiple relapses (representing a 12% risk within 2 years); 46 (67%) of 69 relapses were less severe than initial episodes (p<0·0001). In 177 children, predictors of good outcome and the magnitude of effect of second-line immunotherapy were similar to those of the entire cohort. Interpretation Most patients with anti-NMDAR encephalitis respond to immunotherapy. Second-line immunotherapy is usually effective when first-line treatments fail. In this cohort, the recovery of some patients took up to 18 months. Funding The Dutch Cancer Society, the National Institutes of Health, the McKnight Neuroscience of Brain Disorders award, The Fondo de Investigaciones Sanitarias, and Fundació la Marató de TV3.
The functional and molecular similarities and distinctions between human and murine astrocytes are poorly understood. Here, we report the development of an immunopanning method to acutely purify ...astrocytes from fetal, juvenile, and adult human brains and to maintain these cells in serum-free cultures. We found that human astrocytes have abilities similar to those of murine astrocytes in promoting neuronal survival, inducing functional synapse formation, and engulfing synaptosomes. In contrast to existing observations in mice, we found that mature human astrocytes respond robustly to glutamate. Next, we performed RNA sequencing of healthy human astrocytes along with astrocytes from epileptic and tumor foci and compared these to human neurons, oligodendrocytes, microglia, and endothelial cells (available at http://www.brainrnaseq.org). With these profiles, we identified novel human-specific astrocyte genes and discovered a transcriptome-wide transformation between astrocyte precursor cells and mature post-mitotic astrocytes. These data represent some of the first cell-type-specific molecular profiles of the healthy and diseased human brain.
•We develop the first method to acutely purify fetal and adult human astrocytes•We obtain transcriptome profiles of human neurons, glia, and vascular cells•While similar, human and mouse astrocytes have unique genomic and functional traits•Human astrocytes exist in at least two distinct developmental stages
Zhang et al. developed a method to acutely purify healthy and diseased human astrocytes and to culture them in serum-free conditions. They obtained transcriptome profiles of purified human CNS cell types and discovered two distinct stages of human astrocyte development.
Summary Background A severe form of encephalitis associated with antibodies against NR1–NR2 heteromers of the NMDA receptor was recently identified. We aimed to analyse the clinical and immunological ...features of patients with the disorder and examine the effects of antibodies against NMDA receptors in neuronal cultures. Methods We describe the clinical characteristics of 100 patients with encephalitis and NR1–NR2 antibodies. HEK293 cells ectopically expressing single or assembled NR1–NR2 subunits were used to determine the epitope targeted by the antibodies. Antibody titres were measured with ELISA. The effect of antibodies on neuronal cultures was determined by quantitative analysis of NMDA-receptor clusters. Findings Median age of patients was 23 years (range 5–76 years); 91 were women. All patients presented with psychiatric symptoms or memory problems; 76 had seizures, 88 unresponsiveness (decreased conciousness), 86 dyskinesias, 69 autonomic instability, and 66 hypoventilation. 58 (59%) of 98 patients for whom results of oncological assessments were available had tumours, most commonly ovarian teratoma. Patients who received early tumour treatment (usually with immunotherapy) had better outcome (p=0·004) and fewer neurological relapses (p=0·009) than the rest of the patients. 75 patients recovered or had mild deficits and 25 had severe deficits or died. Improvement was associated with a decrease of serum antibody titres. The main epitope targeted by the antibodies is in the extracellular N-terminal domain of the NR1 subunit. Patients' antibodies decreased the numbers of cell-surface NMDA receptors and NMDA-receptor clusters in postsynaptic dendrites, an effect that could be reversed by antibody removal. Interpretation A well-defined set of clinical characteristics are associated with anti-NMDA-receptor encephalitis. The pathogenesis of the disorder seems to be mediated by antibodies. Funding National Institutes for Health, University of Pennsylvania Institute for Translational Medicine, Lankenau Institute for Medical Research, Foederer Foundation of the Children's Hospital of Philadelphia.
Diffuse intrinsic pontine gliomas (DIPGs) are highly aggressive tumors of childhood that are almost universally fatal. Our understanding of this devastating cancer is limited by a dearth of available ...tissue for study and by the lack of a faithful animal model. Intriguingly, DIPGs are restricted to the ventral pons and occur during a narrow window of middle childhood, suggesting dysregulation of a postnatal neurodevelopmental process. Here, we report the identification of a previously undescribed population of immunophenotypic neural precursor cells in the human and murine brainstem whose temporal and spatial distributions correlate closely with the incidence of DIPG and highlight a candidate cell of origin. Using early postmortem DIPG tumor tissue, we have established in vitro and xenograft models and find that the Hedgehog (Hh) signaling pathway implicated in many developmental and oncogenic processes is active in DIPG tumor cells. Modulation of Hh pathway activity has functional consequences for DIPG self-renewal capacity in neurosphere culture. The Hh pathway also appears to be active in normal ventral pontine precursor-like cells of the mouse, and unregulated pathway activity results in hypertrophy of the ventral pons. Together, these findings provide a foundation for understanding the cellular and molecular origins of DIPG, and suggest that the Hh pathway represents a potential therapeutic target in this devastating pediatric tumor.
Background: Chemotherapy with a platinum agent and a taxane (paclitaxel) is considered the standard of care for treatment of ovarian carcinoma. We compared the combination of docetaxel–carboplatin ...with the combination of paclitaxel–carboplatin as first-line chemotherapy for stage Ic–IV epithelial ovarian or primary peritoneal cancer. Methods: We randomly assigned 1077 patients to receive docetaxel at 75 mg/m2 of body surface area (1-hour intravenous infusion) or paclitaxel at 175 mg/m2 (3-hour intravenous infusion). Both treatments then were followed by carboplatin to an area under the plasma concentration–time curve of 5. The treatments were repeated every 3 weeks for six cycles; in responding patients, an additional three cycles of single-agent carboplatin was permitted. Survival curves were calculated by the Kaplan–Meier method, and hazard ratios were estimated with the Cox proportional hazards model. All statistical tests were two-sided. Results: After a median follow-up of 23 months, both groups had similar progression-free survival (medians of 15.0 months for docetaxel–carboplatin and 14.8 months for paclitaxel–carboplatin; hazard ratio HR docetaxel–paclitaxel = 0.97, 95% confidence interval CI = 0.83 to 1.13; P = .707), overall survival rates at 2 years (64.2% and 68.9%, respectively; HR = 1.13, 95% CI = 0.92 to 1.39; P = .238), and objective tumor (58.7% and 59.5%, respectively; difference between docetaxel and paclitaxel = –0.8%, 95% CI = –8.6% to 7.1%; P = .868) and CA-125 (75.8% and 76.8%, respectively; difference docetaxel–paclitaxel = –1.0%, 95% CI = –7.2% to 5.1%; P = .794) response rates. However, docetaxel–carboplatin was associated with substantially less overall and grade 2 or higher neurotoxicity than paclitaxel–carboplatin (grade ≥2 neurosensory toxicity in 11% versus 30%, difference = 19%, 95% CI = 15% to 24%; P<.001; grade ≥2 neuromotor toxicity in 3% versus 7%, difference = 4%, 95% CI = 1% to 7%; P<.001). Treatment with docetaxel–carboplatin was associated with statistically significantly more grade 3–4 neutropenia (94% versus 84%, difference = 11%, 95% CI = 7% to 14%; P<.001) and neutropenic complications than treatment with paclitaxel–carboplatin, although myelosuppression did not influence dose delivery or patient safety. Global quality of life was similar in both arms, but substantive differences in many symptom scores favored docetaxel. Conclusions: Docetaxel–carboplatin appears to be similar to paclitaxel–carboplatin in terms of progression-free survival and response, although longer follow-up is required for a definitive statement on survival. Thus, docetaxel–carboplatin represents an alternative first-line chemotherapy regimen for patients with newly diagnosed ovarian cancer.
Aims
To understand the role of comorbid substance use disorders (SUDs), or polysubstance use, in the treatment of opioid use disorder (OUD), this study compared patients with OUD only to those with ...additional SUDs and examined association with OUD treatment receipt.
Design, setting and participants
Retrospective national cohort study of Veterans diagnosed with OUD (n = 65 741) receiving care from the US Veterans Health Administration (VHA) in fiscal year (FY) 2017.
Measurements
Patient characteristics were compared among those diagnosed with OUD only versus those with one other SUD (OUD + 1 SUD) and with multiple SUDs (OUD + ≥ 2 SUDs). The study examined the relationship between comorbid SUDs and receipt of buprenorphine, methadone and SUD outpatient treatment during 1‐year follow‐up, adjusting for patient demographic characteristics and clinical conditions.
Findings
Among the 65 741 Veterans with OUD in FY 2017, 41.2% had OUD only, 22.9% had OUD + 1 SUD and 35.9% had OUD + ≥ 2 SUDs. Common comorbid SUDs included alcohol use disorder (41.3%), cocaine/stimulant use disorder (30.0%) and cannabis use disorder (22.4%). Adjusting for patient characteristics, patients with OUD + 1 SUD adjusted odds ratio (aOR) = 0.87, 95% confidence interval (CI) = 0.82–0.93 and patients with OUD +≥ 2 SUDs (aOR = 0.65, 95% CI = 0.61–0.69) had lower odds of receiving buprenorphine compared with OUD only patients. There were also lower odds of receiving methadone for patients with OUD + 1 SUD (aOR = 0.91, 95% CI = 0.86–0.97)and for those with OUD + ≥2 SUDs (aOR = 0.79, 95% CI = 0.74–0.84). Patients with OUD + 1 SUD (aOR = 1.85, 95% CI = 1.77–1.93) and patients with OUD + ≥2 SUDs (aOR = 3.25, 95% CI = 3.103.41) were much more likely to have a SUD clinic visit.
Conclusions
The majority of Veterans in the US Veterans Health Administration diagnosed with opioid use disorder appeared to have at least one comorbid substance use disorder and many have multiple substance use disorders. Despite the higher likelihood of a substance use disorder clinic visit, having a non‐opioid substance use disorder is associated with lower likelihood of buprenorphine treatment, suggesting the importance of addressing polysubstance use within efforts to expand treatment for opioid use disorder.
Background Atopic diseases, including asthma, exacerbate type 2 immune responses and involve a number of immune cell types, including regulatory T (Treg) cells and the emerging type 2 innate lymphoid ...cells (ILC2s). Although ILC2s are potent producers of type 2 cytokines, the regulation of ILC2 activation and function is not well understood. Objective In the present study, for the first time, we evaluate how Treg cells interact with pulmonary ILC2s and control their function. Methods ILC2s and Treg cells were evaluated by using in vitro suppression assays, cell-contact assays, and gene expression panels. Also, human ILC2s and Treg cells were adoptively transferred into NOD SCID γC-deficient mice, which were given isotype or anti–inducible T-cell costimulator ligand (ICOSL) antibodies and then challenged with IL-33 and assessed for airway hyperreactivity. Results We show that induced Treg cells, but not natural Treg cells, effectively suppress the production of the ILC2-driven proinflammatory cytokines IL-5 and IL-13 both in vitro and in vivo . Mechanistically, our data reveal the necessity of inducible T-cell costimulator (ICOS)–ICOS ligand cell contact for Treg cell–mediated ILC2 suppression alongside the suppressive cytokines TGF-β and IL-10. Using a translational approach, we then demonstrate that human induced Treg cells suppress syngeneic human ILC2s through ICOSL to control airway inflammation in a humanized ILC2 mouse model. Conclusion These findings suggest that peripheral expansion of induced Treg cells can serve as a promising therapeutic target against ILC2-dependent asthma.
PDF
