Climate change is today's news, but it isn't a new phenomenon. Centuries-long cycles of heating and cooling are well documented for Europe and the North Atlantic. These variations in climate, ...including the Medieval Warm Period (MWP), AD 900 to 1300, and the early centuries of the Little Ice Age (LIA), AD 1300 to 1600, had a substantial impact on the cultural history of Europe. In this pathfinding volume, William C. Foster marshals extensive evidence that the heating and cooling of the MWP and LIA also occurred in North America and significantly affected the cultural history of Native peoples of the American Southwest, Southern Plains, and Southeast.
Correlating climate change data with studies of archaeological sites across the Southwest, Southern Plains, and Southeast, Foster presents the first comprehensive overview of how Native American societies responded to climate variations over seven centuries. He describes how, as in Europe, the MWP ushered in a cultural renaissance, during which population levels surged and Native peoples substantially intensified agriculture, constructed monumental architecture, and produced sophisticated works of art. Foster follows the rise of three dominant cultural centers-Chaco Canyon in New Mexico, Cahokia on the middle Mississippi River, and Casas Grandes in northwestern Chihuahua, Mexico-that reached population levels comparable to those of London and Paris. Then he shows how the LIA reversed the gains of the MWP as population levels and agricultural production sharply declined; Chaco Canyon, Cahokia, and Casas Grandes collapsed; and dozens of smaller villages also collapsed or became fortresses.
Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, exhibited promising activity in a proof-of-concept study when administered in intravenous (IV) doses to patients with active, ...chronic, noninfectious uveitis. This study compared the efficacy and safety of different IV and subcutaneous (SC) doses of secukinumab in patients with noninfectious uveitis.
Multicenter, randomized, double-masked, dose-ranging, phase 2 clinical trial.
Thirty-seven patients with active noninfectious intermediate uveitis, posterior uveitis, or panuveitis who required corticosteroid-sparing immunosuppressive therapy.
Patients were randomized to secukinumab 300 mg SC every 2 weeks for 4 doses, secukinumab 10 mg/kg IV every 2 weeks for 4 doses, or secukinumab 30 mg/kg IV every 4 weeks for 2 doses. Intravenous or SC saline was administered to maintain masking. Efficacy was assessed on day 57 (2-4 weeks after last dose).
Percentage of patients with treatment response, defined as (1) at least a 2-grade reduction in vitreous haze score or trace or absent vitreous haze in the study eye without an increase in corticosteroid dose and without uveitis worsening or (2) reduction in corticosteroid dosages to prespecified levels without uveitis worsening. Percentage of patients with remission, defined as anterior chamber cell and vitreous haze scores of 0 or 0.5+ in both eyes without corticosteroid therapy or uveitis worsening.
Secukinumab 30 mg/kg IV and 10 mg/kg IV, compared with the 300 mg SC dose, produced higher responder rates (72.7% and 61.5% vs. 33.3%, respectively) and remission rates (27.3% and 38.5% vs. 16.7%, respectively). Statistical and clinical superiority for the 30 mg/kg IV dose compared with the 300 mg SC dose was established in a Bayesian probability model. Other measures, including time to response onset, change in visual acuity, and change in vitreous haze score, showed numeric trends favoring IV dosing. Secukinumab, administered in IV or SC formulations, appeared safe and was well tolerated.
Intravenous secukinumab was effective and well tolerated in noninfectious uveitis requiring systemic corticosteroid-sparing immunosuppressive therapy. Greater activity with IV dosing suggests that patients may not receive sufficient drug with SC administration. High-dose IV secukinumab may be necessary to deliver secukinumab in therapeutic concentrations.
In humans, heterogeneity in the decline of hippocampal-dependent episodic memory is observed during aging. Rodents have been employed as models of age-related cognitive decline and the spatial water ...maze has been used to show variability in the emergence and extent of impaired hippocampal-dependent memory. Impairment in the consolidation of intermediate-term memory for rapidly acquired and flexible spatial information emerges early, in middle-age. As aging proceeds, deficits may broaden to include impaired incremental learning of a spatial reference memory. The extent and time course of impairment has been be linked to senescence of calcium (Ca²⁺) regulation and Ca²⁺-dependent synaptic plasticity mechanisms in region CA1. Specifically, aging is associated with altered function of N-methyl-D-aspartate receptors (NMDARs), voltage-dependent Ca²⁺ channels (VDCCs), and ryanodine receptors (RyRs) linked to intracellular Ca²⁺ stores (ICS). In young animals, NMDAR activation induces long-term potentiation of synaptic transmission (NMDAR-LTP), which is thought to mediate the rapid consolidation of intermediate-term memory. Oxidative stress, starting in middle-age, reduces NMDAR function. In addition, VDCCs and ICS can actively inhibit NMDAR-dependent LTP and oxidative stress enhances the role of VDCC and RyR-ICS in regulating synaptic plasticity. Blockade of L-type VDCCs promotes NMDAR-LTP and memory in older animals. Interestingly, pharmacological or genetic manipulations to reduce hippocampal NMDAR function readily impair memory consolidation or rapid learning, generally leaving incremental learning intact. Finally, evidence is mounting to indicate a role for VDCC-dependent synaptic plasticity in associative learning and the consolidation of remote memories. Thus, VDCC-dependent synaptic plasticity and extrahippocampal systems may contribute to incremental learning deficits observed with advanced aging.
Long-term side effects of glucocorticoids Oray, Merih; Abu Samra, Khawla; Ebrahimiadib, Nazanin ...
Expert opinion on drug safety,
04/2016, Letnik:
15, Številka:
4
Journal Article
Recenzirano
Glucocorticoids represent the standard therapy for reducing inflammation and immune activation in various diseases. However, as with any potent medication, they are not without side effects. ...Glucocorticoid-associated side effects may involve most major organ systems. Musculoskeletal, gastrointestinal, cardiovascular, endocrine, neuropsychiatric, dermatologic, ocular, and immunologic side effects are all possible.
This article analyzes English-language literature and provides an update on the most recent literature regarding side effects of systemic glucocorticoid treatment.
The risk/benefit ratio of glucocorticoid therapy can be improved by proper use. Careful monitoring and using appropriate preventive strategies can potentially minimize side effects.
Systemic lupus erythematosus (SLE) can involve many parts of the eye, including the eyelid, ocular adnexa, sclera, cornea, uvea, retina and optic nerve. Ocular manifestations of SLE are common and ...may lead to permanent blindness from the underlying disease or therapeutic side effects. Keratoconjunctivitis sicca is the most common manifestation. However, vision loss may result from involvement of the retina, choroid and optic nerve. Ocular symptoms are correlated to systemic disease activity and can present as an initial manifestation of SLE. The established treatment includes prompt systemic corticosteroids, steroid-sparing immunosuppressive drugs and biological agents. Local ocular therapies are options with promising efficacy. The early recognition of disease and treatment provides reduction of visual morbidity and mortality.
Around 2 million people are living with or beyond cancer in the UK. However, experiences and needs following primary treatment are relatively neglected. Following treatment, survivors may feel ...particularly vulnerable and face threats to their identity. We present a conceptual framework to inform areas of self-management support to facilitate recovery of health and well-being following primary cancer treatment.
To explain the framework, we draw on data from two studies: UK-wide consultation about cancer patients' research priorities and survivors' self-management in the year following primary cancer treatment.
Self-confidence may be low following treatment. Recovery includes rebuilding lost confidence. Support to manage the impact of cancer on everyday life was a priority. Self-management support included health professionals, peers, employers, family, friends and online resources. However, support was not always available and confidence to access support could be low.
Cancer survivors may struggle to self-manage following primary treatment where confidence is low or support is lacking. Low confidence may be a significant barrier to accessing support. Supporting recovery of self-confidence is an important aspect of recovery alongside physical and psychosocial problems in the context of changing health care and cancer follow-up.
New predictive markers for managing prostate cancer are urgently required because of the highly variable natural history of this disease. At the time of diagnosis, Gleason score provides the gold ...standard for assessing the aggressiveness of prostate cancer. However, the recent discovery of TMPRSS2 fusions to the ERG gene in prostate cancer raises the possibility of using alterations at the ERG locus as additional mechanism-based prognostic indicators. Fluorescence in situ hybridization (FISH) assays were used to assess ERG gene status in a cohort of 445 prostate cancers from patients who had been conservatively managed. The FISH assays detected separation of 5' (labelled green) and 3' (labelled red) ERG sequences, which is a consequence of the TMPRSS2-ERG fusion, and additionally identify interstitial deletion of genomic sequences between the tandemly located TMPRSS2 and ERG gene sequences on chromosome 21. Cancers lacking ERG alterations exhibited favourable cause-specific survival (90% survival at 8 years). We identify a novel category of prostate cancers, characterized by duplication of the fusion of TMPRSS2 to ERG sequences together with interstitial deletion of sequences 5' to ERG (called '2+Edel'), which by comparison exhibited extremely poor cause-specific survival (hazard ratio=6.10, 95% confidence ratio=3.33-11.15, P<0.001, 25% survival at 8 years). In multivariate analysis, '2+Edel' provided significant prognostic information (P=0.003) in addition to that provided by Gleason score and prostate-specific antigen level at diagnosis. Other individual categories of ERG alteration were associated with intermediate or good prognosis. We conclude that determination of ERG gene status, including duplication of the fusion of TMPRSS2 to ERG sequences in 2+Edel, allows stratification of prostate cancer into distinct survival categories.
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