Migraine is a complex neurovascular disorder that is one of the leading causes of disability and a reduced quality of life. Even with such a high societal impact, our understanding of the cellular ...and molecular mechanisms that contribute to migraine headaches is limited. To address this complex disorder, several groups have performed genome-wide association studies to elucidate migraine susceptibility genes, with many identifying transient receptor potential melastatin 8 (TRPM8), a cold-sensitive cation channel expressed in peripheral afferents innervating the trigeminovascular system, and the principal mediator of cold and cold pain associated with injury and disease. Interestingly, these migraine-associated single-nucleotide polymorphisms reside in noncoding regions of TRPM8, with those correlated with reduced migraine risk exhibiting lower TRPM8 expression and decreased cold sensitivity. Nonetheless, as a role for TRPM8 in migraine has yet to be defined, we sought to address this gap in our knowledge using mouse genetics and TRPM8 antagonism to determine whether TRPM8 channels or neurons are required for migraine-like pain (mechanical allodynia and facial grimace) in inducible migraine models. Our results show that both evoked and spontaneous pain behaviors are dependent on both TRPM8 channels and neurons, as well as required in both acute and chronic migraine models. Moreover, inhibition of TRPM8 channels prevented acute but not established chronic migraine-like pain. These results are consistent with its association with migraine in genetic analyses and establish that TRPM8 channels are a component of the underlying mechanisms of migraine.
Mucosal Vaccine Design and Delivery Woodrow, Kim A; Bennett, Kaila M; Lo, David D
Annual review of biomedical engineering,
08/2012, Letnik:
14, Številka:
1
Journal Article
Recenzirano
Mucosal surfaces are a major portal of entry for many human pathogens that are the cause of infectious diseases worldwide. Vaccines capable of eliciting mucosal immune responses can fortify defenses ...at mucosal front lines and protect against infection. However, most licensed vaccines are administered parenterally and fail to elicit protective mucosal immunity. Immunization by mucosal routes may be more effective at inducing protective immunity against mucosal pathogens at their sites of entry. Recent advances in our understanding of mucosal immunity and identification of correlates of protective immunity against specific mucosal pathogens have renewed interest in the development of mucosal vaccines. Efforts have focused on efficient delivery of vaccine antigens to mucosal sites that facilitate uptake by local antigen-presenting cells to generate protective mucosal immune responses. Discovery of safe and effective mucosal adjuvants are also being sought to enhance the magnitude and quality of the protective immune response.
Few studies have assessed U.S. cardiometabolic health trends—optimal levels of multiple risk factors and absence of clinical cardiovascular disease (CVD)—or its impact on health disparities.
The ...purpose of this study was to investigate U.S. trends in optimal cardiometabolic health from 1999 to 2018.
We assessed proportions of adults with optimal cardiometabolic health, based on adiposity, blood glucose, blood lipids, blood pressure, and clinical CVD; and optimal, intermediate, and poor levels of each component among 55,081 U.S. adults in the National Health and Nutrition Examination Survey.
In 2017-2018, only 6.8% (95% CI: 5.4%-8.1%) of U.S. adults had optimal cardiometabolic health, declining from 1999-2000 (P trend = 0.02). Among components of cardiometabolic health, the largest declines were for adiposity (optimal levels: from 33.8% to 24.0%; poor levels: 47.7% to 61.9%) and glucose (optimal levels: 59.4% to 36.9%; poor levels: 8.6% to 13.7%) (P trend <0.001 for each). Optimal levels of blood lipids increased from 29.9% to 37.0%, whereas poor decreased from 28.3% to 14.7% (P trend <0.001). Trends over time for blood pressure and CVD were smaller. Disparities by age, sex, education, and race/ethnicity were evident in all years, and generally worsened over time. By 2017-2018, prevalence of optimal cardiometabolic health was lower among Americans with lower (5.0% 95% CI: 2.8%-7.2%) vs higher education (10.3% 95% CI: 7.6%-13.0%); and among Mexican American (3.2% 95% CI: 1.4%-4.9%) vs non-Hispanic White (8.4% 95% CI: 6.3%-10.4%) adults.
Between 1999 and 2000 and 2017 and 2018, U.S. cardiometabolic health has been poor and worsening, with only 6.8% of adults having optimal cardiometabolic health, and disparities by age, sex, education, and race/ethnicity. These novel findings inform the need for nationwide clinical and public health interventions to improve cardiometabolic health and health equity.
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To determine whether silastic ring laparoscopic Roux-en-Y gastric bypass (SR-LRYGB) or laparoscopic sleeve gastrectomy (LSG) produces superior diabetes remission at 5 years.
In a single-center, ...double-blind trial, 114 adults with type 2 diabetes and BMI 35-65 kg/m2 were randomly assigned to SR-LRYGB or LSG (1:1; stratified by age-group, BMI group, ethnicity, diabetes duration, and insulin therapy) using a web-based service. Diabetes and other metabolic medications were adjusted according to a prespecified protocol. The primary outcome was diabetes remission assessed at 5 years, defined by HbA1c <6% (42 mmol/mol) without glucose-lowering medications. Secondary outcomes included changes in weight, cardiometabolic risk factors, quality of life, and adverse events.
Diabetes remission after SR-LRYGB versus LSG occurred in 25 (47%) of 53 vs. 18 (33%) of 55 patients (adjusted odds ratios 4.5 95% CI 1.6, 15.5; P = 0.009 and 4.2 1.3, 13.4; P = 0.015 in the intention-to-treat analysis). Percent body weight loss was greater after SR-LRYGB than after LSG (absolute difference 10.7%; 95% CI 7.3, 14.0; P < 0.001). Improvements in cardiometabolic risk factors were similar, but HDL cholesterol increased more after SR-LRYGB. Early and late complications were similar in both groups. General health and physical functioning improved after both types of surgery, with greater improvement in physical functioning after SR-LRYGB. People of Māori or Pacific ethnicity (26%) had lower incidence of diabetes remission than those of New Zealand European or other ethnicities (2 of 25 vs. 41 of 83; P < 0.001).
SR-LRYGB provided superior diabetes remission and weight loss compared with LSG at 5 years, with similar low risks of complications.
The extraordinary demands of managing the COVID-19 pandemic has disrupted the world’s ability to care for patients with thoracic malignancies. As a hospital’s COVID-19 population increases and ...hospital resources are depleted, the ability to provide surgical care is progressively restricted, forcing surgeons to prioritize among their cancer populations. Representatives from multiple cancer, surgical, and research organizations have come together to provide a guide for triaging patients with thoracic malignancies as the impact of COVID-19 evolves as each hospital.
Medicare could soon be compelled to cover antiobesity medications, which intensifies the need to address questions of effectiveness and cost among its beneficiaries.
Neonatal cholestasis is a potentially life-threatening condition requiring prompt diagnosis. Mutations in several different genes can cause progressive familial intrahepatic cholestasis, but known ...genes cannot account for all familial cases. Here we report four individuals from two unrelated families with neonatal cholestasis and mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism. Clinical features of severe, persistent NR1H4-related cholestasis include neonatal onset with rapid progression to end-stage liver disease, vitamin K-independent coagulopathy, low-to-normal serum gamma-glutamyl transferase activity, elevated serum alpha-fetoprotein and undetectable liver bile salt export pump (ABCB11) expression. Our findings demonstrate a pivotal function for FXR in bile acid homeostasis and liver protection.
Long acting injectable (LAI) antipsychotics are an alternative to oral antipsychotic (OAP) treatment and may be beneficial for patients in the early stages of schizophrenia. This study aims to ...provide a comprehensive review on the efficacy of first-generation and second-generation LAI antipsychotics in recent-onset, first-episode, and early psychosis patients.
MEDLINE, EMBASE, PsycINFO, and Web of Science Core databases were used to search for studies that used LAIs in early psychosis patients. Studies published up to 06 Jun 2019 were included with no language restrictions applied. Inclusion criteria were a diagnosis of schizophrenia or related disorder, where patients were in their first episode or had a duration of illness ≤5 years.
33 studies were included: 8 RCTs, 4 post-hoc analyses, 2 case reports, and 19 naturalistic studies. The majority of studies evaluated risperidone LAIs (N = 14) and paliperidone palmitate (N = 10), while the remainder investigated fluphenazine decanoate (N = 3), flupentixol decanoate (N = 2), and aripiprazole (N = 1). Two studies did not specify the LAI formulation used, and one cohort study compared the efficacy of multiple different LAI formulations.
While the majority of data is based on naturalistic studies investigating risperidone LAIs or paliperidone palmitate, LAIs may be an effective treatment for early psychosis patients in terms of adherence, relapse reduction, and symptom improvements. There is still a need to conduct more high quality RCTs that investigate the efficacy of different LAI formulations in early psychosis patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The spatial presentation of mechanical information is a key parameter for cell behavior. We have developed a method of polymerization control in which the differential diffusion distance of unreacted ...cross-linker and monomer into a prepolymerized hydrogel sink results in a tunable stiffness gradient at the cell–matrix interface. This simple, low-cost, robust method was used to produce polyacrylamide hydrogels with stiffness gradients of 0.5, 1.7, 2.9, 4.5, 6.8, and 8.2 kPa/mm, spanning the in vivo physiological and pathological mechanical landscape. Importantly, three of these gradients were found to be nondurotactic for human adipose-derived stem cells (hASCs), allowing the presentation of a continuous range of stiffnesses in a single well without the confounding effect of differential cell migration. Using these nondurotactic gradient gels, stiffness-dependent hASC morphology, migration, and differentiation were studied. Finally, the mechanosensitive proteins YAP, Lamin A/C, Lamin B, MRTF-A, and MRTF-B were analyzed on these gradients, providing higher-resolution data on stiffness-dependent expression and localization.
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