The NLRP3 inflammasome is a key component of the innate immune system that induces pro-inflammatory cytokine production and cell death. Although NLRP3 is activated by many pathogens, it only appears ...to be critical for host defense for a limited number of specific infections. NLRP3 is however strongly associated with the initiation and pathology of many inflammatory diseases. If NLRP3 function is largely redundant for host defense, but drives a number of inflammatory diseases, this raises the important question of why evolution has elected to maintain NLRP3 function. We propose that the primary physiological functions of NLRP3 in health are to engage pathways to clear noxious substances (e.g. protein aggregates and crystals), and to regulate metabolism. We discuss the newly identified functions for NLRP3 in metabolic homeostasis, and how NLRP3 beneficial functions in homeostasis may become detrimental during the onset of inflammatory and metabolic diseases. A common feature of most NLRP3-driven diseases is that they are associated with ageing or metabolic excess, and indeed, Nlrp3 deficiency promotes 'healthspan' in ageing mice. This suggests that beneficial functions of NLRP3 in youth may become increasingly countered by NLRP3-dependent pathology as an individual ages, and we propose a general model by which ageing or nutrient excess may provide a tipping point to switch NLRP3 function from beneficial to pathological. The physiological role of NLRP3 in healthy individuals remains incompletely understood and future research will need to address this if NLRP3 is to become a successful therapeutic target for the clinical management of inflammatory diseases.
Abstract
This study tested the hypothesis that patients with PAD have impaired health-related quality of life (HRQoL) to a degree similar to that of patients with other types of cardiovascular ...disease (other-CVD), and also evaluated the clinical features of PAD associated with impaired HRQoL. This was a cross-sectional study in 350 primary care practice sites nationwide with 6,499 participants. The reference group had no clinical or hemodynamic evidence of PAD or other-CVD; the PAD group had an ankle-brachial index < 0.90 or a prior history of PAD; the other-CVD group had a clinical history of cardiac or cerebral vascular disease (but no PAD), and the combined PAD-other-CVD group included both diagnoses. Individuals were assessed using four HRQoL questionnaires including the Walking Impairment Questionnaire (WIQ), Medical Outcomes Study SF-36 (SF-36), Cantril Ladder of Life and the PAD Quality of Life questionnaire. PAD patients had lower WIQ distance scores than the other-CVD group. Both the PAD and other-CVD groups had significantly lower SF-36 Physical Function scores compared with the reference group. The WIQ revealed that PAD patients were more limited by calf pain, whereas other-CVD patients were more limited by chest pain, shortness of breath and palpitations. In conclusion, in this nationwide study, one of the first to directly compare the HRQoL burden of CVD with that of PAD, the evaluation of PAD in office practice revealed a HRQoL burden as great in magnitude as in patients with other forms of CVD.
Off-stoichiometry Heusler ribbons with nominal compositions of Mn
50
Ni
50−x
(Sn, In)
x
(
x
= 6, 8 and 10 at.%) has been produced by melt spinning. Thermal and thermodynamic analyses have been ...performed by means of differential scanning calorimetry scans of the reversible martensitic structural transformation. The transformation temperatures decrease as increasing In or Sn content. The entropy increases with increasing Sn or In content. The dissipation term of entropy is lower than 0.02 in all samples. The martensitic transformation (from austenite to modulated monoclinic 14M martensitic phase) was detected in Mn
50
Ni
50−x
Sn
x
(
x
= 6, 8 and 10 at.%) and Mn
50
Ni
50−x
In
x
(
x
= 6 and 8 at.%) samples. The structural transformation was not detected in the alloy with 10 at.% of indium.
A High Ankle-Brachial Index Is Associated With Increased Cardiovascular Disease Morbidity and Lower Quality of Life Matthew A. Allison, William R. Hiatt, Alan T. Hirsch, Joseph R. Coll, Michael H. ...Criqui We tested the hypothesis that an ankle-brachial index (ABI) ≥1.40 is associated with cardiovascular disease (CVD) morbidity and worse quality of life (QoL). After adjustment for age, gender, and the traditional CVD risk factors, the high ABI group had significantly higher odds for foot ulcers. After the same adjustments and including other prevalent CVD, the high ABI group scored 2.0 points lower on the physical component scale on the Medical Outcomes Study Standard Form-36 and 5.5 points lower on the Walking Impairment Questionnaire walking distance domain (p < 0.05 for both). Individuals with a high ABI have lower scores on several QoL domains.
Peripheral arterial disease (PAD) and diabetes are both associated with a high risk of ischemic events, but the role of intensive blood pressure control in PAD has not been established.
The ...Appropriate Blood Pressure Control in Diabetes study followed 950 subjects with type 2 diabetes for 5 years; 480 of the subjects were normotensive (baseline diastolic blood pressure of 80 to 89 mm Hg). Patients randomized to placebo (moderate blood pressure control) had a mean blood pressure of 137+/-0.7/81+/-0.3 mm Hg over the last 4 years of treatment. In contrast, patients randomized to intensive treatment with enalapril or nisoldipine had a mean 4-year blood pressure of 128+/-0.8/75+/-0.3 mm Hg (P<0.0001 compared with moderate control). PAD, which is defined as an ankle-brachial index <0.90 at the baseline visit, was diagnosed in 53 patients. In patients with PAD, there were 3 cardiovascular events (13.6%) on intensive treatment compared with 12 events (38.7%) on moderate treatment (P=0.046). After adjustment for multiple cardiovascular risk factors, an inverse relationship between ankle-brachial index and cardiovascular events was observed with moderate treatment (P=0.009), but not with intensive treatment (P=0.91). Thus, with intensive blood pressure control, the risk of an event was not increased, even at the lowest ankle-brachial index values, and was the same as in a patient without PAD.
In PAD patients with diabetes, intensive blood pressure lowering to a mean of 128/75 mm Hg resulted in a marked reduction in cardiovascular events.
Pulmonary rehabilitation (PR) is recommended after a severe COPD exacerbation, but its short- and long-term effects on health care utilization have not been fully established.
The aims of this study ...were to evaluate patient compliance with a chronic disease management (CDM) program incorporating home-based exercise training as the main component after a severe COPD exacerbation and to determine its effects on health care utilization in the following year.
COPD patients with a severe exacerbation were included in a case-cohort study at admission. An intervention group participated in a nurse-supervised CDM program during the 2 months after discharge, comprising of home-based PR with exercise components directly supervised by a physiotherapist, while the remaining patients followed usual care.
Nineteen of the twenty-one participants (90.5%) were compliant with the CDM program and were compared with 29 usual-care patients. Compliance with the program was associated with statistically significant reductions in admissions due to respiratory disease in the following year (median interquartile range: 0 0-1 vs 1 0-2.5;
=0.022) and in days of admission (0 0-7 vs 7 0-12;
=0.034), and multiple linear regression analysis confirmed the protective effect of the CDM program (β coefficient -0.785,
=0.014, and
=0.219).
A CDM program incorporating exercise training for COPD patients without limiting comorbidities after a severe exacerbation achieves high compliance and reduces admissions in the year following after the intervention.
We undertook this study to document the functional natural history of patients undergoing major amputation in an academic vascular surgery and rehabilitation medicine practice.
A retrospective review ...was conducted of consecutive patients undergoing major lower extremity amputation and rehabilitation in a university and Department of Veterans Affairs hospital. Main outcome variables included operative mortality, follow-up, survival, median time to incision healing, secondary operative procedures for wound management, and conversion from below-knee amputation (BKA) to above-knee amputation (AKA). For surviving patients, quality of life was determined by degree of ambulation, eg, outdoors, indoors only, or no ambulation; use of a prosthesis; and independence, eg, community housing or nursing facility.
From August 1997 through March 2002, 154 patients (130 men; median age, 62 years) underwent 172 major amputations, 78 AKA and 94 BKA, because of either critical limb ischemia (87%) or diabetic neuropathy (13%). Thirty-day operative mortality was 10%. Mean follow-up was 14 months. Healing at 100 and 200 days, as determined with the Kaplan-Meier method, was 55% and 83%, respectively, for BKA, and 76% and 85%, respectively, for AKA. Twenty-three BKA and 16 AKA required additional operative revision, and 18 BKA ultimately were converted to AKA. Survival was 78% at 1 year and 55% at 3 years. Function in surviving patients at 10 and 17 months, respectively, was as follows: 21% and 29% of patients ambulated outdoors, 28% and 25% ambulated indoors only, and 51% and 46% of patients were nonambulatory; 32% and 42% of patients used prosthetic limbs; and 17% and 8% of patients who lived in the community before amputation required care in a nursing facility.
We were surprised to find that vascular patients in a contemporary setting who require major lower extremity amputation and rehabilitation often remain independent despite infrequent prosthesis use and outdoor ambulation. Although any hope for postoperative ambulation in this population requires salvaging the knee joint, because of the morbidity incurred in both wound healing and rehabilitation efforts, aggressive effort should be reserved for selected patients at good risk. Ability to predict ambulation after BKA in the vascular population is poor.
Background and aims
Clinical trials have shown that intensive low‐density lipoprotein cholesterol (LDL‐C) lowering improves cardiovascular outcomes among patients with atherosclerotic cardiovascular ...disease (ASCVD), but data are limited in real clinical practice, particularly for patients with ASCVD informing different territories.
Methods
FRENA was a prospective registry of consecutive outpatients with coronary, cerebrovascular or peripheral artery disease. We compared the incidence of recurrent events in patients with sustained LDL‐C levels <70 mg/dl compared with those with ≥70 mg/dl.
Results
As of December 2018, 1182 patients were eligible for this study. Among them, 172 (14.5%) had mean LDL‐C levels ≤70 mg/dl, and 1010 (85.5%) had <70 mg/dl. Their clinical characteristics at baseline were similar. During 5 years of follow‐up, 252 patients (21%) suffered major adverse cardiovascular events (MACE). The incidence rates of MACE were 3.42 events per 100 patient‐years (95% confidence interval 95% CI 2.17–5.14) in patients with levels <70 mg/dl and 5.57 (95% CI, 4.87–6.34) in those with ≥70 mg/dl; the rate ratio was 0.61 (95% CI, 0.39–0.92), p = 0.019. On multivariable analysis, patients with LDL‐C levels <70 mg/dl were at lower risk for MACE (hazard ratio HR: 0.61 95% CI, 0.39–0.93 p < 0.05). MACE reduction was driven by a decrease in coronary and peripheral events with no significant effect on stroke.
Conclusions
Long‐term sustained LDL‐C <70 mg/dl in the clinical practice is associated with reduction in cardiovascular and peripheral vascular events with no apparent effect on stroke.
To examine the association of the Patient Assessment of Chronic Illness Care (PACIC) with glycaemic control and the modulating effect of patient activation on this association.
A population-based ...prospective cohort study of people with type 2 diabetes in Queensland, Australia, using data from self-report questionnaires, collected annually from 2008 (N = 3761) to 2010 (N = 3040).
Predictors were the 20-item PACIC (dichotomized at the score of 3), and the 13-item Patient Activation Measure (PAM), dichotomized into activation levels 1 and 2 versus levels 3 and 4. Analyses were restricted to participants whose PACIC and PAM categories did not change over 2 years of follow-up. Outcome variable was self-reported HbA1c of ≤ 7% (53 mmol/mol) versus >7%.
An inverse probability-weighted Poisson regression with a log-link function and a binary response outcome variable (HbA1c) was used to obtain risk ratios (RRs), and the interaction between PACIC and PAM was statistically modelled, taking into consideration patient characteristics and baseline glycaemic status.
The effect of the PACIC was not seen in the activated participants (adjusted RR: 1.1; 95% CI: 0.96-1.2; P = 0.20) but was strongly observed in participants with low activation (adjusted RR: 2.3; 95% CI: 1.6-3.1; P < 0.001). Similarly, there was a positive association between patient activation and glycaemic control when the PACIC was low (adjusted RR: 1.6; 95% CI: 1.3-2.0; P < 0.001).
Better patient-assessed chronic care received consistently over time facilitates achievement of better glycaemic control in patients with low activation.
Type 2 diabetes (T2D) is associated with chronic, low grade inflammation. Activation of the NLRP3 inflammasome and secretion of its target interleukin-1β (IL-1β) have been implicated in pancreatic β ...cell failure in T2D. Specific targeting of the NLRP3 inflammasome to prevent pancreatic β cell death could allow for selective T2D treatment without compromising all IL-1β-associated immune responses. We hypothesized that treating a mouse model of T2D with MCC950, a compound that specifically inhibits NLRP3, would prevent pancreatic β cell death, thereby preventing the onset of T2D.
Diabetic db/db mice were treated with MCC950 via drinking water for 8 weeks from 6 to 14 weeks of age, a period over which they developed pancreatic β cell failure. We assessed metabolic parameters such as body composition, glucose tolerance, or insulin secretion over the course of the intervention.
MCC950 was a potent inhibitor of NLRP3-induced IL-1β in vitro and was detected at high levels in the plasma of treated db/db mice. Treatment of pre-diabetic db/db mice with MCC950, however, did not prevent pancreatic dysfunction and full onset of the T2D pathology. When examining the NLRP3 pathway in the pancreas of db/db mice, we could not detect an activation of this pathway nor increased levels of its target IL-1β.
NLRP3 driven-pancreatic IL-1β inflammation does not play a key role in the pathogenesis of the db/db murine model of T2D.
•Inhibition of NLRP3 via MCC950 in db/db mice did not improve glucose tolerance.•MCC950 treatment did not prevent beta cell loss of function.•Expression of IL1beta and NLRP3 does not appear increased in db/db islets.•We conclude against a role for NLRP3 in db/db pancreatic dysfunction.
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