Regulatory T CD4 + CD25+ lymphocytes increase in symptomatic carotid artery stenosis

Background: Atherosclerosis is a multifactorial disease characterized by an immune-inflammatory remodeling of the arterial wall. Treg and Th17 subpopulations are detectable inside atherosclerotic plaque; however, their behavior in symptomatic carotid artery stenosis (CAS) is not fully elucidated. The aim of this study was to evaluate Th17 and Treg subsets and their ratio in patients affected by symptomatic and asymptomatic CAS.

Methods: 14 patients with symptomatic CAS (CAS-S group), 41 patients with asymptomatic CAS (CAS-A group), 32 subjects with traditional cardiovascular risk factors (RF group), and 10 healthy subjects (HS group) were enrolled. Th17 and Treg frequency was determined by flow cytometry and by histology and immunohistochemistry. Interleukin (IL)-10, IL-17, and metalloproteinase (MMP)-12 levels were measured by ELISA.

Results: Th17 were significantly increased in CAS-A versus RF and versus HS. Tregs were significantly increased in CAS-S versus CAS-A. Tregs/Th17 ratio was significantly reduced in CAS-A versus RF and versus HS, whereas it was significantly increased in CAS-S versus CAS-A.

Conclusions: The results of this study suggest that Th17 are related to the late stages of CAS but not to plaque instability. Moreover, Treg expansion seems to represent a specific cellular pattern displayed by patients with symptomatic CAS and associated with brain injury.

• KEY MESSAGES

• Tregs expansion seems to represent a specific cellular pattern displayed by patients with symptomatic CAS and associated with CD4+ effector depletion and brain ischemic injury.

• Th17 lymphocytes are related to the late stages of CAS but not to plaque instability.

     

Phase II study of fosaprepitant + 5HT3 receptor antagonist + dexamethasone in patients with germ cell tumors undergoing 5-day cisplatin-based chemotherapy: a Hoosier Cancer Research Network study

Purpose

A phase III study adding aprepitant to a 5HT3 receptor antagonist (5HT3-RA) plus dexamethasone in germ cell tumor (GCT) patients treated with 5-day cisplatin combination chemotherapy demonstrated a significant improvement in complete response (CR) (J Clin Onc 30:3998-4003, 2012). Fosaprepitant has demonstrated non-inferiority compared to aprepitant in single-day cisplatin chemotherapy and is approved as a single-dose alternative. This single-arm phase II study is the first clinical trial evaluating fosaprepitant in patients receiving multi-day cisplatin regimen.

Methods

GCT patients receiving a 5-day cisplatin combination chemotherapy were enrolled. Fosaprepitant 150 mg was given IV on days 3 and 5. A 5HT3-RA days 1–5 (days 1, 3, and 5, if palonosetron) plus dexamethasone 20 mg days 1 and 2 and 4 mg po bid days 6, 7, and 8 was administered. Rescue antiemetics were allowed. The primary objective was to determine the CR rate—no emetic episodes or use of rescue medications. Accrual of 64 patients was planned with expected CR?>?27 %.

Results

Sixty-five patients were enrolled of whom 54 were eligible for analysis. Median age was 33. Fifty-one patients received bleomycin, etoposide, and cisplatin (BEP) chemotherapy. CR was observed in 13 (24.1 %) patients (95 % Agresti-Coull binomial C.I. 14.5 %, 37.1 %).

Conclusion

The data in this phase II study, in contrast to our prior phase III study, appears to indicate a lower CR rate with the substitution of fosaprepitant for aprepitant. It is unknown whether the substitution of fosaprepitant for aprepitant provides the same benefit in multi-day cisplatin that was achieved with single-day cisplatin. Trial registration Clinical trial information NCT01736917

     

A comprehensive psychometric evaluation of the UK FIM + FAM

Abstract

Purpose: To evaluate the psychometric properties of the UK FIM?+?FAM. Methods: (a) A systematic literature review integrating the evidence for psychometric qualities of both the original and UK versions, and (b) exploratory and confirmatory factor analysis of admission/discharge data from an inpatient general neuro-rehabilitation cohort using parametric and non-parametric techniques. A prospective cohort of 459 patients with a male:female ratio of 57:43 and mean age of 44.5 (SD 14.3) years participated in this study. Results: Seven published articles together demonstrated acceptable utility, concurrent validity, inter-rater reliability and responsiveness of the UK FIM?+?FAM. Factor analysis demonstrated that all items loaded high (>0.58) on the first principal component and distinct motor and cognitive factors emerged after rotation. A four-factor solution also demonstrated four distinct, interpretable dimensions (Physical, Psychosocial, Communication and Extended Activities of Everyday Living (EADL)). Mokken analysis of the second data set confirmed these dimensions. Cronbach’s αs were 0.97 and 0.96 for the motor and cognitive domains and 0.90–0.97 for the subscales. Analysis of responsiveness demonstrated “large” effect sizes (0.86–1.29). Conclusions: The UK FIM?+?FAM, including the newer EADL module, is a valid, reliable scale of functional independence. It has high internal consistency in two domains and four subscales and is responsive to changes occurring in a general inpatient neuro-rehabilitation population.

• Implications for Rehabilitation

• The UK FIM?+?FAM is a valid, reliable scale of functional independence, which is responsive to changes occurring in a general inpatient neuro-rehabilitation population.

• It can be used to derive a reliable, single score of overall independence and also yields specific information in two main domains and four separate subscales of independence: Physical, Psychosocial, Communication and Extended Activities of Daily Living (EADL).

• The newer EADL item module provides added value, measuring functional independence for community-based activities.

     

血清TT3、FT3、TT4、FT4以及TSH检测意义

目的探讨TT3、FT3、TT4、FT4以及TSH在甲状腺疾病患者中检测的价值;总结分析各指标变化情况。方法收集分析本院200例甲状腺疾病患者,并选取健康者50例作为对照组。用化学发光分析法检测各组甲状腺功能,并对各组各指标的检测值进行比较。结果甲亢组T3、T4、FT3、FT4均高于健康对照组,甲减组T3、T4、FT3、FT4均低于健康对照组。TSH含量甲亢组低于健康对照组,甲减组明显高于健康对照组。与健康对照组比较其差异均有统计学意义。甲亢组FT3诊断符合率为96%,TSH为96%,T3为92%,FT4为90%,T4为88%。甲减组TSH诊断符合率为100%,FT4为93%,T4为90%,FT3为77%,T3为70%。结论 FT3、T3、TSH在甲亢诊断中有临床意义;FT4、T4、TSH在甲减诊断中有临床意义。     

Interferon λ 3 and 4 Genotyping Using High-Resolution Melt Curve Analysis Suitable for Multiple Clinical Sample Types

Many people living with hepatitis C virus (HCV) infection will continue to rely on interferon-based regimens until effective strategies to minimize the cost of directly acting antivirals (DAAs) and to improve treatment access are implemented. Host single-nucleotide polymorphisms related to IFNL3 and IFNL4 are associated with spontaneous clearance of HCV, and pegylated interferon– and DAA-based treatment outcomes. We describe a simple and rapid genotyping method for IFNL rs12979860, rs8099917, and rs368234815 using high-resolution melting analysis for DNA extracted from whole blood, buffy coat, plasma, serum, and dried blood spots. This assay successfully detected all three polymorphisms on DNA extracted by the automated platform easyMAG from all samples when compared to sequenced amplicons. Analysis of 126 participants with recent HCV infection from the Australian Trial in Acute Hepatitis C study demonstrated the prevalence of favorable single-nucleotide polymorphisms were 62%, 51%, and 45% for rs8099917 TT, rs12979860 CC, and rs368234815 TT/TT, respectively. The genotyping assay described here provides a rapid and affordable IFNL3 and IFNL4 genotyping method for a range of clinical sample types. Until global access to DAAs is achieved, IFNL3 and IFNL4 genotyping could identify those likely to clear naturally and in whom treatment could be delayed, or help prioritize DAA treatment to those less likely to respond to interferon-containing regimens.Directly acting antivirals (DAAs) have revolutionized hepatitis C virus (HCV) treatment. However, high associated costs and restricted access mean that many of those living with HCV may not receive the benefit of these new therapies. As such, affordable diagnostic tools are required to prioritize and select cost-effective HCV treatment. Diagnostic tools, such as IFNL3 and IFNL4 genotyping, can predict those most likely to spontaneously clear HCV, for whom treatment could be delayed. These tools may also stratify individuals and prioritize DAA treatment to those less likely to respond to interferon-containing regimens, or identify those likely to respond well to therapy with shortened treatment. A combination of strategies that improve harm reduction and prevention programs, increase HCV screening rates, and optimize treatment regimens are required to reduce the transmission and burden of disease in populations most affected by HCV infection.Spontaneous HCV clearance occurs in 25% of individuals.^1,2 Polymorphisms in IFNL3 [single-nucleotide polymorphism (SNP) rs8099917, located near IFNL3 gene and SNP rs12979860] or called IL-28B, are the strongest host factors predicting both spontaneous HCV clearance in acute infection³ and response to interferon-based treatment in chronic infection.^2,4,5 Recently, Prokunina-Olsson et al⁶ described a new dinucleotide variant rs368234815 (previously designated as ss469415590) that creates (ΔG) or disrupts (TT) an open reading frame of a gene encoding the interferon λ-4 (IFN-λ4) protein. The dinucleotide variant rs368234815 is in high linkage disequilibrium with rs12979860, but is more strongly associated with both HCV clearance, and pegylated interferon-α and ribavirin treatment response in individuals of African ancestry than rs12979860.⁶ Recent findings showed that recombinant IFN-λ4 protein strongly stimulates Jak-STAT signaling and interferon-stimulated gene induction through binding to the IFN-λ receptor.⁷ The active IFN-λ4 protein may therefore be the driver of high baseline hepatic interferon-stimulated gene expression at the time of infection and consequently poor HCV clearance.⁸ Those with the polymorphism resulting in an impaired IFN-λ4 (IFNL4) variant respond better to treatment and have improved rates of spontaneous clearance compared with those who express the active IFN-λ4 variant.⁸There is recent evidence to suggest that IFNL polymorphisms may retain clinical relevance for management of interferon-containing DAA therapy. In treatment-naive patients receiving interferon-containing DAA treatment, the IFNL3 genotype continues to be significantly associated with sustained virological response and treatment duration required to achieve this response.⁹ Recently, the IFNL3 rs12979860 genotype has been shown to be a strong predictor of tissue inflammation and fibrosis during chronic HCV infection,¹⁰ potentially broadening the clinical relevance of IFNL genotypes to disease progression. The authors conclude that the IFNL3 genotype may be an important part of the development of an individualized patient management algorithm.Our aim was to develop a rapid, reliable, and inexpensive method to genotype IFNL3 and IFLN4 SNPs using real-time high-resolution melting (HRM) analysis^11,12 on a range of clinical sample types. This assay was then used to estimate the prevalence of favorable IFNL3 and IFNL4 in recent HCV, using a well-characterized cohort of participants from the Australian Trial in Acute Hepatitis C (ATAHC) study.     

Does the FT3-to-FT4 ratio easily predict the progression of NAFLD and NASH cirrhosis?

BackgroundFactors causing progression from nonalcoholic fatty liver to nonalcoholic steatohepatitis (NASH) and liver cirrhosis remain relatively unknown. We aimed to evaluate the power and effectiveness of the free triiodothyronine (FT3)-to-free thyroxine (FT4) ratio to predict non-alcoholic fatty liver disease (NAFLD)/liver fibrosis and NASH cirrhosis severity.MethodsPatients (n = 436) with NASH-associated liver cirrhosis (n = 68), patients with liver biopsy-proven NAFLD (n = 226), or healthy participants (n = 142) were enrolled between January 2010 and January 2020. The aspartate aminotransferase-to-thrombocyte ratio (APRI), NAFLD fibrosis score, albumin–bilirubin score (ALBI), aspartate aminotransferase (AST)-to-alanine aminotransferase (ALT) ratio, FT3-to-FT4 ratio, and Fibrosis-4 (FIB-4) were calculated and evaluated.ResultsAll parameters were significantly higher in NASH cirrhosis than in the healthy group. Body mass index, ALT, fasting insulin, homeostatic model assessment for insulin resistance, and triglyceride levels were significantly higher in liver biopsy-proven NAFLD than in the healthy group. The APRI, NAFLD fibrosis score, ALBI, AST-to-ALT ratio, FT3-to-FT4 ratio, and FIB-4 were significantly higher in the NASH cirrhosis group than in the healthy group. In patients with biopsy-proven NAFLD, the FT3-to-FT4 ratio was significantly lower than in the healthy group.ConclusionThe FT3-to-FT4 ratio is an effective and useful indicator to predict NAFLD/liver fibrosis and NASH cirrhosis severity.     

免疫化学发光法测定T3、T4及FT3、FT4的结果比较

甲状腺是人体最大的内分泌腺,它合成和分泌的T3、T4是控制人体代谢的主要分泌激素。T3与T4分结合型和游离型两种形式在血液中循环。结合型可看作是该激素在血液中临时贮存,只有游离型的才能进入组织,与靶细胞发挥生理作用。血液循环中,呈游离型的激素很少,血浆中的游离T3(FT3),仅占T3总浓度的0.3%,游离T4(FT4),仅占T4总浓度的0.04%。与甲状腺激素结合的蛋白质主要有三种,其中高亲合力、低溶量的甲状腺结合球蛋白(TBG)是特异的和最主要的结合蛋白,结合率为60～90%;其次为甲状腺素结合前清蛋白(TBPA)和白蛋白(AL)。在临床上可见到诸…     

Differences between measurements of T4 and T3 in pregnant and nonpregnant women using isotope dilution tandem mass spectrometry and immunoassays: are there clinical implications?

BACKGROUND: It has been established that triiodothyronine (T3) and thyroxine (T4) measurements by tandem mass spectrometry (MS/MS) are more specific and are significantly different from immunoassay (IA) measurements (all p< or =0.05) throughout pregnancy. In this study, we examined the clinical implications of these discrepancies. METHODS: Kappa statistics were used to determine the degree to which IA and MS/MS agreed in their identification of out-of-reference interval observations of circulating T4 and T3 from 52 normal, iodine-sufficient women during each trimester of pregnancy. RESULTS: After taking chance agreement into account, the two methods had poor agreement on classification of T3 values at the first (kappa=0.185) and second (kappa=0.183) trimesters, with extremely poor agreement for the third trimester and 1-year postpartum. Agreement on T4 was poor only for the third trimester (kappa=0.183). The two methods agreed on out-of-range values in only 0-25% of T3 cases and 25-66.7% of T4 cases. CONCLUSIONS: The areas of disagreement suggest that women at risk (i.e., with analyte values outside of the 5-95% range) will not be detected using IA. Based on this cohort, our preliminary estimates are that 25-100% of such women would be missed if IA were used to assay the analyte.     

血清T3T4H-TSH、FT3FT4在甲亢和甲减诊断中的评价

目的　评价血清T3 、T4、FT3 、FT4、H TSH在甲亢和甲减诊断中的临床意义。方法　选正常成人 4 0例 ,本院已确诊的甲亢患者 5 0例 ,甲减患者 30例 ,均在我院化验室采用RIA法测定血清T3 、T4、FT3 、FT4、H TSH数据 ,求出x±s,并进行比较 ,求出各种激素在两种疾病诊断中的符合率。结果　FT3 、H TSH对甲亢诊断符合率最高 ,T3 、FT4次之 ,T4的符合率较低 ;FT4、H TSH对甲减诊断符合率最高 ,T4次之 ,FT3 T3 的符合率较低。结论　FT3 、T3 、H TSH在甲亢诊断中意义大 ;FT4、T4、H TSH在甲减诊断中意义大。     

Phencyclidine analog use in Sweden—intoxication cases involving 3-MeO-PCP and 4-MeO-PCP from the STRIDA project

Background. 3-Methoxy-phencyclidine (3-MeO-PCP) and 4-methoxy-phencyclidine (4-MeO-PCP) are analogs of and drug substitutes for the dissociative substance PCP (“Angel dust”), a recreational drug that was most popular in the 1970s. In Sweden, use of methoxylated PCP analogs was noted starting in mid-2013, according to statistics from the Poisons Information Centre. The objective of this case series was to present clinical and bioanalytical data from analytically confirmed non-fatal intoxications associated with 3-MeO-PCP and/or 4-MeO-PCP within the STRIDA project. Study design. Observational case series of consecutive patients with self-reported or suspected exposure to new psychoactive substances (NPS) and who require hospital care. Patients and methods. Blood and urine samples were collected from intoxicated patients presenting at emergency departments (ED) or intensive care units (ICU) all over Sweden. NPS analysis was performed by multicomponent liquid chromatographic–tandem mass spectrometric (LC–MS/MS) and LC–high-resolution MS (LC–HRMS) methods. Data on clinical features were collected during Poisons Information Centre consultations and retrieved from medical records. Results. The Poisons Information Centre registered its first call related to methoxylated PCP analogs in July 2013, while analytically confirmed cases first appeared in October 2013. From July 2013 to March 2015, 1243 cases of suspected NPS intoxication originating from ED or ICU were enrolled in the STRIDA project. During the 21-month period, 56 (4.5%) patients tested positive for 3-MeO-PCP and 11 (0.9%) for 4-MeO-PCP; 8 of these cases involved both substances. The 59 patients were aged 14–55 (median: 26) years and 51 (86%) were men. Co-exposure to other NPSs and/or classical drugs of abuse was common with only 7 cases (12%) indicated to be 3-MeO-PCP single-substance intoxications; prominent clinical signs seen in the latter cases were hypertension (systolic blood pressure ≥ 140 mmHg; 7 cases), tachycardia (≥ 100/min; 5 cases), and altered mental status (4 cases) including confusion, disorientation, dissociation, and/or hallucinations. Mixed-drug users displayed not only the same clinical features, but also more sympathomimetic effects including agitation (38%) and dilated pupils (33%). Patients testing positive for 3-/4-MeO-PCP were typically under medical care for 1–2 days (85%), and 37% of all cases were graded as severe intoxications (Poisoning Severity Score 3). Besides standard supportive therapy, 49% of the patients were treated with benzodiazepines and/or propofol. Conclusion. Laboratory analysis constitutes an important basis for the assessment of NPS hazard and availability. The adverse effects noted in cases of acute intoxications involving 3- and/or 4-MeO-PCP resembled those of other dissociatives such as PCP, ketamine, and methoxetamine. However, similar to intoxications involving other NPS, poly-substance use was found to be common.     

Changes in concentrations of methylglyoxal,d-lactate and glyoxalase activities in liver and plasma of rats fed a 3′-methyl-4-dimethylaminoazobenzene-rich diet

Donryu male albino rats were fed a diet containing 0.064% 3′-methyl-4-dimethylaminoazobenzene (MDAB) for 21 weeks. During the ensuing rat liver carcinogenesis, changes in the concentrations of methylglyoxal,d-lactate and glutathione as well as activities of glyoxalase I and II in liver and plasma were examined. After the start of the diet, hepatic contents of methylglyoxal andd-lactate increased to about 7 and 3 times that of the control, respectively. However, after 21 weeks thed-lactate content decreased from the elevated level, but remained at a higher level of 1.4 times the control. The hepatic glyoxalase I activity increased 1.2 to 1.7 times over the control during carcinogenesis, while glyoxalase II activity increased 160% during the precancerous state and decreased to 55% of control at 21 weeks. The hepatic level of reduced glutathione (GSH) increased and peaked after 4 weeks of the MDAB diet and decreased thereafter to 57% of the control level after 21 weeks. Both pyruvate andl-lactate levels increased in the liver and plasma of MDAB-fed rats when rats had obvious symptoms of hepatoma.     

Responsiveness and Predictive Validity of the Participation Measure–3 Domains, 4 Dimensions in Survivors of Stroke

ObjectivesTo examine the responsiveness and predictive validity of the Participation Measure–3 Domains, 4 Dimensions (PM-3D4D) in people receiving outpatient rehabilitation following stroke.DesignProspective cohort observational study.SettingOutpatient rehabilitation settings.ParticipantsVolunteer patients (N=269) with stroke (mean age ± SD [y], 55.36±12.46; 70.26% male).InterventionsNot applicable.Main Outcome MeasuresThe PM-3D4D was designed to measure 3 domains (Productivity, Social, and Community) and 4 dimensions (Diversity, Frequency, Desire for change, and Difficulty) of participation in individuals with rehabilitation needs. All participants completed the PM-3D4D, the Participation Assessment with Recombined Tools-Objective (PART-O), the Participation Measure for Post-Acute Care (PM-PAC), and the EuroQol-5-Dimension (EQ-5D) at the baseline assessment and again following 3 months of outpatient rehabilitation.ResultsSignificant mean changes in scores were observed for most of the PM-3D4D subscales, with the largest score change observed in the Difficulty subscale (standardized response mean=0.57～0.88). The minimal detectable change and meaningful clinically important differences were calculated for each subscale. The Frequency and Difficulty dimensions of the PM-3D4D demonstrated significantly greater responsiveness than the PART-O and PM-PAC, respectively. The baseline PM-3D4D scores, except for Desire for change subscales, were significantly correlated with the PART-O, PM-PAC, and EQ-5D scores after 3 months of rehabilitation.ConclusionsThis study provides evidence supporting the responsiveness and predictive validity of the PM-3D4D in survivors of stroke. Among all subscales of the PM-3D4D, the Difficulty dimensional scale demonstrated the greatest responsiveness. The Desire for change dimension of the PM-3D4D showed less responsiveness, and we recommend that it be used as a goal-setting tool rather than an outcome measure. The PM-3D4D can potentially be used to predict participation outcomes and the health-related quality of life following rehabilitation interventions.     

200例甲亢T3,T4,FT3,FT4,TSH检测临床分析

1.资料和方法1.1资料 ①病例组:系1994年12月～1996年5月来,我院就诊的200例甲亢患者,其中男79例,女121例,年龄在14岁～65岁,平均29岁.②对照组:为企事业单位健康体检,排除甲状腺、肝、肾疾病及妊娠者,共50例,其中男27例,女23例,年龄18岁～60岁.1.2方法 ①T_3、T_4、FT_3、FT_4、TSH试剂药盒由北京     

Gilbert综合征3个家族4例报告

Gilbert综合征为一家族性、非溶血性、非结合胆红素增高型黄疸。我院在近2年内遇到3个家族4例患者,现报告于下。病例报告例1:女,48岁。10余岁时发现黄疸,以后于疲劳时加重,但无皮肤搔痒及其它不适。一妹也有长期黄疸史。两子女皆无黄疸,体检及血、肝功能检查也无异常。体检:巩膜及皮肤中度黄染,浅表淋巴结无肿     

Lipoprotein distribution and serum concentrations of 7α-hydroxy-4-cholesten-3-one and bile acids: effects of monogenic disturbances in high-density lipoprotein metabolism

BA (bile acid) formation is considered an important final step in RCT (reverse cholesterol transport). HDL (high-density lipoprotein) has been reported to transport BAs. We therefore investigated the effects of monogenic disturbances in human HDL metabolism on serum concentrations and lipoprotein distributions of the major 15 BA species and their precursor C4 (7α-hydroxy-4-cholesten-3-one). In normolipidaemic plasma, approximately 84%, 11% and 5% of BAs were recovered in the LPDS (lipoprotein-depleted serum), HDL and the combined LDL (low-density lipoprotein)/VLDL (very-low-density lipoproteins) fraction respectively. Conjugated BAs were slightly over-represented in HDL. For C4, the respective percentages were 23%, 21% and 56% (41% in LDL and 15% in VLDL) respectively. Compared with unaffected family members, neither HDL-C (HDL-cholesterol)-decreasing mutations in the genes APOA1 [encoding ApoA-I (apolipoprotein A-I], ABCA1 (ATP-binding cassette transporter A1) or LCAT (lecithin:cholesterol acyltransferase) nor HDL-C-increasing mutations in the genes CETP (cholesteryl ester transfer protein) or LIPC (hepatic lipase) were associated with significantly different serum concentrations of BA and C4. Plasma concentrations of conjugated and secondary BAs differed between heterozygous carriers of SCARB1 (scavenger receptor class B1) mutations and unaffected individuals (P<0.05), but this difference was not significant after correction for multiple testing. Moreover, no differences in the lipoprotein distribution of BAs in the LPDS and HDL fractions from SCARB1 heterozygotes were observed. In conclusion, despite significant recoveries of BAs and C4 in HDL and despite the metabolic relationships between RCT and BA formation, monogenic disorders of HDL metabolism do not lead to altered serum concentrations of BAs and C4.     

Proteinase 3–dependent caspase-3 cleavage modulates neutrophil death and inflammation

Caspase-3–mediated spontaneous death in neutrophils is a prototype of programmed cell death and is critical for modulating physiopathological inflammatory responses; however, the underlying regulatory pathways remain ill defined. Here we determined that in aging neutrophils, the cleavage and activation of caspase-3 is independent of the canonical caspase-8– or caspase-9–mediated pathway. Instead, caspase-3 activation was mediated by serine protease proteinase 3 (PR3), which is present in the cytosol of aging neutrophils. Specifically, PR3 cleaved procaspase-3 at a site upstream of the canonical caspase-9 cleavage site. In mature neutrophils, PR3 was sequestered in granules and released during aging via lysosomal membrane permeabilization (LMP), leading to procaspase-3 cleavage and apoptosis. Pharmacological inhibition or knockdown of PR3 delayed neutrophil death in vitro and consistently delayed neutrophil death and augmented neutrophil accumulation at sites of inflammation in a murine model of peritonitis. Adoptive transfer of both WT and PR3-deficient neutrophils revealed that the delayed death of neutrophils lacking PR3 is due to an altered intrinsic apoptosis/survival pathway, rather than the inflammatory microenvironment. The presence of the suicide protease inhibitor SERPINB1 counterbalanced the protease activity of PR3 in aging neutrophils, and deletion of Serpinb1 accelerated neutrophil death. Taken together, our results reveal that PR3-mediated caspase-3 activation controls neutrophil spontaneous death.