OBJECTIVES: Protein concentration measurement in the urine can be problematic in the presence of Bence Jones protein. We have carried out an external quality control assessment with the participation of 79 clinical biochemistry laboratories from the Czech Republic and Slovakia. DESIGN AND METHODS: The laboratories received a reference urine sample obtained from a patient with multiple myeloma and lambda free light chain proteinuria and were asked to type the paraprotein using immunofixation and to measure total urinary protein using their established method, most commonly turbidimetry, pyrogallol red assay, and biuret assay. RESULTS: There was a very wide inter-laboratory variability in the protein concentration readouts with up to three-fold difference in some cases. High-resolution two-dimensional electrophoresis and linear mass spectrometry showed that a high proportion of the urinary paraprotein was composed of lambda light chain fragments with molecular weight of 12kDa. CONCLUSIONS: Our results highlight the challenges of reliable and reproducible measurement of urinary protein concentration in the presence of Bence Jones protein.

• MeSH
• 2D gelová elektroforéza MeSH
• Bence-Jonesova bílkovina moč   MeSH
• lidé MeSH
• proteinurie moč   MeSH
• reprodukovatelnost výsledků MeSH
• spektrometrie hmotnostní - ionizace laserem za účasti matrice MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• adenylsukcinátlyasa nedostatek   MeSH
• dítě MeSH
• fibroblasty enzymologie   MeSH
• kojenec MeSH
• kůže enzymologie   patologie   MeSH
• lidé MeSH
• molekulární konformace MeSH
• svalová hypotonie komplikace   MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH
• Geografické názvy
• Spojené státy americké MeSH

T cell memory relies on the generation of antigen-specific progenitors with stem-like properties. However, the identity of these progenitors has remained unclear, precluding a full understanding of the differentiation trajectories that underpin the heterogeneity of antigen-experienced T cells. We used a systematic approach guided by single-cell RNA-sequencing data to map the organizational structure of the human CD8+ memory T cell pool under physiological conditions. We identified two previously unrecognized subsets of clonally, epigenetically, functionally, phenotypically and transcriptionally distinct stem-like CD8+ memory T cells. Progenitors lacking the inhibitory receptors programmed death-1 (PD-1) and T cell immunoreceptor with Ig and ITIM domains (TIGIT) were committed to a functional lineage, whereas progenitors expressing PD-1 and TIGIT were committed to a dysfunctional, exhausted-like lineage. Collectively, these data reveal the existence of parallel differentiation programs in the human CD8+ memory T cell pool, with potentially broad implications for the development of immunotherapies and vaccines.

• MeSH
• biologické markery MeSH
• buněčná diferenciace imunologie   MeSH
• CD8-pozitivní T-lymfocyty imunologie   metabolismus   MeSH
• homeostáza telomer MeSH
• imunofenotypizace MeSH
• imunologická paměť * MeSH
• lidé MeSH
• lymfoidní progenitorové buňky cytologie   imunologie   metabolismus   MeSH
• myši MeSH
• stanovení celkové genové exprese MeSH
• T-lymfocyty - podskupiny imunologie   metabolismus   MeSH
• výpočetní biologie metody   MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

MHC-E regulates NK cells by displaying MHC class Ia signal peptides (VL9) to NKG2A:CD94 receptors. MHC-E can also present sequence-diverse, lower-affinity, pathogen-derived peptides to T cell receptors (TCRs) on CD8+ T cells. To understand these affinity differences, human MHC-E (HLA-E)-VL9 versus pathogen-derived peptide structures are compared. Small-angle X-ray scatter (SAXS) measures biophysical parameters in solution, allowing comparison with crystal structures. For HLA-E-VL9, there is concordance between SAXS and crystal parameters. In contrast, HLA-E-bound pathogen-derived peptides produce larger SAXS dimensions that reduce to their crystallographic dimensions only when excess peptide is supplied. Further crystallographic analysis demonstrates three amino acids, exclusive to MHC-E, that not only position VL9 close to the α2 helix, but also allow non-VL9 peptide binding with re-configuration of a key TCR-interacting α2 region. Thus, non-VL9-bound peptides introduce an alternative peptide-binding motif and surface recognition landscape, providing a likely basis for VL9- and non-VL9-HLA-E immune discrimination.

• MeSH
• CD8-pozitivní T-lymfocyty MeSH
• difrakce rentgenového záření MeSH
• konformace proteinů MeSH
• lektinové receptory NK-buněk - podrodina C metabolismus   MeSH
• lidé MeSH
• maloúhlový rozptyl MeSH
• MHC antigeny I. třídy * metabolismus   MeSH
• peptidy metabolismus   MeSH
• vazba proteinů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Merrigan, JJ, Tufano, JJ, Fields, JB, Oliver, JM, and Jones, MT. Rest redistribution does not alter hormone responses in resistance-trained women. J Strength Cond Res 34(7): 1867-1874, 2020-The purpose was to examine acute effects of rest redistribution (RR) on perceptual, metabolic, and hormonal responses during back squats. Twelve resistance-trained women (training age 5 ± 2 years; one repetition maximum [1-RM] per body mass, 1.6 ± 0.2) performed traditional (TS, 4 sets of 10 repetitions with 120 seconds interset rest) and RR sets (4 sets of two 5 repetition clusters with 30-second intraset rest and 90-second interset rest) in counterbalanced order, separated by 72 hours. Both conditions were performed at 70% 1RM with 360 seconds of total rest. Ratings of perceived exertion (RPE) were taken after each set. Blood was sampled at baseline, after each set, and at 5, 15, 30, and 60 minutes, as well as 24 and 48 hours after training. Alpha level was p ≤ 0.05. The RPE progressively increased throughout both conditions (p = 0.002) with a greater overall mean for TS (5.81 ± 0.14) than RR (4.71 ± 0.14; p = 0.003). Lactate increased above baseline and remained elevated through 15 minutes post in both conditions (4.00 ± 0.76; p = 0.001), with greater lactate levels for TS (6.33 ± 0.47) than RR (4.71 ± 0.53; p < 0.001). Total testosterone was elevated after set 2 (0.125 ± 0.02; p = 0.011), but no other time point, while free testosterone remained unchanged. Growth hormone continually rose from baseline to set 3 and returned to baseline by 60 minutes post (20.58 ± 3.19). Cortisol and creatine kinase did not change over time. No condition × time interactions existed for any hormone (p > 0.05). Use of rest redistribution resulted in lower perceived effort and lactate responses. Yet, hormone responses during rest redistribution were no different from TS.

• MeSH
• dospělí MeSH
• hydrokortison krev   metabolismus   MeSH
• kreatinkinasa krev   metabolismus   MeSH
• kyselina mléčná krev   MeSH
• lidé MeSH
• lidský růstový hormon krev   MeSH
• mladý dospělý MeSH
• odpočinek fyziologie   MeSH
• odporový trénink metody   MeSH
• testosteron krev   metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH

BACKGROUND: Substance use disorders constitute a major global public health problem, attributable largely to their subsequent comorbidity with other health conditions. This study aimed to investigate the risk of all-cause death and life-years lost following hospitalisation for 28 subsequent physical comorbid conditions in people with a previous hospitalisation for substance use disorder, compared with matched counterparts without substance use disorder. METHODS: We did a retrospective cohort study on data from Czech nationwide registers of all-cause hospitalisations and deaths during the period from Jan 1, 1994, to Dec 31, 2017. The cohorts consisted of individuals who had initially been hospitalised between 15 and 70 years of age (index hospitalisation) and who were subsequently hospitalised with one or more of 28 comorbid physical health conditions. We included individuals with an index hospitalisation for substance use disorders and up to three counterparts without substance use disorders with a subsequent hospitalisation for the same physical health condition, with matching on sex, age (±3 years), work status, and discharge year at first hospitalisation for the subsequent condition. Data on ethnicity were not available. Risk of death due to any cause following the first hospitalisation for each physical health condition until Dec 31, 2017, and life-years lost after disease onset at ages 30, 45, and 60 years, and before 81 years of age, were examined. FINDINGS: From a total 56 229 563 records of hospitalisations identified, we included 121 153 people with hospitalisation for substance use disorders and 6 742 134 people without hospitalisation for substance use disorders in the study. The 28 condition-specific cohorts comprised a median of 6444 individuals (IQR 2033-12 358), ranging from 444 for multiple sclerosis to 36 356 for diseases of the circulatory system. Across the cohorts, the proportion of males ranged from 31·4% for thyroid disorder to 100·0% for prostate disorders. The mean baseline age ranged from 30·0 years (SD 9·1) for chronic viral hepatitis in people with pre-existing substance use disorders to 62·2 years (9·7) for Parkinson's disease in people without pre-existing substance use disorders. After adjusting for potential confounders using stratified Cox proportional hazards models, individuals with a pre-existing substance use disorder had an increased risk of death due to any cause after the onset of 26 out of 28 physical health conditions, relative to their counterparts without substance use disorders, with adjusted hazard ratios ranging from 1·15 (1·09-1·21) for chronic liver disease to 3·86 (2·62-5·67) for thyroid disorder. For seven subsequent health conditions, the risk of death was more than doubled in the group with pre-existing substance use disorders. When compared with the general population via mortality tables, people with pre-existing substance use disorders had substantial losses in life-years after the onset of most of the subsequent physical health conditions regardless of age of onset, and, for the majority of comorbidities, lost considerably more life-years than their counterparts without substance use disorders. INTERPRETATION: A history of hospitalisation for substance use disorders appears to have a significant negative effect on prognosis following the development of various subsequent physical health conditions. These findings strongly suggest that clinical vigilance and high-quality integrated treatment for people with substance use disorders could be life-saving and should be given higher priority on the public health agenda. FUNDING: National Institute for Health and Care Research Applied Research Collaboration East of England at Cambridge and Peterborough National Health Service Foundation Trust.

• MeSH
• dospělí MeSH
• komorbidita MeSH
• lidé MeSH
• poruchy spojené s užíváním psychoaktivních látek * epidemiologie   MeSH
• registrace MeSH
• retrospektivní studie MeSH
• státní lékařství * MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Geografické názvy
• Česká republika MeSH

• MeSH
• aldehydy analogy a deriváty   MeSH
• karcinom farmakoterapie   MeSH
• myši MeSH
• protinádorové látky škodlivé účinky   MeSH
• Check Tag
• myši MeSH

The adaptive immune system is involved in tumor establishment and aggressiveness. Tumors of the ovaries, an immune-privileged organ, spread via transceolomic routes and rarely to distant organs. This is contrary to tumors of non-immune privileged organs, which often disseminate hematogenously to distant organs. Epigenetics-based immune cell quantification allows direct comparison of the immune status in benign and malignant tissues and in blood. Here, we introduce the "cellular ratio of immune tolerance" (immunoCRIT) as defined by the ratio of regulatory T cells to total T lymphocytes. The immunoCRIT was analyzed on 273 benign tissue samples of colorectal, bronchial, renal and ovarian origin as well as in 808 samples from primary colorectal, bronchial, mammary and ovarian cancers. ImmunoCRIT is strongly increased in all cancerous tissues and gradually augmented strictly dependent on tumor aggressiveness. In peripheral blood of ovarian cancer patients, immunoCRIT incrementally increases from primary diagnosis to disease recurrence, at which distant metastases frequently occur. We postulate that non-pathological immunoCRIT values observed in peripheral blood of immune privileged ovarian tumor patients are sufficient to prevent hematogenous spread at primary diagnosis. Contrarily, non-immune privileged tumors establish high immunoCRIT in an immunological environment equivalent to the bloodstream and thus spread hematogenously to distant organs. In summary, our data suggest that the immunoCRIT is a powerful marker for tumor aggressiveness and disease dissemination.

• MeSH
• dospělí MeSH
• epigeneze genetická MeSH
• imunologická tolerance * MeSH
• kolorektální nádory imunologie   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metastázy nádorů MeSH
• mladý dospělý MeSH
• nádorové biomarkery imunologie   MeSH
• nádory ledvin imunologie   patologie   MeSH
• nádory plic imunologie   patologie   MeSH
• nádory prsu imunologie   patologie   MeSH
• nádory vaječníků imunologie   patologie   MeSH
• nádory imunologie   patologie   MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• T-lymfocyty imunologie   patologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND AND OBJECTIVES: N-acetyl-l-leucine (NALL) has been established to improve the neurologic manifestations of Niemann-Pick disease type C (NPC) after 12 weeks in a placebo-controlled trial. In the open-label extension phase (EP) follow-up, data were obtained after 12 and 18 months to evaluate the long-term effects of NALL for NPC. METHODS: This is an ongoing, multinational, multicenter EP. Patients with a genetic diagnosis of NPC aged 4 years or older who completed the placebo-controlled trial were eligible to continue in the EP and receive orally administered NALL 2-3 times per day in 3 tiers of weight-based dosing. The primary end point is the modified 5-domain NPC Clinical Severity Scale (NPC-CSS) (range 0-25 points; lower score representing better neurologic status); data from the EP cohort are compared with the expected annual trajectory of decline (i.e., disease progression) established in natural history studies. Analyses are also performed on exploratory end points, including the 15-domain and 4-domain NPC-CSSs and the Scale for Assessment and Rating of Ataxia (SARA). RESULTS: Fifty-three patients aged 5-67 years (45.3% female, 54.7% male) were enrolled in the EP. After 12 months, the mean (±SD) change from baseline on the 5-domain NPC-CSS was -0.27 (±2.42) with NALL vs +1.5 (±3.16) in the historical cohort (95% CI -3.05 to -0.48; p = 0.009), corresponding to a 118% reduction in annual disease progression. After 18 months, the mean (±SD) change was +0.05 (±2.95) with NALL vs +2.25 (±4.74) in the historical cohort (95% CI -4.06 to -0.35; p = 0.023). The 15-domain and 4-domain NPC-CSSs were consistent with the 5-domain NPC-CSS. The improvements in neurologic manifestations demonstrated in the placebo-controlled trial on the primary SARA end point were sustained over the long-term follow-up. NALL was well tolerated, and no treatment-related adverse events or serious reactions occurred. DISCUSSION: Treatment with NALL was associated with a significant reduction in NPC disease progression after 12 and 18 months, demonstrating a disease-modifying, neuroprotective effect. TRIAL REGISTRATION INFORMATION: The trial is registered with ClinicalTrials.gov (NCT05163288; registered December 6, 2021), EudraCT (2021-005356-10). The first patient was enrolled into the EP on March 8, 2023. The trial was funded by IntraBio Inc. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that NALL reduces disease progression in NPC.

• MeSH
• dítě MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• leucin * analogy a deriváty   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• následné studie MeSH
• neuroprotektivní látky * terapeutické užití   MeSH
• Niemannova-Pickova nemoc typu C * farmakoterapie   MeSH
• předškolní dítě MeSH
• progrese nemoci MeSH
• stupeň závažnosti nemoci MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH

ABSTRACT: Merrigan, JJ, Jones, MT, Malecek, J, Padecky, J, Omcirk, D, Xu, N, Peñailillo, L, and Tufano, JJ. Comparison of traditional and rest-redistribution sets on indirect markers of muscle damage following eccentric exercise. J Strength Cond Res 36(7): 1810-1818, 2022-The purpose was to investigate the effect of rest-redistribution (RR) on muscle damage after eccentric knee extensions. After 2 weeks of eccentric familiarization, 11 resistance-trained men performed 2 work-matched isokinetic unilateral eccentric knee extension protocols at 60°·s-1 using a crossover design, separated by 7 days. Subjects performed 40 repetitions with 285 seconds of rest using traditional sets (TS; 4 sets of 10 with 95 seconds of interset rest) and RR (RR; 20 sets of 2 with 15 seconds of interset rest). Muscle morphology, tensiomyography, range of motion, perceived soreness, and strength were measured before and 0, 24, 48, 72, and 96 hour after RR and TS. There were no protocol × time interactions (p < 0.05). When collapsed across protocol and compared to baseline, echo intensity of the proximal vastus lateralis was 7 ± 9% greater at 0 hour (p = 0.042), echo intensity of the distal vastus lateralis was 6 ± 7% and 9 ± 7% greater at 0 hour (p = 0.048) and 24 hour (p < 0.001), respectively, and passive ROM was 2 ± 1% lower at 48 hour (p = 0.043) after exercise. No other differences existed over time for any other variable. Thus, contrary to concentric performance where RR likely plays a large role in maintaining performance, RR during eccentric isokinetic resistance training does not strongly influence exercise performance and indications of subsequent muscle damage.

• MeSH
• biologické markery MeSH
• čtyřhlavý sval stehenní diagnostické zobrazování   MeSH
• cvičení fyziologie   MeSH
• kosterní svaly * fyziologie   MeSH
• lidé MeSH
• odporový trénink * metody   MeSH
• rozsah kloubních pohybů MeSH
• svalová síla MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH