Critical appraisal of canakinumab in the treatment of adults and children with cryopyrin-associated periodic syndrome (CAPS)

The cryopyrin-associated syndromes (CAPS) include three autosomal-dominant syndromes, that are caused by a mutation in the NLRP3 gene on chromosome 1, encoding the cryopyrin protein. These syndromes, familial cold autoinflammatory syndrome, Muckle-Wells syndrome and neonatal-onset multisystem inflammatory disease, are characterized by urticaria-like rash, fever, central nervous system inflammation, an arthropathy and a risk of the development of amyloidosis in a respectively escalating degree of severity between the various syndromes. Recently the role of cryopyrin in the regulation of interleukin (IL)-1 production and activation was described and anti IL-1 therapies were found to be very effective in treating these syndromes. There are several types of anti IL-1 medications based on different mechanisms of antagonizing IL-1. This paper focuses on the efficacy and safety of canakinumab, a long-acting humanized anti IL-1 antibody, in treating these syndromes

Cascade infrared thermal photon emission

The time development of the excitation energy of molecules and clusters cooling by emission of thermal vibrational infrared radiation has been studied. The energy distributions and the photon emission rates develop into near-universal functions that can be characterized with only a few parameters, irrespective of the precise vibrational spectra and oscillator strengths of the systems. The photon emission constant and emitted power averaged over all thermally populated states vary linearly with total excitation energy with a small offset. The time developments of ensemble internal energy distributions are calculated with respect to their first two moments. For the derived linear dependence of the emission rate constant, these results are exact

Peptide bond formation in the protonated serine dimer following vacuum UV photon-induced excitation

Possible routes for intra-cluster bond formation (ICBF) in protonated serine dimers have been studied. We found no evidence of ICBF following low energy collision-induced dissociation (in correspondence with previous works), however, we do observe clear evidence for ICBF following photon absorption in the 4.6–14 eV range. Moreover, the comparison of photon-induced dissociation measurements of the protonated serine dimer to those of a protonated serine dipeptide provides evidence that ICBF, in this case, involves peptide bond formation (PBF). The experimental results are supported by ab initio molecular dynamics and exploration of several excited state potential energy surfaces, unraveling a pathway for PBF following photon absorption. The combination of experiments and theory provides insight into the PBF mechanisms in clusters of amino acids, and reveals the importance of electronic excited states reached upon UV/VUV light excitatio

Association of components of the metabolic syndrome with the appearance of aggregated red blood cells in the peripheral blood. An unfavorable hemorheological finding

Abstract Background Components of the metabolic syndrome are associated with low-grade inflammation. This can be accompanied by the synthesis of sticky proteins and erythrocyte aggregation

Vacuum UV studies of protonated serine clusters

International audienceAbstract In a recent work, we have shown that photon absorption can cause a chemical bond to be created between the two monomers within a protonated serine dimer, a process known as intra-cluster bond formation, despite this process not occurring following thermal excitation via low energy collision-induced dissociation (LE-CID). Here we show further evidence for non-statistical photon-induced dissociation (PID) of the protonated serine dimer. In addition we discuss LE-CID and PID studies of the protonated serine octamer, showing that in this case as well, PID leads to non-statistical fragmentation and to the formation of two bonds between three neighboring monomers

Transitioning from having no metabolic abnormality nor obesity to metabolic impairment in a cohort of apparently healthy adults

Abstract Introduction The global prevalence of metabolic syndrome and its association with increased morbidity and mortality has been rigorously studied. However, the true prevalence of “metabolic health”, i.e. individuals without any metabolic abnormalities is not clear. Here, we sought to determine the prevalence of “metabolically healthy” individuals and characterize the “transition phase” from metabolic health to development of dysfunction over a follow-up period of 5 years. Methods We included 20,507 individuals from the Tel Aviv Sourasky Medical Center Inflammation Survey (TAMCIS) which comprises apparently healthy individuals attending their annual health survey. A second follow-up visit was documented after 4.8 (± 0.6) years. We defined a group of metabolically healthy participants without metabolic abnormalities nor obesity and compared their characteristics and change in biomarkers over time to participants who developed metabolic impairment on their follow-up visit. The intersections of all metabolic syndrome components and elevated high sensitivity C-reactive protein (hs-CRP) were also analyzed. Results A quarter of the cohort (5379 individuals, (26.2%) did not fulfill any metabolic syndrome criteria during their baseline visit. A total of 985 individuals (12.7% of returning participants) developed metabolic criteria over time with hypertension being the most prevalent component to develop among these participants. Individuals that became metabolically impaired over time demonstrated increased overlap between metabolic syndrome criteria and elevated hs-CRP levels. The group that became metabolically impaired over time also presented higher delta values of WBC, RBC, liver biomarkers, and uric acid compared with participants who were consistently metabolically impaired. LDL-C (low-density lipoprotein cholesterol) delta levels were similar. Conclusions Roughly one-quarter of apparently healthy adults are defined as “metabolically healthy” according to current definitions. The transition from health to metabolic dysfunction is accompanied with active inflammation and several non-metabolic syndrome biomarkers. Aggressive screening for these biomarkers, blood pressure and hs-CRP might help identify apparently healthy individuals at increased risk of developing metabolic syndrome over time

First Year of Israeli Newborn Screening for Severe Combined Immunodeficiency—Clinical Achievements and Insights

Severe combined immunodeficiency (SCID), the most severe form of T cell immunodeficiency, is detectable through quantification of T cell receptor excision circles (TRECs) in dried blood spots obtained at birth. Herein, we describe the results of the first year of the Israeli SCID newborn screening (NBS) program. This important, life-saving screening test is available at no cost for every newborn in Israel. Eight SCID patients were diagnosed through the NBS program in its first year, revealing an incidence of 1:22,500 births in the Israeli population. Consanguine marriages and Muslim ethnic origin were found to be a risk factor in affected newborns, and a founder effect was detected for both IL7Rα and DCLRE1C deficiency SCID. Lymphocyte subset analysis and TREC quantification in the peripheral blood appear to be sufficient for confirmation of typical and leaky SCID and ruling out false positive (FP) results. Detection of secondary targets (infants with non-SCID lymphopenia) did not significantly affect the management or outcomes of these infants in our cohort. In the general, non-immunodeficient population, TREC rises along with gestational age and birth weight, and is significantly higher in females and the firstborn of twin pairs. Low TREC correlates with both gestational age and birth weight in extremely premature newborns. Additionally, the rate of TREC increase per week consistently accelerates with gestational age. Together, these findings mandate a lower cutoff or a more lenient screening algorithm for extremely premature infants, in order to reduce the high rate of FPs within this group. A significant surge in TREC values was observed between 28 and 30 weeks of gestation, where median TREC copy numbers rise by 50% over 2 weeks. These findings suggest a maturational step in T cell development around week 29 gestation, and imply moderate to late preterms should be screened with the same cutoff as term infants. The SCID NBS program is still in its infancy, but is already bearing fruit in the early detection and improved outcomes of children with SCID in Israel and other countries

Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency

Inherited CARMIL2 deficiency underlies infections, EBV+ smooth muscle tumors, and mucocutaneous inflammation. CARMIL2 deficiency impairs CD28 signaling only partially in T cells. The comparison of CARMIL2 and CD28 deficiency in humans suggests that CARMIL2 governs immunological pathways beyond CD28. Patients with inherited CARMIL2 or CD28 deficiency have defective T cell CD28 signaling, but their immunological and clinical phenotypes remain largely unknown. We show that only one of three CARMIL2 isoforms is produced and functional across leukocyte subsets. Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-kappa B but not AP-1 and NFAT activation in T cells stimulated via CD28. Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4(+) and CD8(+) memory T cells and CD4(+) T(REG)s. Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak. CARMIL2 deficiency is fully penetrant by the age of 10 yr and is characterized by numerous infections, EBV+ smooth muscle tumors, and mucocutaneous inflammation, including inflammatory bowel disease. Patients with somatic reversions of a mutant allele in CD4(+) T cells have milder phenotypes. Our study suggests that CARMIL2 governs immunological pathways beyond CD28

Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency

International audiencePatients with inherited CARMIL2 or CD28 deficiency have defective T cell CD28 signaling, but their immunological and clinical phenotypes remain largely unknown. We show that only one of three CARMIL2 isoforms is produced and functional across leukocyte subsets. Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-κB but not AP-1 and NFAT activation in T cells stimulated via CD28. Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4 + and CD8 + memory T cells and CD4 + T REG s. Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak. CARMIL2 deficiency is fully penetrant by the age of 10 yr and is characterized by numerous infections, EBV + smooth muscle tumors, and mucocutaneous inflammation, including inflammatory bowel disease. Patients with somatic reversions of a mutant allele in CD4 + T cells have milder phenotypes. Our study suggests that CARMIL2 governs immunological pathways beyond CD28