Alpha1-antitrypsin deficiency: An updated review.

Alpha1-antitrypsin deficiency (AATD) is a rare autosomal recessive disease associated with the homozygous Z variant of the SERPINA1 gene. Clinical expression of AATD, reported 60 years ago associate a severe deficiency, pulmonary emphysema and/or liver fibrosis. Pulmonary emphysema is due to the severe alpha1-antitrypsin deficiency of the ZZ homozygous status and is favored by smoking. Liver fibrosis is due to the ZZ homozygous status and is favored by obesity and excessive chronic alcohol intake, with a risk of liver cancer. Diagnosis is based on serum level and either isoelectric focusing determination of the biochemical phenotype or PCR detection of some variants. SERPINA1 gene sequencing is necessary in case of discrepancies between the results of these tests. No treatment is available for the liver disease in AATD. Although no specific trial has been performed, COPD in AATD should be treated as per COPD recommendations. Based on a randomized clinical trial, augmentation therapy is indicated in non-smoking adults less than 70 years of age with emphysema at chest CT, confirmed homozygous AATD, and FEV1 between 35% and 70% of predicted. In contrast Z heterozygosis (MZ or SZ) brings a risk of lung or liver disease only in association with further risk factors. Early detection, in all patients with COPD and chronic liver disease, is critical for the correct information of Z variant carriers. News ways of correcting the liver production of alpha1-antitrypsin will modify the care of AATD patients.

Evaluation of apathy among institutionalized older persons: Its mediating role between cognitive functioning and lack of awareness.

OBJECTIVES: The main objective of this study was to determine the directions of the relationships between apathy, cognitive deficits and lack of awareness. METHODS: One hundred and twenty-one older persons living in nursing homes, aged between 65 and 99 years old, participated in the study. Cognitive functioning, autonomy, depressive and anxious symptoms, general self-efficacy, self-esteem and apathy were evaluated through tests and questionnaires. Lack of awareness was calculated using the patient-caregiver discrepancy method. The sample was divided into two groups (n1 = 60, n2 = 61) depending on cognitive functioning level (Dementia Rating Scale < median score: 120). We first explored the characteristics of each group. Then, we compared the mode of evaluation of apathy. Finally, we investigated the direction of relationships by applying mediation analyses. RESULTS: Older persons in the low cognitive functioning group were less autonomous, had a lower cognitive functioning level, higher caregiver-rated apathy and higher lack of awareness than the high cognitive functioning group (ps < 0.05). Evaluation differences were found only in the low cognition group. Caregiver-rated apathy totally mediated the relationship between cognitive functioning (predictor) and lack of awareness (dependent variable) for the whole sample (90%) and for the low cognitive functioning group (100%). CONCLUSIONS: Cognitive deficits should be taken into account when evaluating apathy. Interventions should combine cognition training and emotion intervention to reduce lack of awareness. Future research should develop a therapy dedicated to apathy among older persons without pathologies.

Evaluation of TTV replication as a biomarker of immune checkpoint inhibitors efficacy in melanoma patients.

Torque Teno Virus (TTV) is a small, non-enveloped, single-stranded and circular DNA virus that infects the majority of the population worldwide. Increased levels of plasma TTV viral load have been observed in various situations of immune deficiency or dysregulation, and several studies have suggested that TTV levels may be inversely correlated with immune competence. The measurement of TTV viremia by qPCR has been proposed as a potential biomarker for the follow-up of functional immune competence in immunosuppressed individuals, particularly hematopoietic stem cell transplant recipients. We hypothesized that TTV viral load could be used as a prognostic marker of immune checkpoint inhibitor (ICI) efficacy, and therefore investigated the TTV viral load in melanoma patients treated with nivolumab or pembrolizumab before and after 6 months of treatment. In the present study, TTV viral load was not different in melanoma patients before anti-PD-1 introduction compared to healthy volunteers, was not modified by ICI treatment and did not allowed to distinguish patients with treatment-sensitive tumor from patients with treatment-resistant tumor.

Diagnostic yield of commercial immunodots to diagnose paraneoplastic neurologic syndromes.

OBJECTIVE: To investigate the diagnostic yield of commercial immunodots to detect onconeural antibodies associated with paraneoplastic neurologic syndromes (PNSs), we analyzed the proportion of confirmed positive results using alternative techniques. METHODS: Sera (n = 5,300) of patients with suspected PNS were tested by PNS+2 blot (Ravo Diagnostika; January 2016-May 2017) or EUROLINE PNS 12 Ag (Euroimmun; July 2017-November 2018). Positive samples were further explored by in-house indirect immunofluorescence and a third in-house technique (Western blot or cell-based assay) using recombinant protein. Those found negative by these 2 techniques were considered as nonconfirmed. We analyzed the relationship between band intensity and final confirmation. Clinical data were collected for all confirmed results and nonconfirmed EUROLINE immunodots. RESULTS: PNS+2 blot was positive in 128/1,658 (7.7%) sera and confirmed in 47/128 (36.7%). EUROLINE was positive in 186/3,626 (5.1%) and confirmed in 56/186 (30.1%). Confirmation was highly variable among the antibodies tested, from 7.2% (PNS+2 blot) and 5.8% (EUROLINE) for anti-Yo to 88.2% (PNS+2 blot) and 65.0% (EUROLINE) for anti-Hu. None of the 27 weak positive sera by EUROLINE was confirmed. Band intensity in confirmed cases was variable among the antibodies from strong positive for all anti-Yo (n = 3) and anti-Hu (n = 11) to positive (n = 19) or strong positive (n = 9) for anti-SOX1. Among patients with a nonconfirmed EUROLINE result and available clinical information, all had an alternative diagnosis, and only 6.7% had cancer. CONCLUSIONS: Immunodots may be useful for PNS screening, but a threshold should be established for each antibody, and clinical information and confirmation by other techniques are essential. CLASSIFICATION OF EVIDENCE: The study provides Class IV evidence that immunodot assays for onconeural antibodies accurately identify patients with paraneoplastic neurologic syndromes.

Acute Renal Colic Due to Immunoglobulin Free Light Chain Kidney Stones: A Case Report of an Unusual Complication of Multiple Myeloma.

Kidney failure is common in patients with a monoclonal gammopathy, most frequently due to hypercalcemia or myeloma cast nephropathy. Immunoglobulin crystallization is an uncommon phenomenon that also results in kidney injury. We report the case of a 74-year-old man with recurrent renal colic and acute kidney injury. He presented with κ light chain Bence-Jones proteinuria, hypogammaglobulinemia, anemia, and high plasma κ light chain level, leading to the diagnosis of κ light chain multiple myeloma. One calculus was collected and its analysis revealed a unique protein structure consisting of κ immunoglobulin free light chain. Genetic sequencing of the κ light chain identified a subgroup of variable domain previously identified as prone to crystallization. Eight cycles of cyclophosphamide-bortezomib-dexamethasone chemotherapy resulted in a partial hematologic response and kidney recovery without recurrence of renal colic. This rare case of urinary light chain nephrolithiasis highlights the importance of genetic and molecular analysis of the immunoglobulin variable domain to better understand the wide spectrum of monoclonal gammopathies.

Fibromyalgia patients make scarce reference to pain in self-defining memories.

OBJECTIVE: Self-defining memories (SDMs) are vivid, emotionally intense and well-rehearsed autobiographical memories that provide fundamental information about one's cognitive affective motivational representation of self. Exploring SDMs in fibromyalgia (FM) is of interest for understanding the psychopathology of this disorder and improving clinical interventions. Our aim was to compare patients and healthy controls (HC) on SDM characteristics. METHOD: We included 25 patients with FM and 24 HC matched for age, sex and education level. Each participant described five SDMs, which were coded for content, specificity, integration, tension, redemption, contamination, affective response, date, and reference to pain. We statistically controlled our results for the most plausible confounding factors related to FM that could affect SDM recall, namely depression, anxiety, cognitive inhibition, pain severity and medication. RESULTS: Compared with HC, patients retrieved less specific SDMs with a more negative emotional valence but less tension. They reported more relationship-related memories, and fewer redemptive ones, with less meaning-making. The number of memories referring to physical or psychological pain did not differ between groups. None of the confounding factors we analysed could explain (either alone or in combination) the statistical differences between groups for SDMs characteristics. CONCLUSION: We discuss functional avoidance and alexithymia as two main factors for poor reference to pain in patients' SDMs that further reveal affective dysregulation in FM. In clinical practice, remediating the way in which pain is integrated into SDMs in FM may help to mitigate its negative impact on everyday life.

One-Year Follow-Up of Natural Killer Cell Activity in Multiple Myeloma Patients Treated With Adjuvant Lenalidomide Therapy.

Multiple myeloma (MM) is a proliferation of tumoral plasma B cells that is still incurable. Natural killer (NK) cells can recognize and kill MM cells in vitro and can limit MM growth in vivo. Previous reports have shown that NK cell function is impaired during MM progression and suggested that treatment with immunomodulatory drugs (IMIDs) such as lenalidomide (LEN) could enhance it. However, the effects of IMIDs on NK cells have been tested mostly in vitro or in preclinical models and supporting evidence of their effect in vivo in patients is lacking. Here, we monitored NK cell activity in blood samples from 10 MM patients starting after frontline induction chemotherapy (CTX) consisting either of association of bortezomib-lenalidomide-dexamethasone (Velcade Revlimid Dexamethasone) or autologous stem-cell transplantation (SCT). We also monitored NK cell activity longitudinally each month during 1 year, after maintenance therapy with LEN. Following frontline chemotherapy, peripheral NK cells displayed a very immature phenotype and retained poor reactivity toward target cells ex vivo. Upon maintenance treatment with LEN, we observed a progressive normalization of NK cell maturation, likely caused by discontinuation of chemotherapy. However, LEN treatment neither activated NK cells nor improved their capacity to degranulate or to secrete IFN-γ or MIP1-ß following stimulation with MHC-I-deficient or antibody-coated target cells. Upon LEN discontinuation, there was no reduction of NK cell effector function either. These results caution against the use of LEN as single therapy to improve NK cell activity in patients with cancer and call for more preclinical assessments of the potential of IMIDs in NK cell activation.

A Case of Type 2 Hypersensitivity to Rasburicase Diagnosed with a Natural Killer Cell Activation Assay.

Drug hypersensitivity reactions can lead to different clinical pictures depending on the underlying immunological mechanism. Diagnosis tests are already available to assess the most frequent drugs hypersensitivity reactions, which are mediated by specific IgE or T cells. However, it remains challenging to diagnose type 2 hypersensitivity reactions (T2HR), which can lead to severe cytopenia and liver failure. Here, we describe a case of T2HR to rasburicase, an uricolytic agent used to prevent tumor lysis syndrome. In this patient, sensitization was associated with the production of specific IgG able to bind to leukocytes. We found that patient NK cells were specifically activated in the presence of rasburicase and autologous serum, which led to exocytosis of lytic granules. This antibody-dependent cell cytotoxicity mechanism may lead to cytopenia observed in the patient. Moreover, this NK cell activation assay could be used to improve the diagnosis of a T2HR to rasburicase and, by extent, to other drugs. These data also suggest that NK cells could play an important role in the pathophysiological mechanism of T2HR.

Multicenter Evaluation of Cystatin C Measurement after Assay Standardization.

BACKGROUND: Since 2010, a certified reference material ERM-DA471/IFCC has been available for cystatin C (CysC). This study aimed to assess the sources of uncertainty in results for clinical samples measured using standardized assays. METHODS: This evaluation was performed in 2015 and involved 7 clinical laboratories located in France and Belgium. CysC was measured in a panel of 4 serum pools using 8 automated assays and a candidate isotope dilution mass spectrometry reference measurement procedure. Sources of uncertainty (imprecision and bias) were evaluated to calculate the relative expanded combined uncertainty for each CysC assay. Uncertainty was judged against the performance specifications derived from the biological variation model. RESULTS: Only Siemens reagents on the Siemens systems and, to a lesser extent, DiaSys reagents on the Cobas system, provided results that met the minimum performance criterion calculated according to the intraindividual and interindividual biological variations. Although the imprecision was acceptable for almost all assays, an increase in the bias with concentration was observed for Gentian reagents, and unacceptably high biases were observed for Abbott and Roche reagents on their own systems. CONCLUSIONS: This comprehensive picture of the market situation since the release of ERM-DA471/IFCC shows that bias remains the major component of the combined uncertainty because of possible problems associated with the implementation of traceability. Although some manufacturers have clearly improved their calibration protocols relative to ERM-DA471, most of them failed to meet the criteria for acceptable CysC measurements.

Executive functions in adult offspring of alcohol-dependent probands: toward a cognitive endophenotype?

BACKGROUND: Executive function (EF) impairment in alcohol dependence (AD) has been related to the toxic effects of alcohol on frontal lobes. However, this impairment could be partially present before the onset of the disease and might constitute a vulnerability factor. Although a considerable body of research has investigated executive functioning among AD patients, much less attention has been directed toward high-risk individuals. Most studies were carried out among children or adolescents, and very few were conducted in adults. The aim of this study was to examine EF in a group of adult offspring of AD individuals. METHODS: One hundred and fifty-five nonalcoholic adults with (family history positive [FHP]) or without (family history negative [FHN]) family history of AD were included in the study. All participants were screened for past and current psychiatric diagnoses, and alcohol, tobacco, and other substance use. They were compared on self-rated impulsiveness using the Barratt Impulsiveness Scale-11 (BIS-11) and EF using a neuropsychological test battery. RESULTS: Group comparison revealed that FHP participants had significantly higher BIS-11 scores than the FHN participants, while neuropsychological examination revealed lower EF scores for FHP participants. Hierarchical regression analysis revealed that the number of AD family members was a predictor of EF results, whereas impulsiveness was not. CONCLUSIONS: Nonalcoholic adult offspring of AD individuals showed increased impulsiveness and decreased EF, suggesting weakness of 2 distinct neurobehavioral decision systems. Findings support evidence that EF weaknesses may qualify as a suitable endophenotype candidate for AD.