Impact of the COVID-19 pandemic on symptoms of anxiety and depression and health-related quality of life in older patients with chronic kidney disease.

BACKGROUND: Older patients with advanced chronic kidney disease are at increased risk for a severe course of the coronavirus disease-2019 (COVID-19) and vulnerable to mental health problems. We aimed to investigate prevalence and associated patient (demographic and clinical) characteristics of mental wellbeing (health-related quality of life [HRQoL] and symptoms of depression and anxiety) before and during the COVID-19 pandemic in older patients with advanced chronic kidney disease. METHODS: An ongoing Dutch multicentre prospective cohort study enrols patients of ≥70 years with an eGFR < 20 mL/min/1.73m2 from October 2018 onward. With additional questionnaires during the pandemic (May-June 2020), disease-related concerns about COVID-19 and general anxiety symptoms were assessed cross-sectionally, and depressive symptoms, HRQoL, and emotional symptoms longitudinally. RESULTS: The 82 included patients had a median age of 77.5 years (interquartile range 73.9-82.1), 77% were male and none had tested positive for COVID-19. Cross-sectionally, 67% of the patients reported to be more anxious about COVID-19 because of their kidney disease, and 43% of the patients stated that their quality of life was reduced due to the COVID-19 pandemic. Compared to pre-COVID-19, the presence of depressive symptoms had increased (11 to 22%; p = .022) and physical HRQoL declined (M = 40.4, SD = 10.1 to M = 36.1, SD = 10.4; p < .001), particularly in males. Mental HRQoL (M = 50.3, SD = 9.6 to M = 50.4, SD = 9.9; p = .913) and emotional symptoms remained similar. CONCLUSIONS: Older patients with advanced chronic kidney disease suffered from disease-related anxiety about COVID-19, increased depressive symptoms and reduced physical HRQoL during the COVID-19 pandemic. The impact of the pandemic on this vulnerable patient group extends beyond increased mortality risk, and awareness of mental wellbeing is important. TRIAL REGISTRATION: The study is registered at the Netherlands Trial Register (NTR), trial number NL7104. Date of registration: 06-06-2018.

Clinical implications of isolated troponinemia following immune checkpoint inhibitor therapy.

Cardiovascular adverse events induced by immune checkpoint inhibitors (ICIs) have gained significant interest over the past decade due to their impact on short- and long-term outcomes. They were initially thought to be rare, but the increasing use of ICIs in the treatment of both advanced and early stages of various malignancies has resulted in a substantial increase in their incidence. Different guidelines have proposed screening measures for ICI-induced myocarditis by incorporating troponin measurements at baseline and during the first few weeks of treatment. However, no specific guidelines have been developed yet regarding the interpretation of an asymptomatic rise in troponins. This state-of-the art review aims to provide an overview of the clinical relevance of elevated troponins during checkpoint inhibition and recommendations on how to manage elevated troponin levels during ICI therapy.

[Autonomic hyperreflexia after spinal cord injury : perioperative management]. / L'hyperréflexie autonome après lésion médullaire : prise en charge en période périopératoire.

Spinal cord injury can have widespread consequences beyond the disruption of sensory and motor functions. Injury at or above the sixth thoracic spinal cord segment frequently leads to dysregulation of the autonomic nervous system, which results in a syndrome called autonomic hyperreflexia or dysreflexia. It is a hypertensive crisis triggered by visceral or somatic stimuli below the level of the injury and caused by sympathetic spinal reflexes not modulated by regulatory centers in the brain. Patients with spinal cord injuries frequently undergo surgery for multiple reasons. Because of the potentially lethal complications of autonomic hyperreflexia, physicians, and in particular anaesthesiologists, must be aware of the underlying pathophysiological mechanisms and adequate perioperative management.

Les lésions de la moelle épinière peuvent avoir de nombreuses conséquences autres que la perturbation des fonctions sensitives et motrices. Une lésion d'un niveau médullaire supérieur ou égal au sixième segment thoracique (T6) entraîne, fréquemment, une dysrégulation du système nerveux autonome et le développement d'un syndrome appelé hyperréflexie ou dysréflexie autonome. Il s'agit d'une crise hypertensive déclenchée par des stimuli viscéraux ou somatiques sous le niveau de la lésion et causée par des réflexes sympathiques médullaires non modulés par les centres régulateurs encéphaliques. Les patients porteurs de lésions médullaires bénéficient, régulièrement, d'interventions chirurgicales pour des raisons multiples. Les complications potentiellement létales de l'hyperréflexie autonome exigent des médecins et, en particulier, des anesthésistes-réanimateurs une connaissance des mécanismes physiopathologiques sous-jacents et une prise en charge péri-interventionnelle adéquate.

Nephrotic syndrome due to lupus-like glomerulonephritis in an HIV-positive patient.

Lupus nephritis, a well-known complication in systemic lupus erythematosus, is characterised by a proliferative glomerulonephritis or membranous nephropathy along with a full-house immunofluorescence pattern on renal biopsy. There are very few exceptions in which similar histopathological findings are present, but case reports show that an increasing number of HIV-positive patients (mostly black Africans, but also white patients) have HIV-immune complex disease (HIVICK), which can mimic lupus nephritis. Lupus-like HIVICK is treated differently than 'true' lupus nephritis, so distinction is warranted.

[PERIOPERATIVE VISUAL LOSS AFTER SPINE SURGERY: A CASE REPORT]. / Cécité post-opératoire après chirurgie rachidienne.

Perioperative visual loss is a rare but devastating complication that may follow spine surgery in the prone position. So far, the incidence, mechanisms and risk factors have not been clearly established. Most commonly, the visual loss results from an ischemic optic neuropathy. We describe the case of a 68 year-old woman who underwent a lumbar laminectomy in the prone position. Upon recovery from anesthesia, the patient complained of total left blindness. This visual loss was, slowly and only partially, recovered after 72 hours. We discuss the most common causes of postoperative visual loss, the risk factors and preventive strategy.

Paper or Plastic? Exploring the Effects of Natural Enrichment on Behavioural and Neuroendocrine Responses in Long-Evans Rats.

Enriched environments are beneficial to neurobiological development; specifically, rodents exposed to complex, rather than standard laboratory, environments exhibit evidence of neuroplasticity and enhanced cognitive performance. In the present study, the nature of elements placed in the complex environment was investigated. Accordingly, rats (n = 8 per group) were housed either in a natural environment characterised by stimuli such as dirt and rocks, an artificial environment characterised by plastic toys and synthetic nesting materials, a natural/artificial environment characterised by a combination of artificial and natural stimuli or a laboratory standard environment characterised by no enrichment stimuli. Following exposure to emotional and cognitive behavioural tasks, including a cricket hunting task, a novel object preference task and a forced swim task, brains were processed for glial fibrillary acidic protein (GFAP)-, neuronal nuclei (NeuN)- and brain-derived neurotrophic factor (BDNF) immunoreactivity. Baseline and stress foecal samples were collected to assess corticosterone (CORT) and dehydroepiandrosterone (DHEA). Natural environment animals exhibited shorter diving latencies and increased diving frequencies in the second forced swimming task, along with higher DHEA/CORT ratios, and higher GFAP immunoreactivity in the hippocampus. The type of environmental enrichment did not influence levels of BDNF immunoreactivity in the CA1, CA3 and dentate gyrus of the hippocampus; however, natural environment animals exhibited higher levels of NeuN immunoreactivity in the retrosplenial cortex, an area involved in spatial memory and other cognitive functions. These results suggest that, in addition to enhancing behavioural and endocrinological variables associated with resilience, exposure to natural stimuli might alter plasticity in brain areas associated with cortical processing and learning.

The role of titin and extracellular matrix remodelling in heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is characterised by a high incidence of metabolic comorbidities that share the potential to induce both systemic and coronary microvascular inflammation and oxidative stress. These pathophysiological alterations contribute to increased passive stiffness of the myocardium and to diastolic dysfunction, both hallmarks of HFpEF. Passive myocardial stiffness depends mainly on two components: the extracellular matrix (ECM) and the cardiomyocytes. Quantitative and qualitative changes in collagen metabolism leading to myocardial fibrosis determine the ECM-based stiffness of the myocardium. Different noninvasive diagnostic tools to assess myocardial fibrosis are being developed, some of which have demonstrated to correlate with clinical status and prognosis. Cardiomyocytes mainly alter the passive stiffness through alterations in the giant myofilament titin, which serves as a spring. By modifying its phosphorylation state or by direct oxidative effects, titin determines cardiomyocyte-based passive stiffness. Probably the relative importance of cardiomyocyte-based changes is more important in the beginning of the disease, whereas ECM-based changes become more prominent in the more advanced stages. The present review focuses on these changes in ECM and cardiomyocytes in HFpEF and their potential prognostic and therapeutic implications.

Thinking beyond the mass: ANCA-associated vasculitis mimicking a pancreatic malignancy.

Isolated pancreatic involvement is a rare initial presentation in patients with ANCA-associated vasculitis. We report a patient with a suspected malignant pancreatic mass, referred to our hospital for pancreaticoduodenectomy. However, the pancreatic mass proved to be the initial manifestation of ANCA-associated vasculitis.

Modeling paternal attentiveness: distressed pups evoke differential neurobiological and behavioral responses in paternal and nonpaternal mice.

With the exception of parturition and lactation, male California deer mice (Peromyscus californicus) exhibit the same parental responses toward offspring as conspecific females. A closely related species, Peromyscus maniculatus, however, rarely exhibits paternal responses. In the current study, a comparative species approach was used to assess paternal responses in both Peromyscus species with varying levels of paternal experience (biological fathers, pup-exposed virgins, and pup-naïve virgins). Of special interest was the persistence of the males to direct their attention toward a distressed pup housed in a small enclosure (i.e., a barrier existed between males and pups). In addition to pup-directed responses, non-pup-directed responses such as grooming, resting and jumping were recorded. Subsequently, all animals' brains were assessed for fos-immunoreactivity (ir) in several areas previously associated with the paternal brain circuit. Overall, P. californicus exhibited more pup-directed responses as well as less fos-ir in brain areas involved in emotional integration and processing such as the insula and anterior cingulate. In addition to increased activation of emotional regulatory areas, P. maniculatus males, observed to direct their behavior away from the pup, exhibited higher fos-ir in the nucleus accumbens (involved in goal acquisition), perhaps due to a heightened motivation to avoid the pups. Interestingly, experience with pups altered the lateral septum and amygdala activation of P. maniculatus to levels similar to P. californicus biological fathers. Finally, fos-ir was increased in the medial preoptic area, involved in the maintenance of maternal behavior, in the biological fathers of both species. Thus, although biological predispositions toward pup-directed behaviors were observed in P. californicus males, evidence of a few shifts toward the paternal neural activation profile was apparent in P. maniculatus males. Specifically, modifications in fear responses and social processing may represent the cornerstones of the gradual shift from social tentativeness to social attentiveness in the presence of pups.

Fatherhood alters behavioural and neural responsiveness in a spatial task.

The hormones and experiences of pregnancy, parturition and lactation have been shown to dramatically remodel the female rat's hippocampus, potentially enhancing behaviours critical for meeting the increased demands of motherhood. Previous work in our laboratory has also suggested that pup exposure, apart from pregnancy and lactation, constitutes an important influence on ancillary maternal behaviour (e.g. foraging behaviour). In the present study, we press the parental model further by examining the effect of pup exposure on the hippocampus of males from a biparental mouse species, the California mice (Peromyscus californicus). Males were either Fathers (i.e. first-time fathers housed with a female from mating until 7 days after parturition), pup-exposed virgins (PEV; i.e. sexually naïve males briefly exposed to pups daily for 7 days) or Virgins (i.e. never exposed to females or pups). A dry-land maze (DLM), as used for assessing spatial learning, was employed to determine the foraging abilities of the males. The results indicated that, on the most challenging day of testing (i.e. acquisition day), California mouse Fathers demonstrated superior memory for the task compared to PEVs and Virgins. In addition to the behavioural data, significantly more fos-immunoreactivity was observed in the CA1, CA3 and dentate gyrus regions of the hippocampi of Fathers than PEVs or Virgins in response to the probe trial. Additionally, a trend for altered performance on the DLM was observed in the PEVs on the last day of testing, which was accompanied by the highest levels of nestin-immunoreactivity, an indicant of neuroplasticity, of the three groups. In summary, these data suggest that, in accordance with previous observations of maternal rats, the paternal brain is similarly influenced by parental experience, as demonstrated by accompanying modifications to relevant neurobiological and behavioural responses.

Surgical resection of a sphenoid wing meningioma in a patient with Glanzmann thrombasthenia.

Glanzmann thrombasthenia (GT) is a rare autosomal recessive disorder characterized by a deficiency or functional defect of platelet glycoprotein (GP) IIb/IIIa. Physiologically, this platelet receptor mediates aggregation of activated platelets by binding the adhesive proteins, fibrinogen, von Willebrand factor (VWF) and fibronectin. This facilitates attachment and aggregation of platelets at sites of vascular injury. We reported the management of a pterional meningioma resection in a patient with Glanzmann thrombasthenia, with recombinant factor VIIa (rFVIIa - NovoSeven) as haemostatic agent. A 48-year-old woman suffering from Glanzmann thrombasthenia was scheduled for spheno-orbital meningioma en plaque surgery. Because of repeated platelet transfusions, this patient developed isoantibodies against missing GPIIbIIIa and alloantibodies against Human Leukocyte Antigen (HLA) leading to refractoriness to platelet transfusions. We observed that Novoseven offered sufficient haemostasis conditions. Therefore, we noticed a deep vein thrombosis. This imposed us to use low weight molecular heparin despite recent surgery.

Description of a new species, Bifidobacterium crudilactis sp. nov., isolated from raw milk and raw milk cheeses.

A new Bifidobacterium species is described based on the study of ten Gram-positive strains with fructose-6-phosphate phosphoketolase activity. They are part of a phenotypic group comprising 141 strains isolated from raw milk and raw milk cheeses in French raw milk cheese factories. This group was separated by a numerical analysis based on API 50CH, API 32A tests and growth at 46 degrees C. A strong similarity of 16S rRNA sequences (99.8%) was shown between strain FR62/b/3(T) and Bifidobacterium psychraerophilum LMG 21775(T). However, low DNA-DNA relatedness was observed between their DNAs (31%). The new isolates are able to grow at low temperatures (all ten strains up to 5 degrees C) and strain FR62/b/3(T) grows under aerobic conditions, as does B. psychraerophilum. However, contrary to B. psychraerophilum, they do not ferment L-arabinose, D-xylose, arbutin or melezitose, but they do acidify lactose. The DNA G+C content of FR62/b/3(T) is 56.4mol%. Therefore, the name Bifidobacterium crudilactis sp. nov. is proposed, with its type strain being FR62/b/3(T) (=LMG 23609(T)=CNCM I-3342(T)).

Adenosine and dialysis hypotension.

In this issue, Imai et al. report the results of a double-blind placebo-controlled study on the effect of an adenosine A1 receptor antagonist, FK352, on the incidence of dialysis hypotension in hypotension-prone patients. This Commentary discusses the use of selective adenosine A1 receptor antagonists for the prevention of dialysis hypotension from the perspective of the potential role of adenosine in its pathogenesis.

Extracorporal albumin dialysis (MARS) improves cholestasis and normalizes low apo A-I levels in a patient with benign recurrent intrahepatic cholestasis (BRIC).

The familial cholestatic diseases Benign Recurrent Intrahepatic Cholestasis (BRIC) and Progessive Familial Intrahepatic Cholestasis type 1 (PFIC1) are characterized by intermittent or permanently elevated plasma bile salt levels, therapy-resistant extreme pruritus and peculiar biochemical abnormalities including low apolipoprotein apo A-I. Previously, symptomatic improvement has been demonstrated in BRIC patients after extracorporal albumin dialysis (MARS). We hypothesized that MARS improves cholestasis, induces changes in the bile salt profile and normalizes apo A-I serum levels in BRIC. A 17-year-old-female patient with BRIC experienced an episode of cholestasis lasting for more than 6 months with extreme pruritus and diarrhoea not responding to standard therapy. During a period of five days the patient was treated 3 x 8 h with MARS. The procedures were well tolerated and resulted in reduction of plasma bile salts by 58%. The plasma bile salt profile changed into a more hydrophilic composition after MARS. Diarrhoea discontinued and the pruritus improved significantly from 9 to 4 on a subjective scale. These effects lasted 4 months until a relapse occurred. Low plasma apo A-I levels (0.52 g/l) normalized after MARS (0.98 g/l). The procedures were well tolerated. Fatigue was noted as the only transient side-effect. In conclusion, MARS may induce a long-term symptomatic improvement and decrease of cholestatic markers in BRIC. Further studies evaluating efficacy and mechanism of MARS in patients with BRIC are needed.

In vitro cytokine production and proliferation of T cells from patients with anti-proteinase 3- and antimyeloperoxidase-associated vasculitis, in response to proteinase 3 and myeloperoxidase.

OBJECTIVE: To investigate in vitro proliferative responses of CD4+ T cells and generation of specific cytokines induced by stimulation of peripheral blood mononuclear cells (PBMCs) from patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis with the autoantigens proteinase 3 (PR3) and myeloperoxidase (MPO). METHODS: PBMCs from vasculitis patients with PR3 ANCA or MPO ANCA and from healthy controls were stimulated for 7 days with PR3, MPO, or control stimuli. Proliferation of CD4+ T cells was assessed by flow cytometry, using the proliferation marker Ki-67. Levels of the pro-proliferative cytokines interleukin-2 (IL-2) and IL-6 and of the Th1 and Th2 cytokines interferon-gamma (IFN gamma) and IL-10 in culture supernatants were determined. RESULTS: PR3 and MPO induced proliferative responses in CD4+ T cells from individual patients with ANCA-associated vasculitides and healthy controls in vitro. Neither PR3 nor MPO elicited significant IL-2 production. Levels of IL-6 were highest after stimulation with PR3 but low after stimulation with MPO, independent of study group. Stimulation with PR3, and to a lesser extent with MPO, induced a Th2 cytokine milieu, characterized by high production of IL-6 and IL-10 and low production of IFN gamma in patients and controls. CONCLUSION: PR3 and MPO promote proliferation of CD4+ T cells from patients with ANCA-associated vasculitides, but also cross-stimulate T cells from healthy individuals. Strong IL-10 production elicited by PR3 in vitro may act as an inhibitory signal for T cell proliferation and may have an important immunoregulatory function in vivo.

In vitro T lymphocyte responses to proteinase 3 (PR3) and linear peptides of PR3 in patients with Wegener's granulomatosis (WG).

T cell-mediated immunity is thought to play an important role in the pathogenesis of WG. In previous studies a minority of WG patients as well as some healthy controls showed in vitro proliferation of their peripheral blood mononuclear cells (PBMC) to PR3, the main autoantigen in WG. The relevant peptides responsible for this in vitro proliferation have not been identified. In order to define immunogenic peptides, PBMC of 13 WG patients in remission and 10 healthy controls were tested for proliferation to linear peptides of PR3 and to whole PR3. Fifty overlapping peptides spanning the whole PR3 sequence were synthesized. Peptides were tested in pools of five peptides and as single peptide. PBMC of two WG patients and one healthy control proliferated to whole PR3 and to peptide pools. In addition, 10 WG patients and eight healthy controls that did not proliferate to whole PR3 did proliferate to pools of PR3 peptides. Although more WG patients tended to react to particular peptide pools, no significant difference was seen between lymphocyte proliferation to PR3 peptides of WG patients and that of healthy controls. The pools of peptides recognized were mainly located at the N- and C-terminus of PR3. No correlation was observed between HLA type and proliferation on particular peptide pools. No proliferation of PBMC was observed to single peptides. In conclusion, T cells of WG patients proliferate in vitro more frequently to PR3 peptides than to the whole PR3 protein. Peptides derived from the signal sequence, the propeptide or peptides located at the C-terminus of PR3 induce highest levels of proliferation. No specific PR3 sequence could be identified that was preferentially recognized by PBMC of WG patients compared with controls.

Antiproteinase 3- and antimyeloperoxidase-associated vasculitis.

Antiproteinase 3- and antimyeloperoxidase-associated vasculitis. Wegener's granulomatosis, microscopic polyangiitis, and idiopathic pauci-immune necrotizing crescentic glomerulonephritis (NCGN) are strongly associated with antineutrophil cytoplasmic autoantibodies (ANCAs) directed against either proteinase 3 (anti-PR3) or myeloperoxidase (anti-MPO). This has led some investigators to prefer combining these diseases under the common heading of ANCA-associated vasculitides. However, it is increasingly recognized that there are characteristic differences between patients with anti-PR3 and those with anti-MPO-associated vasculitis. This review focuses on the clinical, histopathologic, and possibly pathophysiologic differences between anti-PR3- and anti-MPO-associated vasculitis. Although there is considerable overlap, the anti-PR3- and anti-MPO-associated vasculitides are each characterized by particular clinical and histopathological findings. Extrarenal organ manifestations and respiratory tract granulomas occur more frequently in patients with anti-PR3 than in those with anti-MPO. Anti-PR3-positive patients with NCGN generally have a more dramatic deterioration of their renal function compared with anti-MPO-positive patients. The term "ANCA-associated vasculitis" is considered as a useful concept in the presence of systemic vasculitis. Likewise, in the presence of vasculitis, the terms "anti-PR3-associated vasculitis" and "anti-MPO-associated vasculitis" are useful concepts.

In vitro up-regulation of E-selectin and induction of interleukin-6 in endothelial cells by autoantibodies in Wegener's granulomatosis and microscopic polyangiitis.

OBJECTIVE: In patients with Wegener's granulomatosis (WG) or microscopic polyangiitis (MPA) autoantibodies to myeloid granule proteins (ANCA), particularly proteinase 3 (Pr3) and myeloperoxidase (MPO), and to endothelial cells (AECA) are frequently detected. The role of these autoantibodies in the development of vascular injury is incompletely understood. Since the expression of E-selectin and the production of interleukin 6 by endothelial cells is an early step in the sequence of events leading to vascular injury, we examined the capacity of IgG fractions from patients with WG and/or MPA to activate endothelial cells to the expression of E-selectin and the production of IL-6. We related those findings to the presence of ANCA and AECA in the IgG preparations. METHODS: Human umbilical vein endothelial cells (HUVEC) were incubated with immunoglobulin (IgG) preparations from 28 patients (17 positive for anti-Pr3, 10 for anti-MPO, and one for anti-Pr3/MPO) with active vasculitis and from 10 healthy volunteers. The final IgG concentration in the activation assay was 2 mg/ml. TNF alpha (10 ng/ml) and LPS (10 ng/ml) were used as positive controls for HUVEC activation. The extent of HUVEC activation was assessed by the measurement of E-selectin expression by flow cytometry (after 4 hours of incubation) and the production of interleukin 6 by ELISA (after 24 hours). RESULTS: We found that 11 of the 28 ANCA positive IgG samples were capable of activating endothelial cells: six samples induced IL-6 production alone, one sample upregulated E-selectin expression alone, and four samples induced both IL-6 production and E-selectin upregulation. Five of 17 anti-Pr3 positive samples (one of which was also positive for AECA) and 6 of 10 anti-MPO positive samples (all simultaneously positive for AECA) induced endothelial cell activation. AECA positive samples that induced endothelial cell activation (n = 7) had higher AECA titres than samples that did not induce endothelial cell activation (n = 6). CONCLUSION: Our data suggest that the activation of endothelial cells in patients with WG and MPA can be induced by circulating autoantibodies. Both ANCA and AECA can be responsible for this effect.