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Primary lymphatic anomalies may present in a myriad of ways and are highly heterogenous. Careful consideration of the presentation can lead to an accurate clinical and/or molecular diagnosis which will assist with management. The most common presentation is lymphoedema, swelling resulting from failure of the peripheral lymphatic system. However, there may be internal lymphatic dysfunction, for example, chylous reflux, or lymphatic malformations, including the thorax or abdomen. A number of causal germline or postzygotic gene mutations have been discovered. Some through careful phenotyping and categorisation of the patients based on the St George’s classification pathway/algorithm. The St George’s classification algorithm is aimed at providing an accurate diagnosis for patients with lymphoedema based on age of onset, areas affected by swelling and associated clinical features. This has enabled the identification of new causative genes. This update brings the classification of primary lymphatic disorders in line with the International Society for the Study of Vascular Anomalies 2018 classification for vascular anomalies. The St George’s algorithm considers combined vascular malformations and primary lymphatic anomalies. It divides the types of primary lymphatic anomalies into lymphatic malformations and primary lymphoedema. It further divides the primary lymphoedema into syndromic, generalised lymphatic dysplasia with internal/systemic involvement, congenital-onset lymphoedema and late-onset lymphoedema. An audit and update of the algorithm has revealed where new genes have been discovered and that a molecular diagnosis was possible in 26% of all patients overall and 41% of those tested.

In blinded randomised controlled trials, statin therapy has been associated with few adverse events (AEs). By contrast, in observational studies, larger increases in many different AEs have been reported than in blinded trials. In the Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial, patients aged 40–79 years with hypertension, at least three other cardiovascular risk factors, and fasting total cholesterol concentrations of 6·5 mmol/L or lower, and who were not taking a statin or fibrate, had no history of myocardial infarction, and were not being treated for angina were randomly assigned to atorvastatin 10 mg daily or matching placebo in a randomised double-blind placebo-controlled phase. In a subsequent non-randomised non-blind extension phase (initiated because of early termination of the trial because efficacy of atorvastatin was shown), all patients were offered atorvastatin 10 mg daily open label. We classified AEs using the Medical Dictionary for Regulatory Activities. We blindly adjudicated all reports of four prespecified AEs of interest—muscle-related, erectile dysfunction, sleep disturbance, and cognitive impairment—and analysed all remaining AEs grouped by system organ class. Rates of AEs are given as percentages per annum. The blinded randomised phase was done between February, 1998, and December, 2002; we included 101 80 patients in this analysis (5101 [50%] in the atorvastatin group and 5079 [50%] in the placebo group), with a median follow-up of 3·3 years (IQR 2·7–3·7). The non-blinded non-randomised phase was done between December, 2002, and June, 2005; we included 9899 patients in this analysis (6409 [65%] atorvastatin users and 3490 [35%] non-users), with a median follow-up of 2·3 years (2·2–2·4). During the blinded phase, muscle-related AEs (298 [2·03% per annum] vs 283 [2·00% per annum]; hazard ratio 1·03 [95% CI 0·88–1·21]; p=0·72) and erectile dysfunction (272 [1·86% per annum] vs 302 [2·14% per annum]; 0·88 [0·75–1·04]; p=0·13) were reported at a similar rate by participants randomly assigned to atorvastatin or placebo. The rate of reports of sleep disturbance was significantly lower among participants assigned atorvastatin than assigned placebo (149 [1·00% per annum] vs 210 [1·46% per annum]; 0·69 [0·56–0·85]; p=0·0005). Too few cases of cognitive impairment were reported for a statistically reliable analysis (31 [0·20% per annum] vs 32 [0·22% per annum]; 0·94 [0·57–1·54]; p=0·81). We observed no significant differences in the rates of all other reported AEs, with the exception of an excess of renal and urinary AEs among patients assigned atorvastatin (481 [1·87%] per annum vs 392 [1·51%] per annum; 1·23 [1·08–1·41]; p=0·002). By contrast, during the non-blinded non-randomised phase, muscle-related AEs were reported at a significantly higher rate by participants taking statins than by those who were not (161 [1·26% per annum] vs 124 [1·00% per annum]; 1·41 [1·10–1·79]; p=0·006). We noted no significant differences between statin users and non-users in the rates of other AEs, with the exception of musculoskeletal and connective tissue disorders (992 [8·69% per annum] vs 831 [7·45% per annum]; 1·17 [1·06–1·29]; p=0·001) and blood and lymphatic system disorders (114 [0·88% per annum] vs 80 [0·64% per annum]; 1·40 [1·04–1·88]; p=0·03), which were reported more commonly by statin users than by non-users. These analyses illustrate the so-called nocebo effect, with an excess rate of muscle-related AE reports only when patients and their doctors were aware that statin therapy was being used and not when its use was blinded. These results will help assure both physicians and patients that most AEs associated with statins are not causally related to use of the drug and should help counter the adverse effect on public health of exaggerated claims about statin-related side-effects. Pfizer, Servier Research Group, and Leo Laboratories.

Nociceptor sensory neurons are specialized to detect potentially damaging stimuli, protecting the organism by initiating the sensation of pain and eliciting defensive behaviours. Bacterial infections produce pain by unknown molecular mechanisms, although they are presumed to be secondary to immune activation. Here we demonstrate that bacteria directly activate nociceptors, and that the immune response mediated through TLR2, MyD88, T cells, B cells, and neutrophils and monocytes is not necessary for Staphylococcus aureus -induced pain in mice. Mechanical and thermal hyperalgesia in mice is correlated with live bacterial load rather than tissue swelling or immune activation. Bacteria induce calcium flux and action potentials in nociceptor neurons, in part via bacterial N -formylated peptides and the pore-forming toxin α-haemolysin, through distinct mechanisms. Specific ablation of Nav1.8-lineage neurons, which include nociceptors, abrogated pain during bacterial infection, but concurrently increased local immune infiltration and lymphadenopathy of the draining lymph node. Thus, bacterial pathogens produce pain by directly activating sensory neurons that modulate inflammation, an unsuspected role for the nervous system in host–pathogen interactions. This study shows that most known mediators of immunity, such as TLR2, MyD88, T cells or B cells, and neutrophils and monocytes, are dispensable for pain produced by Staphylococcus aureus infection; instead, bacterial products, such as N -formylated peptides and α-haemolysin, induce pain by directly activating nociceptor neurons, which in turn modulate inflammation. Bacteria can be a pain Bacterial infections such as those caused by Staphylococcus produce pain thought to be secondary to the immune response and inflammation. Now Clifford Woolf and colleagues report a previously unsuspected mechanism of pain induction during bacterial infection: a direct pathogen-mediated activation of nociceptors. They find that pain produced by Staphylococcus aureus infection in mice is independent of most known mediators of immunity. Rather, the bacteria produce two classes of molecules — formylated peptides and pore-forming toxins — that induce pain by directly activating nociceptor neurons that in turn modulate inflammation.

The early phase of systemic sclerosis (SSc) presents edema as one of the main features: this is clinically evident in the digital swelling (puffy fingers) as well as in the edematous skin infiltration of the early active diffuse subset. Other organs could be affected by this same disease process, such as the lung (with the appearance of ground glass opacities) and the heart (with edematous changes on cardiac magnetic resonance imaging). The genesis of tissue edema is tightly linked to pathological changes in the endothelium: various reports demonstrated the effect of transforming growth factor β, vascular endothelial growth factor and hypoxia-reperfusion damage with reactive oxygen species generation in altering vascular permeability and extravasation, in particular in SSc. This condition has an alteration in the glycocalyx thickness, reducing the protection of the vessel wall and causing non-fibrotic interstitial edema, a marker of vascular leak. Moreover, changes in the junctional adhesion molecule family and other adhesion molecules, such as ICAM and VCAM, are associated with an increased myeloid cells' extravasation in the skin and increased myofibroblasts transformation with further vascular leak and cellular migration. This mini-review examines current knowledge on determinants of vascular leak in SSc, shedding light on the role of vascular protection. This could enhance further studies in the light of drug development for early treatment, suggesting that the control of vascular leakage should be considered in the same way that vasodilation and inflammation reduction, as potential therapeutic targets.

Caspase-8 joins RIPK at the death Caspase-8 mediates apoptosis induced by 'death receptors' on the cell's surface. At the same time, it is able to prevent receptor interacting protein kinase (RIPK)-dependent necrosis. Without caspase-8, mice die during embryonic development, but why this happens is not clear. Two groups show that this lethality is not caused by the absence of apoptosis, but by the RIPK3-dependent necrosis that is unleashed without caspase-8. Mice lacking both caspase-8 and RIP3 develop into viable, immunocompetent adults, but have a progressive lymphoaccumulative disease similar to that in mice that lack the CD95 death receptor. Oberst et al . also show that caspase-8 forms a proteolytically active complex with FLICE-like inhibitory protein long (FLIPL), and that this complex is required for protection against RIP3-dependent necrosis. Caspase-8 mediates apoptosis induced by death receptors. At the same time, this protease is able to prevent RIP-dependent necrosis. Without caspase-8 mice die during their embryonic development. Two papers now show that lethality is not caused by the absence of apoptosis, but by RIP3-dependent necrosis that is unleashed without caspase-8. Mice that lack both caspase-8 and RIP3 develop into viable, immunocompetent, fertile adult mice, but suffer from a progressive lymphoaccumulative disease similar to mice that lack the death receptor CD95. Apoptosis and necroptosis are complementary pathways controlled by common signalling adaptors, kinases and proteases; among these, caspase-8 (Casp8) is critical for death receptor-induced apoptosis. This caspase has also been implicated in non-apoptotic pathways that regulate Fas-associated via death domain (FADD)-dependent signalling and other less defined biological processes as diverse as innate immune signalling and myeloid or lymphoid differentiation patterns 1 . Casp8 suppresses RIP3–RIP1 (also known as RIPK3–RIPK1) kinase complex-dependent 2 , 3 , 4 necroptosis 5 that follows death receptor activation as well as a RIP3-dependent, RIP1-independent necrotic pathway that has emerged as a host defence mechanism against murine cytomegalovirus 6 . Disruption of Casp8 expression leads to embryonic lethality in mice between embryonic days 10.5 and 11.5 (ref. 7 ). Thus, Casp8 may naturally hold alternative RIP3-dependent death pathways in check in addition to promoting apoptosis. We find that RIP3 is responsible for the mid-gestational death of Casp8-deficient embryos. Remarkably, Casp8 −/− Rip3 −/− double mutant mice are viable and mature into fertile adults with a full immune complement of myeloid and lymphoid cell types. These mice seem immunocompetent but develop lymphadenopathy by four months of age marked by accumulation of abnormal T cells in the periphery, a phenotype reminiscent of mice with Fas-deficiency ( lpr/lpr ; also known as Fas ). Thus, Casp8 contributes to homeostatic control in the adult immune system; however, RIP3 and Casp8 are together completely dispensable for mammalian development.

Background Adverse local tissue reactions (ALTR) around metal-on-metal (MOM) hip arthroplasties are increasingly being recognized as a cause of failure. These reactions may be associated with intraoperative tissue damage and complication rates as high as 50% after revision. Although MRI can identify ALTR in MOM hips, it is unclear whether the MRI findings predict those at revision surgery. Questions/purposes We therefore (1) identified which MRI characteristics correlated with histologically confirmed ALTR (using the aseptic lymphocytic vasculitis-associated lesions [ALVAL] score) and intraoperative tissue damage and (2) developed a predictive model using modified MRI to detect ALVAL and quantify intraoperative tissue damage. Methods We retrospectively reviewed 68 patients with failed MOM hip arthroplasties who underwent preoperative MRI and subsequent revision surgery. Images were analyzed to determine synovial volume, osteolysis, and synovial thickness. The ALVAL score was used to grade tissue samples, thus identifying a subset of patients with ALTR. Intraoperative tissue damage was graded using a four-point scale. Random forest analysis determined the sensitivity and specificity of MRI characteristics in detecting ALVAL (score ≥ 5) and intraoperative tissue damage. Results Maximal synovial thicknesses and synovial volumes as determined on MRI correlated with the ALVAL score and were higher in cases of severe intraoperative tissue damage. Our MRI predictive model showed sensitivity and specificity of 94% and 87%, respectively, for detecting ALVAL and 90% and 86%, respectively, for quantifying intraoperative tissue damage. Conclusions MRI is sensitive and specific in detecting ALVAL and tissue damage in patients with MOM hip implants. MRI can be used as a screening tool to guide surgeons toward timely revision surgery. Level of Evidence Level III, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence.

Expansions of a hexanucleotide repeat (GGGGCC) in the noncoding region of the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Decreased expression of C9orf72 is seen in expansion carriers, suggesting that loss of function may play a role in disease. We found that two independent mouse lines lacking the C9orf72 ortholog (3110043O21Rik) in all tissues developed normally and aged without motor neuron disease. Instead, C9orf72 null mice developed progressive splenomegaly and lymphadenopathy with accumulation of engorged macrophage-like cells. C9orf72 expression was highest in myeloid cells, and the loss of C9orf72 led to lysosomal accumulation and altered immune responses in macrophages and microglia, with age-related neuroinflammation similar to C9orf72 ALS but not sporadic ALS human patient tissue. Thus, C9orf72 is required for the normal function of myeloid cells, and altered microglial function may contribute to neurodegeneration in C9orf72 expansion carriers.

IgG4-related disease sometimes involves regional and/or systemic lymph nodes, and often clinically and/or histologically mimics multicentric Castleman's disease or malignant lymphoma. In this study, we examined clinical and pathologic findings of nine patients with systemic IgG4-related lymphadenopathy. None of these cases were associated with human herpes virus-8 or human immunodeficiency virus infection, and there was no T-cell receptor or immunoglobulin gene rearrangement. Histologically, systemic IgG4-related lymphadenopathy was classified into two types by the infiltration pattern of IgG4-positive cells: interfollicular plasmacytosis type and intra-germinal center plasmacytosis type. The interfollicular plasmacytosis type showed either Castleman's disease-like features or atypical lymphoplasmacytic and immunoblastic proliferation-like features. By contrast, the intra-germinal center plasmacytosis type showed marked follicular hyperplasia, and infiltration of IgG4-positive cells mainly into the germinal centers, and some cases exhibited features of progressively transformed germinal centers. Interestingly, eight of our nine (89%) cases showed eosinophil infiltration in the affected lymph nodes, and examined patients showed high elevation of serum IgE. Laboratory examinations revealed elevation of serum IgG4 and soluble interleukin-2 receptors. However, the levels of interleukin-6, C-reactive protein, and lactate dehydrogenase were within normal limits or only slightly elevated in almost all patients. One patient showed a high interleukin-6 level whereas C-reactive protein was within the normal limit. Autoantibodies were examined in five patients and detected in four. Compared with the previously reported cases of multicentric Castleman's disease, our patients with systemic IgG4-related lymphadenopathy were significantly older and had significantly lower C-reactive protein and interleukin-6 levels. In conclusion, in our systemic IgG4-related lymphadenopathy showed pathologic features only partially overlapping those of multicentric Castleman's disease, and serum data (especially C-reactive protein and interleukin-6) are useful for differentiating the two. Our findings of eosinophil infiltration in the affected tissue and elevation of serum IgE may suggest an allergic mechanism in the pathogenesis of systemic IgG4-related lymphadenopathy.

Kaposiform lymphangiomatosis (KLA) is a rare, frequently aggressive, systemic disorder of the lymphatic vasculature, occurring primarily in children. Even with multimodal treatments, KLA has a poor prognosis and high mortality rate secondary to coagulopathy, effusions, and systemic involvement. We hypothesized that, as has recently been found for other vascular anomalies, KLA may be caused by somatic mosaic variants affecting vascular development. We performed exome sequencing of tumor samples from five individuals with KLA, along with samples from uninvolved control tissue in three of the five. We used digital polymerase chain reaction (dPCR) to validate the exome findings and to screen KLA samples from six other individuals. We identified a somatic activating NRAS variant (c.182 A>G, p.Q61R) in lesional tissue from 10/11 individuals, at levels ranging from 1% to 28%, that was absent from the tested control tissues. The activating NRAS p.Q61R variant is a known “hotspot” variant, frequently identified in several types of human cancer, especially melanoma. KLA, therefore, joins a growing group of vascular malformations and tumors caused by somatic activating variants in the RAS/PI3K/mTOR signaling pathways. This discovery will expand treatment options for these high-risk patients as there is potential for use of targeted RAS pathway inhibitors.

Background As the application of Chimeric Antigen Receptor T-cell (CAR-T) therapy in cancer treatment becomes increasingly widespread, associated hematologic and lymphatic system adverse events pose significant challenges to its clinical use. Therefore, we aim to comprehensively investigate and summarize the hematologic and lymphatic system AEs associated with CAR-T therapy. Methods We extracted CAR-T-related adverse event reports from the FDA Adverse Event Reporting System (FAERS) database for the period from August 2017 to December 2023. Disproportionality analysis using the Reporting Odds Ratio (ROR) and Information Component (IC) was performed to identify CAR-T-associated hematologic and lymphatic system AEs. We employed LASSO regression analysis to identify hematologic and lymphatic system AEs associated with mortality. Results In the FAERS database, we identified 1,600 individual case safety reports of hematologic and lymphatic system AEs related to CAR-T therapy. The median age of patients was 57 years (interquartile range [IQR] 32–67), with fatal outcomes in 15.3% of cases. We identified 25 significant adverse event signals associated with CAR-T therapy. B-cell aplasia (ROR025 = 1054.56, IC025 = 4.74), cytopenia (ROR025 = 17.27, IC025 = 3.81), hypofibrinogenemia (ROR025 = 100.18, IC025 = 2.46), anemia (ROR025 = 1.87, IC025 = 0.59), febrile bone marrow aplasia (ROR025 = 55.32, IC025 = 2.70), and pancytopenia (ROR025 = 7.18, IC025 = 1.42) were the most significant hematologic and lymphatic system AEs for tisa-cel, axi-cel, brexu-cel, liso-cel, ide-cel, and cilta-cel, respectively. Most hematologic and lymphatic system AEs occurred within 10 days post-CAR-T infusion. Hematologic and lymphatic system AEs were associated with a mortality rate of 15.3%. Our analysis revealed 15 hematologic and lymphatic system AEs closely associated with mortality in CAR-T-treated patients, including splenic hemorrhage, disseminated intravascular coagulation, and pancytopenia. Conclusions Our study found that hematologic and lymphatic system AEs were more closely associated with anti-CD19 CAR-T and CAR-T containing CD28. Splenic hemorrhage, disseminated intravascular coagulation, and pancytopenia were identified as hematologic and lymphatic system AEs that, while less frequently reported clinically, were highly associated with mortality.