Hereditary transthyretin amyloidosis presenting with prominent autonomic dysfunction.

A 56-year-old man reported 2 years of slowly progressive exertional fatigue, presyncope, paraesthesia, generalised weakness and nocturnal bowel frequency. He had an abnormal Valsalva ratio and significant postural hypotension. Serum N-terminal pro-B-type natriuretic peptide and troponin T were elevated. Transthoracic echocardiogram identified thickening of the biventricular walls, interatrial septum and atrioventricular valve leaflets. Global longitudinal strain was reduced with relative apical sparing, suspicious for cardiac amyloidosis. Technetium-99m and 3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy supported a diagnosis of transthyretin amyloidosis (ATTR). However, urinary Bence Jones protein (kappa) was identified despite a normal kappa/lambda light chain ratio and no serum paraprotein. Bone marrow and buccal biopsy provided histological confirmation of amyloid. The bone marrow had no evidence of plasma cell dyscrasia but positive TTR immunohistochemistry. The patient had a T60A genetic mutation for hereditary ATTR. Overlapping cardiac and autonomic symptoms prompt an amyloid workup, which then must distinguish AL amyloid from ATTR pathology.

Bariatric surgery tourism in the COVID-19 era.

Background: Since the start of the Covid-19 pandemic primary and secondary health care services in Northern Ireland have observed an increase in the number of patients who have had bariatric surgery outside of the UK. This study sought to estimate the frequency of bariatric surgery tourism and to audit indications, blood monitoring and medical complications. Methods: All primary care centres within the Western Health Social Care Trust (WHSCT) were invited to document the number of patients undergoing bariatric surgery between January 1, 2017 and December 31, 2022. For one primary care centre, patients who underwent bariatric surgery were assessed against the National Institute of Health and Clinical Excellence (NICE) guideline indications for bariatric surgery. In addition, the blood monitoring of these patients was audited against the British Obesity and Metabolic Surgery Society (BOMSS) guidelines for up to two years following surgery. Medical contacts for surgical complications of bariatric surgery were recorded. Results: Thirty-five of 47 (74.5%) GP surgeries replied to the survey, representing 239,961 patients among 325,126 registrations (73.8%). In the six year study period 463 patients had reported having bariatric surgery to their GP. Women were more likely to have had bariatric surgery than men (85.1% versus 14.9%). There was a marked increase in the number of patients undergoing bariatric surgery with each year of the study (p<0.0001 chi square for trend). Twenty-one of 47 patients (44.7%) evaluated in one primary care centre fulfilled NICE criteria for bariatric surgery. The level of three-month monitoring ranged from 23% (for vitamin D) to 89% (electrolytes), but decreased at two years to 9% (vitamin D) and 64% (electrolytes and liver function tests). Surgical complication prevalence from wound infections was 19% (9 of 44). Antidepressant medications were prescribed for 23 of 47 patients (48.9%). Conclusions: The WHSCT has experienced a growing population of patients availing of bariatric surgery outside of the National Health Service. In view of this and the projected increase in obesity prevalence, a specialist obesity management service is urgently required in Northern Ireland.

Germinal center expansion but not plasmablast differentiation is proportional to peptide-MHCII density via CD40-CD40L signaling strength.

T follicular helper (TFH) cells promote expansion of germinal center (GC) B cells and plasma cell differentiation. Whether cognate peptide-MHCII (pMHCII) density instructs selection and cell fate decisions in a quantitative manner remains unclear. Using αDEC205-OVA to differentially deliver OVA peptides to GC B cells on the basis of DEC205 allelic copy number, we find DEC205+/+ B cells take up 2-fold more antigen than DEC205+/- cells, leading to proportional TFH cell help and B cell expansion. To validate these results, we establish a caged OVA peptide, which is readily detected by OVA-specific TFH cells after photo-uncaging. In situ uncaging of peptides leads to multiple serial B-T contacts and cell activation. Differential CD40 signaling, is both necessary and sufficient to mediate 2-fold differences in B cell expansion. While plasmablast numbers are increased, pMHCII density does not directly control the output or quality of plasma cells. Thus, we distinguish the roles TFH cells play in expansion versus differentiation.

IL-1 and IL-1ra are key regulators of the inflammatory response to RNA vaccines.

The use of lipid-formulated RNA vaccines for cancer or COVID-19 is associated with dose-limiting systemic inflammatory responses in humans that were not predicted from preclinical studies. Here, we show that the 'interleukin 1 (IL-1)-interleukin 1 receptor antagonist (IL-1ra)' axis regulates vaccine-mediated systemic inflammation in a host-specific manner. In human immune cells, RNA vaccines induce production of IL-1 cytokines, predominantly IL-1ß, which is dependent on both the RNA and lipid formulation. IL-1 in turn triggers the induction of the broad spectrum of pro-inflammatory cytokines (including IL-6). Unlike humans, murine leukocytes respond to RNA vaccines by upregulating anti-inflammatory IL-1ra relative to IL-1 (predominantly IL-1α), protecting mice from cytokine-mediated toxicities at >1,000-fold higher vaccine doses. Thus, the IL-1 pathway plays a key role in triggering RNA vaccine-associated innate signaling, an effect that was unexpectedly amplified by certain lipids used in vaccine formulations incorporating N1-methyl-pseudouridine-modified RNA to reduce activation of Toll-like receptor signaling.

Dynamic CD138 surface expression regulates switch between myeloma growth and dissemination.

The canonical plasma cell marker CD138 (syndecan-1) is highly expressed on the myeloma cell surface, but its functional role in vivo is unclear, as well as the ontogeny of CD138-high and CD138-negative (neg) myeloma cells. In this study we used an in vivo murine Vk*MYC myeloma model where CD138 is heterogeneously expressed depending on tumor size. We find that in comparison to CD138-neg myeloma cells, the CD138-high subset of myeloma cells is highly proliferative, less apoptotic, and enhanced IL-6R signaling, which is known to promote survival. In addition CD138-high myeloma engrafts better than its CD138-neg counterpart. In contrast, CD138-neg cells are more motile both in vitro and in vivo, and more readily disseminate and spread to other bones in vivo than CD138-high subset. Neutralizing CD138 rapidly triggers migration of myeloma cells in vivo and leads to intravasation, which results in increased dissemination to other bones. Both murine and human myeloma cells can rapidly recycle CD138 surface expression through endocytic trafficking, in response to serum levels. Blocking CD138 enhances myeloma sensitivity to bortezomib chemotherapy and significantly reduces tumor size compared to bortezomib treatment alone. Thus, our data show that CD138 surface expression dynamically regulates a switch between growth vs. dissemination for myeloma, in response to nutrient conditions.

Transforming Growth Factor-beta signaling in αß thymocytes promotes negative selection.

In the thymus, the T lymphocyte repertoire is purged of a substantial portion of highly self-reactive cells. This negative selection process relies on the strength of TCR-signaling in response to self-peptide-MHC complexes, both in the cortex and medulla regions. However, whether cytokine-signaling contributes to negative selection remains unclear. Here, we report that, in the absence of Transforming Growth Factor beta (TGF-ß) signaling in thymocytes, negative selection is significantly impaired. Highly autoreactive thymocytes first escape cortical negative selection and acquire a Th1-like-phenotype. They express high levels of CXCR3, aberrantly accumulate at the cortico-medullary junction and subsequently fail to sustain AIRE expression in the medulla, escaping medullary negative selection. Highly autoreactive thymocytes undergo an atypical maturation program, substantially accumulate in the periphery and induce multiple organ-autoimmune-lesions. Thus, these findings reveal TGF-ß in thymocytes as crucial for negative selection with implications for understanding T cell self-tolerance mechanisms.

CD138 mediates selection of mature plasma cells by regulating their survival.

Antibody secreting cells (ASCs) are critical effector cells and long-lived sentinels for immune memory. ASCs are highly dependent on exogenous soluble factors such as interleukin-6 (IL-6) and APRIL, to prevent their cell death. We have found that the canonical surface marker of ASCs, CD138 (syndecan-1), which is upregulated during ASC maturation, is required in a cell-intrinsic manner to mount an effective long-term humoral immune response following immunization. Surface expression of CD138 increased heparan sulfate levels on ASCs, which are known to bind pro-survival cytokines, leading to increased survival in a cell-intrinsic manner in vivo. In IL-6 and APRIL-deficient hosts, ASCs underwent extensive apoptosis independently of CD138 expression. We propose a model in which CD138 expression on fully mature ASCs provides a selective survival advantage over less mature, newly minted ASCs, by enhancing pro-survival cytokine signaling.

Diagnostic test results in primary CNS vasculitis: A systematic review of published cases.

BACKGROUND: Primary CNS vasculitis (PCNSV) can be diagnosed using cerebral angiography or histopathology combined with clinical features. The original diagnostic criteria, which weigh each test equally, have not been validated. Limited sensitivity and specificity for biopsy and angiography are recognized. We systematically reviewed results of diagnostic tests performed in patients with an ultimate diagnosis of PCNSV. METHODS: We searched the OVID Medline database and bibliographies for original cases of PCNSV. We recorded demographics, diagnostic tests used, and assessed agreement between angiography and biopsy when both tests were performed. We also recorded MRI and CSF results. RESULTS: We found 701 original cases with PCNSV diagnosed with angiography or pathology. A total of 269 patients (38.4%) had both cerebral angiography and histopathologic testing (biopsy/postmortem). Classic angiographic features of vasculitis were associated with pathologic confirmation in just 32 patients (4.6%). Seventy-four patients (10.6%) with any abnormality on angiography had a normal biopsy, and 99 patients (14.1%) with abnormal biopsies had normal angiography. Brain MRI was abnormal in 505/541 patients (93.3%) and CSF was abnormal in 360/484 patients (74.4%). Increasing use of angiography and decreasing histopathologic testing were found over time. CONCLUSIONS: Cerebral angiography and pathologic tissue examination were undertaken in a minority of published cases with a diagnosis of PCNSV. When both diagnostic tests were performed, disagreement between them was more than 5 times more likely than agreement. Diagnostic criteria for PCNSV may require revision to classify the clinical, pathologic, and radiologic features of this condition more accurately.

Targeting netrin-1/DCC interaction in diffuse large B-cell and mantle cell lymphomas.

DCC (Deleted in Colorectal Carcinoma) has been demonstrated to constrain tumor progression by inducing apoptosis unless engaged by its ligand netrin-1. This has been shown in breast and colorectal cancers; however, this tumor suppressive function in other cancers is not established. Using a transgenic mouse model, we report here that inhibition of DCC-induced apoptosis is associated with lymphomagenesis. In human diffuse large B-cell lymphoma (DLBCL), an imbalance of the netrin-1/DCC ratio suggests a loss of DCC-induced apoptosis, either via a decrease in DCC expression in germinal center subtype or by up-regulation of netrin-1 in activated B-cell (ABC) one. Such imbalance is also observed in mantle cell lymphoma (MCL). Using a netrin-1 interfering antibody, we demonstrate both in vitro and in vivo that netrin-1 acts as a survival factor for ABC-DLBCL and MCL tumor cells. Together, these data suggest that interference with the netrin-1/DCC interaction could represent a promising therapeutic strategy in netrin-1-positive DLBCL and MCL.

Clinical and diagnostic findings in patients with elevated cerebrospinal bilirubin.

INTRODUCTION: Cerebrospinal fluid (CSF) spectroscopy can identify subarachnoid haemorrhage (SAH) when CT is negative in patients presenting with acute severe headache. The primary objective of this study was to evaluate the clinical use and usefulness of CSF spectrophotometry. Secondary objectives were to identify other causes of elevated CSF bilirubin, to analyse headache descriptions and to compare clinical features in patients with an elevated CSF bilirubin among those with and without an intracranial vascular cause of SAH (avSAH). METHODS: Consecutive patients admitted to two hospitals in Enniskillen and Londonderry between 1 January 2004 and 30 September 2014 with CSF spectroscopy bilirubin results were identified from a clinical chemistry laboratory dataset. Patients with elevated CSF bilirubin were studied. Clinical demographics, delays to investigation and final diagnoses were recorded. Patients with avSAH were compared with patients without avSAH. RESULTS: Among 1813 patients with CSF spectrophotometry results, requests increased more than threefold during the study (p<0.001). Fifty-six patients had elevated CSF bilirubin. Ten (17.9%) had avSAH, of which 8 (14.3%) had aneurysmal SAH. Non-vascular causes of elevated CSF bilirubin included meningitis, spontaneous intracranial hypotension and carcinomatous meningitis. Headache descriptions varied. Time from headache onset to admission, CT scan and lumbar puncture did not differ significantly for patients with avSAH and non-avSAH. CSF red cell counts were higher among patients with avSAH than patients with non-avSAH (p=0.005). CONCLUSIONS: CSF bilirubin measurement has an important role in identifying avSAH in CT-negative patients presenting with a thunderclap headache. Better clinical selection of patients is required as CSF spectrophotometry, although sensitive, is not specific for SAH.

Idiopathic Intracranial Hypertension in the Northwest of Northern Ireland: Epidemiology and Clinical Management.

BACKGROUND: There is limited literature on the epidemiology of idiopathic intracranial hypertension (IIH). The diagnosis and management of IIH require a multidisciplinary approach. We sought to study the incidence as well as prevalence of IIH and to evaluate the current management of IIH in the northwest of Northern Ireland. METHODS: Medical records of patients diagnosed with IIH between 2007 and 2014 in a general hospital in Northern Ireland were reviewed. Clinical and outcome data were retrieved. RESULTS: There were 45 patients with IIH, 44 women: 1 man. The mean age at presentation was 29.4 (SD 9.8) years and mean body mass index (BMI) 39.8 (SD 9.5) kg/ m(2). All patients had neuroimaging, 44 (98%) had CT/MR venogram and 41 (91%) had visual perimetry. The crude incidence of IIH was 2.36 per 100,000 (95% CI 1.65-3.37). For women, the incidence was 4.65 per 100,000/year (95% CI 3.25-6.66). The prevalence was 14.3 per 100,000 overall (95% CI 9.72-20.9) but 28.1 per 100,000 in women (95% CI 19.2-41.2). Visual field defects were identified in 25 of 41 (61%); 4 patients (9%) required shunting procedures. At follow-up, the mean BMI decreased by 1.6 kg/m(2) (p = 0.024). CONCLUSIONS: The incidence of IIH in the northwest of Northern Ireland is among the highest ever reported and probably reflects the known increase in obesity.

An unusual cause of hemifacial spasm.

Hemifacial spasm is not an infrequent presentation and a vascular loop is commonly implicated. Cerebellopontine angle (CPA) lesions are uncommon but can be excluded with appropriate imaging. There have been only around 150 case reports of CPA lipoma; hemifacial spasm has been associated only in eight cases. We present an additional case and discuss the literature and management.

Two different presentations, one diagnosis.

Acute confusion and hyponatraemia are common presentations in acute medicine. We report two cases of anti-voltage gated potassium channel (VGKC) antibody-related limbic encephalitis highlighting the variable presentation of this condition. Both patients were thoroughly investigated with MRI scan of brain, lumbar puncture, EEG as well as infective and autoimmune screens for encephalitis. Anti-VGKC antibodies were positive for both patients and prompt treatment with immunotherapy yielded good recovery. Patients presenting with confusion and seizures who have no demonstrable infectious or metabolic cause should have investigation for an autoimmune cause expedited. In addition, psychiatric presentations with atypical features such as drowsiness should prompt similar investigations. The outcome of anti-VGKCrelated limbic encephalitis is improved with early treatment employing steroids or immunotherapy.

TGF-ß prevents T follicular helper cell accumulation and B cell autoreactivity.

T follicular helper (Tfh) cells contribute to the establishment of humoral immunity by controlling the delivery of helper signals to activated B cells; however, Tfh development must be restrained, as aberrant accumulation of these cells is associated with positive selection of self-reactive germinal center B cells and autoimmunity in both humans and mice. Here, we show that TGF-ß signaling in T cells prevented Tfh cell accumulation, self-reactive B cell activation, and autoantibody production. Using mice with either T cell-specific loss or constitutive activation of TGF-ß signaling, we demonstrated that TGF-ß signaling is required for the thymic maturation of CD44⁺CD122⁺Ly49⁺CD8⁺ regulatory T cells (Tregs), which induce Tfh apoptosis and thus regulate this cell population. Moreover, peripheral Tfh cells escaping TGF-ß control were resistant to apoptosis, exhibited high levels of the antiapoptotic protein BCL2, and remained refractory to regulation by CD8+ Tregs. The unrestrained accumulation of Tfh cells in the absence of TGF-ß was dependent on T cell receptor engagement and required B cells. Together, these data indicate that TGF-ß signaling restrains Tfh cell accumulation and B cell-associated autoimmunity and thereby controls self-tolerance.

Blockade of B7-H1 (programmed death ligand 1) enhances humoral immunity by positively regulating the generation of T follicular helper cells.

T follicular helper (T(FH)) cells are critical initiators in the development of T cell-dependent humoral immunity and the generation of protective immunity. We demonstrate that T(FH) cell accumulation and Ab production are negatively regulated by B7-H1 (programmed death ligand 1) in response to both helminth infection and active immunization. Following immunization of B7-H1(-/-) mice with keyhole limpet hemocyanin or helminth Ags, there is a profound increase in induction of T(FH) cells as a result of increased cell cycling and decreased apoptosis relative to wild-type mice. The increase in T(FH) cells in the absence of B7-H1 was associated with significant elevations in Ag-specific Ig response. Cotransfer experiments in vivo demonstrated that B7-H1 expression on B cells was required for negatively regulating T(FH) cell expansion and production of Ag-specific Ig. Treatment of immunized wild-type mice with anti-B7-H1 or anti-programmed death 1 mAbs, but not anti-B7-DC, led to a significant expansion of the T(FH) cell population and an enhanced Ag-specific Ig response. Our results demonstrate that the coinhibitory B7-H1/programmed death 1 pathway can limit the expansion of T(FH) cells and constrain Ag-specific Ig responses. This finding has direct implications for investigations examining the feasibility of therapeutically manipulating this pathway and reveals new insights into the regulation of the humoral immune response.

Recurrent posterior circulatory emboli from a mildly stenosed bicuspid aortic valve.

Bicuspid aortic valve (BAV) is a common condition but is only rarely associated with embolic complications. We describe a 42-year-old man with recurrent posterior circulatory ischemic strokes that resulted in ataxia and cognitive impairment. Transesophageal echocardiography demonstrated a BAV with mild stenosis, moderate calcification, and a dilated ascending aorta. The degree of calcification and the valve phenotype might be important factors implicating the BAV as a rare cause of ischemic stroke.

Neuroimaging reports in a general hospital: results from a quality-improvement program.

OBJECTIVE: Neurologists working in district general hospitals (DGHs) in the UK frequently rely on neuroimaging reports from general radiologists. Neuroradiologists and general radiologists may disagree in the interpretation of magnetic resonance imaging and computerized tomographs of brain and spine. We sought to analyse disagreements between reports from general radiologists and neuroradiologists in selected patients and to examine the impact of a four-point quality-improvement program in a DGH neuroimaging reporting service. METHODS: A single neurologist selected patients for reporting by neuroradiologists following a recommendation from general radiologists, or because of a concern by the neurologist. Differences between general radiologists and neuroradiologists in pre-planned primary and secondary findings and advice for further investigations were compared. RESULTS: Primary finding disagreements occurred in 41 of 307 patients (13.4%) and secondary finding disagreements were identified in 62 patients (20.2%). There was no evidence from either result of improvement compared to an earlier study, p=0.45 and p=0.52 respectively. Neuroradiologists suggested further investigations in 42 patients (13.7%). Recurrent areas of disagreement included distinguishing perivascular spaces from ischemia, while recurrent missed lesions included subdural hemorrhage and cortical dysplasia. CONCLUSIONS: Despite implementation of a quality-improvement program neuroradiologists frequently identified major discrepancies and recommended additional investigations in this DGH neuroimaging service. Future research should identify interventions which are more effective in improving neuroimaging reports in DGHs.

Activated human neonatal CD8+ T cells are subject to immunomodulation by direct TLR2 or TLR5 stimulation.

In conditions of optimal priming, the neonate possesses competency to mount quantitatively adult-like responses. Vaccine formulations containing sufficiently potent adjuvants may overcome the neonate's natural tendency for immunosuppression and provoke a similarly robust immune response. TLR expression on T cells represents the possibility of directly enhancing T cell immunity. We examined the ex vivo responsiveness of highly purified human cord blood-derived CD8(+) T cells to direct TLR ligation by a repertoire of TLR agonists. In concert with TCR stimulation, only Pam(3)Cys (palmitoyl-3-Cys-Ser-(Lys)(4)) and flagellin monomers significantly enhanced proliferation, CD25(+) expression, IL-2, IFN-gamma, TNF-alpha, and intracellular granzyme B expression. TLR2 and TLR5 mRNA was detected in the CD8(+) T cells. Blocking studies confirmed that the increase in IFN-gamma production was by the direct triggering of surface TLR2 or TLR5. The simultaneous exposure of CD8(+) T cells to both TLR agonists had an additive effect on IFN-gamma production. These data suggest that a combination of the two TLR ligands would be a potent T cell adjuvant. This may represent a new approach to TLR agonist-based adjuvant design for future human neonatal vaccination strategies requiring a CD8(+) component.

Acute polymyositis following renal transplantation.

Myositis is a rare complication following renal transplantation and is most commonly the result of drug-mediated myotoxicity. Other causative disorders include viral infection, electrolyte imbalance and myositis of autoimmune origin. We describe a 60-year-old patient who developed acute polymyositis 4 weeks after a 000 human leukocyte antigen (HLA) mismatch cadaveric renal transplant. Following an uncomplicated transplant course with maintenance triple immunosuppression (prednisolone, mycophenolate mofetil and cyclosporine), the patient presented with severe symmetrical proximal muscle weakness associated with a rise in serum creatine kinase to 46800 U/L. Electromyography confirmed myopathic changes and muscle biopsy demonstrated extensive muscle-fiber necrosis with an inflammatory infiltrate. There were no obviously culpable drugs and viral studies were negative. Prompt initiation of high-dose steroid therapy led to clinical and biochemical recovery. Acute polymyositis may occur following renal transplantation. Potential mechanisms include viral antigen transmission or a localized form of graft vs. host disease.