`Silk Route Disease' (Beh?et's Disease)

Behçet''s disease is a multisystem disorder in which orogenital ulceration is associated with troublesome generalized uveitis, erythema nodosum, pyoderma, dermatographism, seronegative arthritis, and neurologic and cardiovascular symptoms. There is no diagnostic laboratory test; the diagnosis is based on the disorder''s multisystem clinical features. A points scoring system is helpful in distinguishing it from other multisystem disorders that mimic it. It occurs most frequently in an area coinciding with the old Silk Route, between latitudes 30° and 45° north, in Asian and Eurasian populations, and it has an HLA-B51 affinity. The cause remains unknown, but a postulated trigger factor is a herpesvirus with cofactors that include ethnic group, human leukocyte antigen affinities, T-cell and autonomic imbalance, circulating immune complexes, autoimmunity, blood viscosity, decreased fibrinolysis, and zinc deficiency. Treatment includes administering corticosteroids, azathioprine, chlorambucil, cyclosporine, and colchicine, and fibrinolytic therapy.     

Isaacs' syndrome.

Systemic lupus erythematosus (SLE) is a chronic multisystem inflammatory disease having definite etiologic associations with ethnic, genetic, viral and immunologic factors. Its pathologic hallmark, vasculitis, is currently felt to be the end result of an immune-complex mechanism. Several clinical and serologic variants of SLE are recognized including discoid lupus erythematosus (DLE), mixed connective tissue disease (MCTD) and drug-induced equivalents—such as procainamide-induced lupus (PIL). The distinguishing features of these variants as well as their prognosis and therapy are discussed in relation to recent developments in the immunopathogenesis of SLE.     

Impact of bile acids on the growth of human cholangiocarcinoma via FXR

Mast cell activation disease comprises disorders characterized by accumulation of genetically altered mast cells and/or abnormal release of these cells' mediators, affecting functions in potentially every organ system, often without causing abnormalities in routine laboratory or radiologic testing. In most cases of mast cell activation disease, diagnosis is possible by relatively non-invasive investigation. Effective therapy often consists simply of antihistamines and mast cell membrane-stabilising compounds supplemented with medications targeted at specific symptoms and complications. Mast cell activation disease is now appreciated to likely be considerably prevalent and thus should be considered routinely in the differential diagnosis of patients with chronic multisystem polymorbidity or patients in whom a definitively diagnosed major illness does not well account for the entirety of the patient's presentation.     

Genetic aspects of Sjögren's syndrome

Sjögren's syndrome is a multisystem inflammatory rheumatic disease that is classified into primary and secondary forms, with cardinal features in the eye (keratoconjunctivitis sicca) and mouth (xerostomia). The aetiology behind this autoimmune exocrinopathy is probably multifactorial and influenced by genetic as well as by environmental factors that are as yet unknown. A genetic predisposition to Sjögren's syndrome has been suggested on the basis of familial aggregation, animal models and candidate gene association studies. Recent advances in molecular and genetic methodologies should further our understanding of this complex disease. The present review synthesizes the current state of genetics in Sjögren's syndrome.     

Mesenchymal stem cell therapy and acute graft-versus-host disease: a review

Mesenchymal stem cells (MSCs) are being widely studied as potential cell therapy agents due to their immunomodulatory properties, which have been established by in vitro studies and in several clinical trials. Within this context, mesenchymal stem cell therapy appears to hold substantial promise, particularly in the treatment of conditions involving autoimmune and inflammatory components. Nevertheless, many research findings are still contradictory, mostly due to difficulties in characterization of the effects of MSCs in vivo. The purpose of this review is to report the mechanisms underlying mesenchymal stem cell therapy for acute graft-versus-host disease, particularly with respect to immunomodulation, migration, and homing, as well as report clinical applications described in the literature.     

Immunological mechanisms in the pathogenesis of vinyl chloride disease.

Vinyl chloride (VC) disease is a multisystem disorder incorporating Raynaud''s phenomenon, acro-osteolysis, thrombocytopenia, portal fibrosis, and hepatic and pulmonary dysfunction. Immunological and immunochemical investigations showed the presence of circulating immune complexes in 19 out of 28 patients with the disease and in a further two out of 30 workers exposed to VC. The immunological data were reviewed in relation to the clinical picture of the disease and to the available evidence on the metabolism of VC. The results suggest that VC disease is an immune complex disorder and that the immune response is initiated by the adsorption of VC or a metabolite on to tissue or plasma protein.     

The pursuit of euthymia

Psychiatrists often consider the positive characteristics displayed by a patient in their clinical judgment, yet current assessment and treatment strategies are shifted on the side of psychological dysfunction. Euthymia is a transdiagnostic construct referring to the presence of positive affects and psychological well‐being, i.e., balance and integration of psychic forces (flexibility), a unifying outlook on life which guides actions and feelings for shaping future accordingly (consistency), and resistance to stress (resilience and tolerance to anxiety or frustration). There is increasing evidence that the evaluation of euthymia and its components has major clinical implications. Specific instruments (clinical interviews and questionnaires) may be included in a clinimetric assessment strategy encompassing macro‐analysis and staging. The pursuit of euthymia cannot be conceived as a therapeutic intervention for specific mental disorders, but as a transdiagnostic strategy to be incorporated in an individualized therapeutic plan. A number of psychotherapeutic techniques aiming to enhance positive affects and psychological well‐being (such as well‐being therapy, mindfulness‐based cognitive therapy, and acceptance and commitment therapy) have been developed and validated in randomized controlled clinical trials. The findings indicate that flourishing and resilience can be promoted by specific interventions leading to a positive evaluation of one's self, a sense of continuing growth and development, the belief that life is purposeful and meaningful, satisfaction with one's relations with others, the capacity to manage effectively one's life, and a sense of self‐determination.     

Action of estrogens in the aging brain: Dementia and cognitive aging

Background

Menopause is associated with sharp declines in concentrations of circulating estrogens. This change in hormone milieu has the potential to affect brain functions relevant to dementia and cognitive aging.

Scope of review

Focused review of published results of randomized clinical trials of estrogen-containing hormone therapy for Alzheimer's disease treatment and dementia prevention, observational research on cognition across the menopause transition, and observational research on the association of hormone therapy and Alzheimer's disease risk.

Major conclusions

Clinical trial evidence supports conclusions that estrogen therapy does not improve dementia symptoms in women with Alzheimer's disease and that estrogen-containing hormone therapy initiated after about age 65 years increases dementia risk. Hormone therapy begun in this older postmenopausal group does not ameliorate cognitive aging. Cognitive outcomes of midlife hormone exposures are less well studied. There is no strong indication of short-term cognitive benefit of hormone use after natural menopause, but clinical trial data are sparse. Little research addresses midlife estrogen use after surgical menopause; limited clinical trial data imply short-term benefit of prompt initiation at the time of oophorectomy. Whether exogenous estrogen exposures in the early postmenopause affect Alzheimer risk or cognitive aging much later in life is unanswered by available data. Observational results raise the possibility of long-term cognitive benefit, but bias is a concern in interpreting these findings.

General significance

Estrogen-containing hormone therapy should not be initiated after age 65 to prevent dementia or remediate cognitive aging. Further research is needed to understand short-term and long-term cognitive effects of estrogen exposures closer to the age of menopause.     

Establishing a robust chimeric antigen receptor T-cell therapy program in Australia: the Royal Prince Alfred Hospital experience

>himeric antigen receptor (CAR) T-cell therapy is a novel approved cancer treatment that has shown remarkable efficacy in the treatment of patients with relapsed leukemia and lymphoma. Implementation of CAR T-cell therapy in a hospital setting requires careful and detailed planning because of the complexities in delivering this specialist service. A multi-disciplinary approach with dedicated funding is required to meet clinical, scientific, logistic and regulatory requirements. Tisagenlecleucel was the first approved CAR T-cell therapy in Australia. The treatment has been made available to Australian patients in specialist public hospitals through federal and state funding. Royal Prince Alfred Hospital (RPAH) is one of Australia's oldest tertiary referral public health care institutions and was approved for the provision of CAR T-cell therapy service in 2019. A multi-disciplinary clinical program has been established for the collection and cryopreservation of donor cells shipped for manufacturing as well as for the receipt, storage and administration of CAR T-cell therapy and patient management. The program encompasses a Therapeutic Goods Administration-accredited apheresis unit and a state-of-the-art facility for cell processing, cryopreservation and storage. The program's clinical expertise extends to hematology, oncology, intensive care, pharmacy, neurology and radiology services with direct experience in managing patients receiving CAR T-cell therapies. The introduction of CAR T-cell therapies at RPAH was a complex undertaking facilitated by the existing infrastructure and clinical expertise.     

Osteopontin as a biomarker for COVID-19 severity and multisystem inflammatory syndrome in children: A pilot study

This study sought to evaluate the candidacy of plasma osteopontin (OPN) as a biomarker of COVID-19 severity and multisystem inflammatory condition in children (MIS-C) in children. A retrospective analysis of 26 children (0–21 years of age) admitted to Children’s Healthcare of Atlanta with a diagnosis of COVID-19 between March 17 and May 26, 2020 was undertaken. The patients were classified into three categories based on COVID-19 severity levels: asymptomatic or minimally symptomatic (control population, admitted for other non-COVID-19 conditions), mild/moderate, and severe COVID-19. A fourth category of children met the Centers for Disease Control and Prevention''s case definition for MIS-C. Residual blood samples were analyzed for OPN, a marker of inflammation using commercial ELISA kits (R&D), and results were correlated with clinical data. This study demonstrates that OPN levels are significantly elevated in children hospitalized with moderate and severe COVID-19 and MIS-C compared to OPN levels in mild/asymptomatic children. Further, OPN differentiated among clinical levels of severity in COVID-19, while other inflammatory markers including maximum erythrocyte sedimentation rate, C-reactive protein and ferritin, minimum lymphocyte and platelet counts, soluble interleukin-2R, and interleukin-6 did not. We conclude OPN is a potential biomarker of COVID-19 severity and MIS-C in children that may have future clinical utility. The specificity and positive predictive value of this marker for COVID-19 and MIS-C are areas for future larger prospective research studies.     

The neurological presentations of childhood and adult mitochondrial disease: established syndromes and phenotypic variations

Mitochondrial disorders are caused by mutations of nuclear or mitochondrial DNA encoded genes involved in oxidative phosphorylation (OXPHOS). Mutations in these critical genes are associated with specific clinical syndromes with diverse presentations (DiMauro and Schon, 2003. NEJM 348, 2656; Hart et al., 2002. Mitochondrial Disorders in Neurology). Since mitochondria are present in many of our organs and play a key role in energy metabolism, mitochondrial encephalomyopathies often present as multisystem disorders which may manifest with neurologic, cardiac, endocrine, gastrointestinal, hepatic, renal and/or hematologic involvement (DiMauro and Bonilla, 1997. The Molecular and Genetic Basis of Neurological Disease; Vu et al., 2002. Neurol. Clin. N. Am. 20, 809). This chapter will address adult and childhood onset mitochondrial DNA encephalomyopathies, characteristic clinical presentations, as well as their molecular characterization.     

Implantation of Total Artificial Heart in Congenital Heart Disease

In patients with end-stage heart failure (HF), a total artificial heart (TAH) may be implanted as a bridge to cardiac transplant. However, in congenital heart disease (CHD), the malformed heart presents a challenge to TAH implantation. In the case presented here, a 17 year-old patient with congenital transposition of the great arteries (CCTGA) experienced progressively worsening HF due to his congenital condition. He was hospitalized multiple times and received an implantable cardioverter defibrillator (ICD). However, his condition soon deteriorated to end-stage HF with multisystem organ failure. Due to the patient''s grave clinical condition and the presence of complex cardiac lesions, the decision was made to proceed with a TAH. The abnormal arrangement of the patient''s ventricles and great arteries required modifications to the TAH during implantation.With the TAH in place, the patient was able to return home and regain strength and physical well-being while awaiting a donor heart. He was successfully bridged to heart transplantation 5 months after receiving the device. This report highlights the TAH is feasible even in patients with structurally abnormal hearts, with technical modification.     

Participation in clinical trials among women living with HIV in Canada

BACKGROUND: To describe participation in clinical trials among HIV-positive women enrolled since 1993 in the Canadian Women''s HIV Study, a prospective open cohort study. METHODS: All HIV-positive women being followed at hospital-based or community-based clinics at 28 sites in 11 Canadian cities were eligible to participate in the Canadian Women''s HIV Study. Baseline and follow-up information was collected for 413 women every 6 months by study nurses using standardized questionnaires. Data included sociodemographic variables, HIV exposure group, CD4 count, disease classification, use of antiretroviral therapies and participation in clinical trials. RESULTS: At study intake 15.0% (62/413) of the women had participated in a clinical trial; an additional 8.5% (35/413) participated during a median follow-up of 18 months. Multivariate analysis revealed that the following factors were independently associated with participation in a clinical trial: white race (adjusted odds ratio [OR] 3.38, p = 0.001), current use of antiretroviral therapy (adjusted OR 2.01, p = 0.008), completion of secondary school (adjusted OR 1.97, p = 0.024) and residence in the Prairies or Atlantic provinces (adjusted OR 1.98, p = 0.043). INTERPRETATION: Although the overall clinical trial participation rate of 23.5% was relatively high among HIV-positive women, injection drug users were underrepresented in this study population, and non-white women, women who did not complete high school and women not receiving antiretroviral therapy were less likely than white women, women of higher education and women receiving antiretroviral therapy to participate in clinical trials in Canada. Because of the importance of trial participants being representative of the population for which therapeutic agents are intended, HIV clinical trials must recruit women with lower literacy levels, non-white women, women not receiving antiretroviral therapy and women who are injection drug users to ensure generalizability of research findings. Further study is needed to assess factors that act as barriers and motivators to women''s participation in HIV clinical trials.     

Indications for surgery in necrotizing pancreatitis.

The decision to operate on a patient with severe acute pancreatitis is often difficult and requires mature clinical judgment. Indications that are widely accepted include to establish the differential diagnosis, when the surgeon is concerned that the symptoms are due to a disease other than pancreatitis for which an operation is mandatory; in persistent and severe biliary pancreatitis, when an obstructing gallstone is lodged in the ampulla of Vater and cannot be managed endoscopically; in the presence of infected pancreatic necrosis; and to drain a pancreatic abscess, if percutaneous drainage does not produce the desired result. Other indications that are less well defined and somewhat controversial are the presence of sterile pancreatic necrosis involving 50% or more of the pancreas, when the pancreatitis persists despite maximal medical therapy, and when a patient''s condition deteriorates. For these last three indications, guidelines have been presented that permit a logical approach to management, although uncertainty remains. Surgeons should strive to describe in detail and precisely the clinical state of their patients at the time that an operation is done, as well as the findings and technical details of the operation. This should allow further refinement in the management of this vexing problem.     

Hypnosis,memory and amnesia.

Hypnotized subjects respond to suggestions from the hypnotist for imaginative experiences involving alterations in perception and memory. Individual differences in hypnotizability are only weakly related to other forms of suggestibility. Neuropsychological speculations about hypnosis focus on the right hemisphere and/or the frontal lobes. Posthypnotic amnesia refers to subjects'' difficulty in remembering, after hypnosis, the events and experiences that transpired while they were hypnotized. Posthypnotic amnesia is not an instance of state-dependent memory, but it does seem to involve a disruption of retrieval processes similar to the functional amnesias observed in clinical dissociative disorders. Implicit memory, however, is largely spared, and may underlie subjects'' ability to recognize events that they cannot recall. Hypnotic hypermnesia refers to improved memory for past events. However, such improvements are illusory: hypermnesia suggestions increase false recollection, as well as subjects'' confidence in both true and false memories. Hypnotic age regression can be subjectively compelling, but does not involve the ablation of adult memory, or the reinstatement of childlike modes of mental functioning, or the revivification of memory. The clinical and forensic use of hypermnesia and age regression to enhance memory in patients, victims and witnesses (e.g. recovered memory therapy for child sexual abuse) should be discouraged.     

Toward deconstructing the phenotype of late-onset Pompe disease

Pompe disease (glycogen storage disease type 2 or acid maltase deficiency) is a rare autosomal recessive lysosomal storage disorder. Since the advent of ERT a lot has been learned about the phenotypic spectrum especially in the late onset patients. We describe in detail 44 patients diagnosed with late-onset Pompe disease (LOPD) at our neuromuscular department from 1985 to 2011 and compare them to patients with LOPD in the literature of the past 40 years. Study of the Munich LOPD group revealed varying musculoskeletal and cardio-cerebrovascular manifestation patterns. Several of these symptom patterns commonly appeared in conjunction with one another, highlighting the multisystem involvement of this condition. Common symptom patterns include: (i) Classic limb girdle and diaphragmatic weakness, (ii) rigid spine syndrome (RSS), scoliosis, and low body mass, and (iii) several cardio-cerebrovascular manifestation patterns. The most common presentation, limb girdle and diaphragmatic weakness, appeared in 78% (34/44) of our patients and over 80% of those in the literature. Sixteen percent (7/44) of our patients presented with rigid spine, scoliosis, and low body mass. Although scoliosis had a reported frequency of 33% in the general LOPD patient population, the literature only occasionally reported low body mass and RSS. Importantly, a multisystem extramuscular finding accompanied by cardio-cerebrovascular manifestations was found in 29% (13/44) of our LOPD patients; the literature showed an increasing prevalence of this latter finding. By examining the phenotype of patients with confirmed LOPD, we found a more subtle clinical multisystem involvement in LOPD. Whether patients presenting with the different symptom patterns respond differently to enzyme replacement therapy remains a key question for future research. ? 2012 Wiley Periodicals, Inc.     

CAR-T Cell Therapy for Breast Cancer: From Basic Research to Clinical Application

Breast cancer rises as the most commonly diagnosed cancer in 2020. Among women, breast cancer ranks first in both cancer incidence rate and mortality. Treatment resistance developed from the current clinical therapies limits the efficacy of therapeutic outcomes, thus new treatment approaches are urgently needed. Chimeric antigen receptor (CAR) T cell therapy is a type of immunotherapy developed from adoptive T cell transfer, which typically uses patients'' own immune cells to combat cancer. CAR-T cells are armed with specific antibodies to recognize antigens in self-tumor cells thus eliciting cytotoxic effects. In recent years, CAR-T cell therapy has achieved remarkable successes in treating hematologic malignancies; however, the therapeutic effects in solid tumors are not up to expectations including breast cancer. This review aims to discuss the development of CAR-T cell therapy in breast cancer from preclinical studies to ongoing clinical trials. Specifically, we summarize tumor-associated antigens in breast cancer, ongoing clinical trials, obstacles interfering with the therapeutic effects of CAR-T cell therapy, and discuss potential strategies to improve treatment efficacy. Overall, we hope our review provides a landscape view of recent progress for CAR-T cell therapy in breast cancer and ignites interest for further research directions.     

Improvement in circulating superoxide dismutase levels: role of nonsteroidal anti-inflammatory drugs in rheumatoid arthritis

Superoxide anion radical plays a significant role in inflammation, like rheumatoid arthritis. Superoxide dismutase enzyme known to dismutate superoxide anion radical does not play any significant role in this multisystem disease. This paper reports that very low levels of circulating superoxide dismutase levels are observed in patients with rheumatoid arthritis and these levels significantly improve with NSAID therapy. The possible mechanism of the action is discussed.     

Cold Injury in Civil Disaster

Patients exposed to cold environment following a disaster may be suffering from local cold injury or from systemic cold injury (accidental hypothermia). The treatment of the former is well established and consists of rapid rewarming of the frozen parts and physical therapy; early amputation is not advisable. Recommendations for the assessment and treatment of total body cooling, based on case reports of accidental hypothermia, on the results of animal experiments and on the clinical experience with induced hypothermia, are not well established and are controversial. Since, at temperatures below 30° C., death may be caused by cardiac arrhythmias and since, at this low level, spontaneous rewarming may not be possible, active rewarming is recommended at this stage. At a higher temperature level, vigorous warming is dangerous, and the patient''s own regulatory mechanisms should be allowed to restore the temperature.     

Arachidonic acid metabolites and colchicine in Behçet's disease (BD)

Vasculitis is accepted to be the basis of Behçet's disease (BD) which is a multisystem disease, and the arachidonic acid(AA) metabolites acting as balancing mediators in the organism are accepted to be responsible for the vasculitis.In this study, we examined the prostaglandin E₂ (PGE₂) and leukotriene C₄ (LTC₄) levels of the patients with BD before and after colchicine therapy. We found a statistical decrease in the PGE₂ and LTC₄ levels after colchicine therapy compared to the previous levels, concluding that colchicine inhibits the inflammation and the polymorphonuclear leukocyte (PML) chemotaxis by inhibiting the cyclooxygenase and lipoxygenase patways.