Mitotically inactivated embryonic stem cells can be used as an in vivo feeder layer to nurse damaged myocardium after acute myocardial infarction: a preclinical study.

RATIONALE: Various types of viable stem cells have been reported to result in modest improvement in cardiac function after acute myocardial infarction. The mechanisms for improvement from different stem cell populations remain unknown. OBJECTIVE: To determine whether irradiated (nonviable) embryonic stem cells (iESCs) improve postischemic cardiac function without adverse consequences. METHODS AND RESULTS: After coronary artery ligation-induced cardiac infarction, either conditioned media or male murine or male human iESCs were injected into the penumbra of ischemic myocardial tissue of female mice or female rhesus macaque monkeys, respectively. Murine and human iESCs, despite irradiation doses that prevented proliferation and induced cell death, significantly improved cardiac function and decreased infarct size compared with untreated or media-treated controls. Fluorescent in situ hybridization of the Y chromosome revealed disappearance of iESCs within the myocardium, whereas 5-bromo-2'-deoxyuridine assays revealed de novo in vivo cardiomyocyte DNA synthesis. Microarray gene expression profiling demonstrated an early increase in metabolism, DNA proliferation, and chromatin remodeling pathways, and a decrease in fibrosis and inflammatory gene expression compared with media-treated controls. CONCLUSIONS: As a result of irradiation before injection, ex vivo and in vivo iESC existence is transient, yet iESCs provide a significant improvement in cardiac function after acute myocardial infarction. The mechanism(s) of action of iESCs seems to be related to cell-cell exchange, paracrine factors, and a scaffolding effect between iESCs and neighboring host cardiomyocytes.

Severe Neurocysticercosis in an Immunocompetent Male Without Travel to an Endemic Region: A Case Report.

Neurocysticercosis is a neglected parasitic cause of seizures in the United States. It can have a wide array of presentations depending on the location and number of cysticercoids. The severity of symptoms varies with the location of the lesion in the brain and to the extent of the number of neurocysticercoids and host immune response. In the severe form of neurocysticercosis, it can present as an acute encephalitic picture. We present a case of severe neurocysticercosis in a patient without any significant travel history. Neurocysticercosis in nonendemic areas can be diagnostically challenging, given the lack of travel history as in our patient. Neurocysticercosis should be kept as a differential in all cases of seizures without prior history of seizure episodes.

Autologous nonmyeloablative hematopoietic stem cell transplantation in patients with severe anti-TNF refractory Crohn disease: long-term follow-up.

We evaluated the safety and clinical outcome of autologous nonmyeloablative hematopoietic stem cell transplantation (HSCT) in patients with severe Crohn disease (CD) defined as a Crohn Disease Activity Index (CDAI) greater than 250, and/or Crohn Severity Index greater than 16 despite anti-tumor necrosis factor therapy. Stem cells were mobilized from the peripheral blood using cyclophosphamide (2.0 g/m(2)) and G-CSF (10 µg/kg/day), enriched ex vivo by CD34(+) selection, and reinfused after immune suppressive conditioning with cyclophosphamide (200 mg/kg) and either equine antithymocyte globulin (ATG, 90 mg/kg) or rabbit ATG (6 mg/kg). Eighteen of 24 patients are 5 or more years after transplantation. All patients went into remission with a CDAI less than 150. The percentage of clinical relapse-free survival defined as the percent free of restarting CD medical therapy after transplantation is 91% at 1 year, 63% at 2 years, 57% at 3 years, 39% at 4 years, and 19% at 5 years. The percentage of patients in remission (CDAI < 150), steroid-free, or medication-free at any posttransplantation evaluation interval more than 5 years after transplantation has remained at or greater than 70%, 80%, and 60%, respectively. This trial was registered at www.clinicaltrials.gov as NCT0027853.

Community-Acquired Acinetobacter radioresistens Bacteremia in an Immunocompetent Host.

Acinetobacter species are gram-negative coccobacilli ubiquitous in nature and widely distributed in the environment. Acinetobacter baumannii is a bacteria commonly seen in the hospital setting, responsible for causing a wide range of bloodstream infections, urinary tract infections, secondary meningitis, infective endocarditis, and wound infections, and is the cause of outbreaks mainly due to its antimicrobial resistance patterns. The use of broad-spectrum antibiotic coverage with carbapenems is essential in the hospital setting. Therefore, carbapenem-resistant Acinetobacter baumannii (CRAB) poses as a very challenging pathogen. Acinetobacter radioresistens, a rare species in comparison to the more prevalent Acinetobacter baumannii, is an underestimated agent in causing nosocomial infections and also is a potential disseminator of resistance genes. It is also resistant to gamma radiation at 4-8 times higher than other Acinetobacter spp. and is the source of the class D OXA-23 carbapenemase that can confer carbapenem resistance. Therefore, immediate and precise identification of A. radioresistens is crucial for the clinical management of multidrug-resistant bacteremia.

Rare Angina: A Case Report of Ludwig's Angina.

Ludwig's angina is the rapidly progressive cellulitis of the soft tissue of the neck and the floor of the mouth. Airway compromise is a frequent and potentially fatal sequela of Ludwig's angina. Here we present a case of a 54-year-old African American male who presented with fever associated with painful swelling of the mouth and anterior neck. He was febrile and hypoxic on presentation. Imaging showed extensive involvement of the neck and mediastinum to the level of the clavicles. The diagnosis of Ludwig's angina of periodontal origin was made, and intubation was performed for airway protection. Management was done by surgical debridement along with a course of broad-spectrum antibiotics. The patient's condition improved, and he was discharged on oral antibiotics with a referral to a dentist. Our case demonstrates that early diagnosis, airway management, treatment with broad-spectrum antibiotics, and surgical intervention are vital for the successful management of severe cases of Ludwig's angina.

May-Thurner Syndrome: An Anatomic Predisposition to Deep Vein Thrombosis.

May-Thurner syndrome (MTS) is a rare clinical condition caused by extrinsic compression of the left common iliac vein by the right common iliac artery, leading to venous stasis and predisposing to thrombus formation. Here, we present the case of a 39-year-old female with no obviously known other risk factors predisposing to thrombosis who presented with severe left leg pain and swelling for a week. The international normalized ratio was elevated and the venous Doppler study showed extensive thrombosis extending from the left common iliac vein to the common femoral vein and the popliteal vein. She was diagnosed with MTS and treated with catheter-directed mechanical thrombolysis and thrombectomy, along with angioplasty of the left common iliac vein and external iliac vein, with near-complete resolution post-treatment. MTS should be suspected in patients who present with unilateral limb thrombosis regardless of the presence of predisposing factors. Timely management with endovascular procedures is necessary to help prevent other potential life-threatening complications.

A Case Report of Acute Transient Encephalopathy Following a Trans-esophageal Echocardiography.

Methemoglobinemia is caused due to an increase in methemoglobin in the blood, impairing oxygen transfer to tissues. Acquired methemoglobinemia is caused by various drugs like local anesthetics, antibiotics, nitrates, nitrites, and food additives. We present a case of a 73-year-old male who presented with cyanosis, altered mental status, and hypoxia following transesophageal echocardiography. Arterial blood gas analysis revealed methemoglobinemia. He had been given topical lidocaine and benzocaine spray before the procedure. He improved after the administration of methylene blue. The case highlights the importance of considering methemoglobinemia in patients presenting with cyanosis, altered mental status, and hypoxia after endoscopic procedures.

Granulomatosis With Polyangiitis: A Pauci-Immune Rapidly Progressive Glomerulonephritis With Isolated Renal Involvement in an Elderly Male.

Granulomatosis with polyangiitis (GPA) is a necrotizing vasculitis with upper and lower respiratory tract and renal system involvement. We present a case of a 59-year-old male presenting with complaints of abdominal pain with deranged renal function and acute increase in creatinine level. On investigation, the antineutrophil cytoplasmic autoantibody, cytoplasmic (c-ANCA) was found to be significantly elevated in association with pauci-immune crescentic glomerulonephritis on biopsy. This was diagnostic of Wegener's granulomatosis. He was treated with intravenous cyclophosphamide 10 mg/kg/pulse along with steroids at 1 mg/kg/day for induction and trimethoprim/sulfamethoxazole (TMP-SMX) 80/400 mg for pneumocystis carinii pneumonia (PCP) prophylaxis after a negative tuberculosis QuantiFERON® assay (Qiagen, Netherlands). On discharge, he was on TMP-SMX prophylaxis for PCP, prednisone 60 mg daily, and cyclophosphamide on pulse dosing every 14 days with instructions to follow up. The patient showed improvement in therapy.

Utilizing the Most Accurate Preoperative Risk Calculator.

The most commonly used preoperative assessment tools include the American College of Surgeons National Surgical Quality Improvement Program and the Revised Cardiac Risk Index. These tools seek to predict the risk of an individual experiencing postoperative complications, including but not limited to mortality, myocardial infarction, pneumonia, stroke, venous thromboembolism, and pneumonia. Many published studies have sought to objectively quantify the utility of the preoperative risk calculations by retrospectively compiling data for patients who underwent the same or comparable surgeries to compare actual complications to predicted complications. Therefore, we searched these studies to review the literature to draw more general conclusions and recommend which risk calculator is best for different types of surgeries.

Successful Treatment of Respiratory Syncytial Virus Infection in an Immunocompromised Patient With Ribavirin.

Respiratory syncytial virus (RSV) is a frequent cause of respiratory tract infections in children. Still, it can also cause seasonal outbreaks affecting persons of all ages, especially those with comorbidities or immunocompromised states. Ribavirin is one of the two approved therapies for the treatment of RSV respiratory tract infections. Unfortunately, its aerosolized formulation has been approved only in children, and the oral formulation is not frequently used to treat the infection. However, ribavirin has demonstrated morbidity and mortality benefit in immunocompromised patients. A 70-year-old female had started chemotherapy for a diagnosis of B-cell acute lymphoblastic leukemia (B-ALL). She developed an upper respiratory tract infection (URTI) along with positive RSV status. We started her on oral ribavirin therapy, which had to be stopped after five days of treatment due to an acute hemolytic reaction. She was re-initiated on oral ribavirin after cessation of medication for seven days and showed improvement. Therefore, ribavirin can be used in immunocompromised patients with RSV infection under proper supervision.

HIV Encephalopathy Mimicking Acute Demyelinating Processes.

Human immunodeficiency virus (HIV) encephalopathy lies in the severe spectrum of HIV-associated neurological disorder (HAND) and ranges from asymptomatic condition to minor neurological features to severe dementia. Cerebrospinal fluid (CSF) analysis helps to rule out the presence of other opportunistic infections. Neuroimaging helps establish the diagnosis. We report a case of a 39-year-old African American female who presented with signs and symptoms suggestive of acute multiple sclerosis (MS) flares in the setting of advanced acute immunodeficiency syndrome (AIDS) encephalopathy. She presented with bilateral lower extremity muscle weakness and pain with apparent cognitive decline. Notable laboratory findings included leukopenia with normal neutrophils and positive serology for HIV-1. The MRI showed mild post-contrast enhancement suggestive of demyelinating disease, favoring MS over progressive multifocal leukoencephalopathy (PML). Cerebrospinal fluid analysis was significant for positive oligoclonal bands and negative serology. She was started on antiretroviral therapy (ART) for AIDS while holding steroids due to the possibility of worsening AIDS. After treatment for HIV, she showed immunologic and functional status improvement. HIV encephalopathy must be diagnosed by ruling out other similar presenting neurological illnesses for tactful patient management.

Embryonic stem cells as an alternate marrow donor source: engraftment without graft-versus-host disease.

A single embryonic stem cell (ESC) line can be repetitively cryopreserved, thawed, expanded, and differentiated into various cellular components serving as a potentially renewable and well-characterized stem cell source. Therefore, we determined whether ESCs could be used to reconstitute marrow and blood in major histocompatibility complex (MHC)-mismatched mice. To induce differentiation toward hematopoietic stem cells (HSCs) in vitro, ESCs were cultured in methylcellulose with stem cell factor, interleukin (IL)-3, and IL-6. ESC-derived, cytokine-induced HSCs (c-kit+/CD45+) were isolated by flow cytometry and injected either intra bone marrow or intravenously into lethally irradiated MHC-mismatched recipient mice. From 2 wk to 6 mo after injection, the peripheral blood demonstrated increasing ESC-derived mononuclear cells that included donor-derived T and B lymphocytes, monocytes, and granulocytes without clinical or histologic evidence of graft-versus-host disease (GVHD). Mixed lymphocyte culture assays demonstrated T cell tolerance to both recipient and donor but intact third party proliferative responses and interferon gamma production. ESCs might be used as a renewable alternate marrow donor source that reconstitutes hematopoiesis with intact immune responsiveness without GVHD despite crossing MHC barriers.

Hematopoietic mixed chimerism derived from allogeneic embryonic stem cells prevents autoimmune diabetes mellitus in NOD mice.

Embryonic stem cell (ESC)-derived hematopoietic stem cells (HSC), unlike HSC harvested from the blood or marrow, are not contaminated by lymphocytes. We therefore evaluated whether ESC-derived HSC could produce islet cell tolerance, a phenomenon termed graft versus autoimmunity (GVA), without causing the usual allogeneic hematopoietic stem cell transplant complication, graft-versus-host disease (GVHD). Herein, we demonstrate that ESC-derived HSC may be used to prevent autoimmune diabetes mellitus in NOD mice without GVHD or other adverse side effects. ESC were cultured in vitro to induce differentiation toward HSC, selected for c-kit expression, and injected either i.v. or intra-bone marrow (IBM) into sublethally irradiated NOD/LtJ mice. Nine of 10 mice from the IBM group and 5 of 8 from the i.v. group did not become hyperglycemic, in contrast to the control group, in which 8 of 9 mice developed end-stage diabetes. All mice with >5% donor chimerism remained free of diabetes and insulitis, which was confirmed by histology. Splenocytes from transplanted mice were unresponsive to glutamic acid decarboxylase isoform 65, a diabetic-specific autoantigen, but responded normally to third-party antigens. ESC-derived HSC can induce an islet cell tolerizing GVA effect without GVHD. This study represents the first instance, to our knowledge, of ESC-derived HSC cells treating disease in an animal model.

Primary pulmonary Kaposi Sarcoma in a newly diagnosed cisgender heterosexual HIV positive patient presenting before cutaneous manifestations.

AIDS-related Kaposi sarcoma (KS) is a vascular malignancy that usually presents with mucocutaneous lesions. Bronchopulmonary involvement as an initial manifestation is a rare phenomenon. This case describes a young male presenting with pulmonary symptoms mimicking HIV-related opportunistic infection who was eventually diagnosed with primary pulmonary KS. The aim of this report is to emphasize that KS should be recognized as a differential diagnosis in AIDS patients presenting with pulmonary symptoms. Making the diagnosis may be a difficult task, at times, requiring invasive procedures such as lung biopsy.

Nonmyeloablative hematopoietic stem cell transplantation for systemic lupus erythematosus.

CONTEXT: Manifestations of systemic lupus erythematosus (SLE) may in most patients be ameliorated with medications that suppress the immune system. Nevertheless, there remains a subset of SLE patients for whom current strategies are insufficient to control disease. OBJECTIVE: To assess the safety of intense immunosuppression and autologous hematopoietic stem cell support in patients with severe and treatment-refractory SLE. DESIGN, SETTING, AND PARTICIPANTS: A single-arm trial of 50 patients with SLE refractory to standard immunosuppressive therapies and either organ- or life-threatening visceral involvement. Patients were enrolled from April 1997 through January 2005 in an autologous nonmyeloablative hematopoietic stem cell transplantation (HSCT) study at a single US medical center. INTERVENTIONS: Peripheral blood stem cells were mobilized with cyclophosphamide (2.0 g/m2) and granulocyte colony-stimulating factor (5 microg/kg per day), enriched ex vivo by CD34+ immunoselection, cryopreserved, and reinfused after treatment with cyclophosphamide (200 mg/kg) and equine antithymocyte globulin (90 mg/kg). MAIN OUTCOME MEASURES: The primary end point was survival, both overall and disease-free. Secondary end points included SLE Disease Activity Index (SLEDAI), serology (antinuclear antibody [ANA] and anti-double-stranded (ds) DNA), complement C3 and C4, and changes in renal and pulmonary organ function assessed before treatment and at 6 months, 12 months, and then yearly for 5 years. RESULTS: Fifty patients were enrolled and underwent stem cell mobilization. Two patients died after mobilization, one from disseminated mucormycosis and another from active lupus after postponing the transplantation for 4 months. Forty-eight patients underwent nonmyeloablative HSCT. Treatment-related mortality was 2% (1/50). By intention to treat, treatment-related mortality was 4% (2/50). With a mean follow-up of 29 months (range, 6 months to 7.5 years) for patients undergoing HSCT, overall 5-year survival was 84%, and probability of disease-free survival at 5 years following HSCT was 50%. Secondary analysis demonstrated stabilization of renal function and significant improvement in SLEDAI score, ANA, anti-ds DNA, complement, and carbon monoxide diffusion lung capacity adjusted for hemoglobin. CONCLUSIONS: In treatment-refractory SLE, autologous nonmyeloablative HSCT results in amelioration of disease activity, improvement in serologic markers, and either stabilization or reversal of organ dysfunction. These data are nonrandomized and thus preliminary, providing the foundation and justification for a definitive randomized trial. Clinical Trial Registration ClinicalTrials.gov Identifier: NCT00271934.

Stem cell transplantation for autoimmune diseases.

Hematopoietic stem cell transplantation is an increasingly used therapy for treatment of autoimmune diseases and severe immune-mediated disorders. We address some general concepts and principles in the development of hematopoietic stem cell transplantation in order to understand the principles and design of safe autologous and allogeneic transplant regimens for these unique diseases.

Antiphospholipid syndrome in patients with systemic lupus erythematosus treated by autologous hematopoietic stem cell transplantation.

Systemic lupus erythematosus (SLE) is the most common disease associated with antiphospholipid syndrome (APS). We, therefore, evaluated 46 patients with refractory SLE treated by autologous hematopoietic stem cell transplantation (HSCT) for a history of APS prior to transplantation. The prevalence of SLE-related APS in our patient population was 61% (28 of 46 patients with refractory SLE). Nineteen of 28 patients with APS had lupus anticoagulant (LA) or high titers of anticardiolipin antibodies (ACLAs), either immunoglobulin (Ig)G or IgM, when evaluated at study entry. Six of 8 evaluable LA+ patients became and remained LA-; 5 of 7 initially ACLA IgG+ patients and 9 of 11 ACLA IgM+ patients demonstrated normalization of ACLA titers when followed after HSCT. Eighteen of 22 patients refractory to chronic anticoagulation discontinued anticoagulation therapy a median of 4 months after transplantation; 78% of them remained free of thrombotic events and in complete SLE remission for up to 78 months (median, 15 months) after HSCT. There was no treatment-related mortality. Autologous HSCT may be performed safely in patients with APS and appears to be effective therapy for eliminating ALPAs and preventing thrombotic complications in patients with SLE.

Autologous hematopoietic stem cell transplantation in patients with refractory Crohn's disease.

BACKGROUND & AIMS: Crohn's disease (CD) is an immunologically mediated inflammatory disease of the gastrointestinal tract. Due to a high morbidity and/or an increase in mortality in refractory cases, a new treatment approach is needed. In theory, maximum immune ablation by autologous hematopoietic stem cell transplantation (HSCT) can induce a remission. METHODS: We conducted a phase 1 HSCT study in 12 patients with refractory CD. Candidates were younger than 60 years of age with a Crohn's Disease Activity Index (CDAI) of 250-400 despite conventional therapies including infliximab. Peripheral blood stem cells were mobilized with cyclophosphamide and granulocyte colony-stimulating factor and CD34 + enriched. The immune ablative (conditioning) regimen consisted of 200 mg/kg cyclophosphamide and 90 mg/kg equine antithymocyte globulin. RESULTS: The procedure was well tolerated with anticipated cytopenias, neutropenic fever, and disease-related fever, diarrhea, anorexia, nausea, and vomiting. The median days for neutrophil and platelet engraftment were 9.5 (range, 8-11) and 9 (range, 9-18), respectively. The initial median CDAI was 291 (range, 250-358). Symptoms and CDAI improved before hospital discharge, whereas radiographic and colonoscopy findings improved gradually over months to years following HSCT. Eleven of 12 patients entered a sustained remission defined by a CDAI < or =150. After a median follow-up of 18.5 months (range, 7-37 months), only one patient has developed a recurrence of active CD, which occurred 15 months after HSCT. CONCLUSIONS: Autologous HSCT may be performed safely and has a marked salutary effect on CD activity. A randomized study will be needed to confirm the efficacy of this therapy.