UF Health Shands Hospital

Chronic hepatitis C (non-A, non-B hepatitis) is a common and often progressive viral liver disease. To assess the efficacy of therapy with the antiviral agent interferon alfa, we randomly assigned 166 patients with chronic hepatitis C to treatment with either 3 million or 1 million units of recombinant interferon alfa three times weekly for 24 weeks, or to no treatment. The probability of normalization or near normalization of the serum alanine aminotransferase levels after six months of interferon therapy was 46 percent in patients treated with 3 million units of interferon (P less than 0.001) and 28 percent in those treated with 1 million units (P less than 0.02), but only 8 percent in untreated patients. The serum alanine aminotransferase level became completely normal in 22 of the 26 patients (85 percent) who responded to treatment with 3 million units of interferon and 9 of the 16 patients (56 percent) who responded to treatment with 1 million units. The patients who received 3 million units of interferon had histologic improvement because of the regression of lobular and periportal inflammation. Relapse within six months after the completion of treatment occurred in 51 percent of the patients treated with 3 million units of interferon and 44 percent of those treated with 1 million units. We conclude that a 24-week course of interferon therapy is effective in controlling disease activity in many patients with hepatitis C, although relapse after the cessation of treatment is common.

Using cell-based aptamer selection, we have developed a strategy to use the differences at the molecular level between any two types of cells for the identification of molecular signatures on the surface of targeted cells. A group of aptamers have been generated for the specific recognition of leukemia cells. The selected aptamers can bind to target cells with an equilibrium dissociation constant (K(d)) in the nanomolar-to-picomolar range. The cell-based selection process is simple, fast, straightforward, and reproducible, and, most importantly, can be done without prior knowledge of target molecules. The selected aptamers can specifically recognize target leukemia cells mixed with normal human bone marrow aspirates and can also identify cancer cells closely related to the target cell line in real clinical specimens. The cell-based aptamer selection holds a great promise in developing specific molecular probes for cancer diagnosis and cancer biomarker discovery.

Neural stem cells from neurogenic regions of mammalian CNS are clonogenic in an in vitro culture system exploiting serum and anchorage withdrawal in medium supplemented with methyl cellulose and the pleiotropic growth factors EGF, FGF2, and insulin. The aim of this study was to test whether cortical glial tumors contain stem-like cells capable, under this culture system, of forming clones showing intraclonal heterogeneity in the expression of neural lineage-specific proteins. The high frequencies of clone-forming cells (about 0.1-10 x 10(-3)) in clinical tumor specimens with mutated p53, and in neurogenic regions of normal human CNS, suggest that the ability to form clones in this culture system is induced epigenetically. RT-PCR analyses of populations of normal brain- and tumor-derived sister clones revealed transcripts for nestin, neuron-specific enolase, and glial fibrillary acidic protein (GFAP). However, the tumor-derived clones were different from clones derived from neurogenic regions of normal brain in the expression of transcripts specific for genes associated with neural cell fate determination via the Notch-signaling pathway (Delta and Jagged), and cell survival at G2 or mitotic phases (Survivin). Moreover, the individual glioma-derived clones contain cells immunopositive separately for GFAP or neuronal beta-III tubulin, as well as single cells coexpressing both glial and neuronal markers. The data suggest that the latent critical stem cell characteristics can be epigenetically induced by growth conditions not only in cells from neurogenic regions of normal CNS but also in cells from cortical glial tumors. Moreover, tumor stem-like cells with genetically defective responses to epigenetic stimuli may contribute to gliomagenesis and the developmental pathological heterogeneity of glial tumors.

BACKGROUND: Adeno-associated virus type 1/sarcoplasmic reticulum Ca(2+)-ATPase was assessed in a randomized, double-blind, placebo-controlled, phase 2 study in patients with advanced heart failure. METHODS AND RESULTS: Thirty-nine patients received intracoronary adeno-associated virus type 1/sarcoplasmic reticulum Ca(2+)-ATPase or placebo. Seven efficacy parameters were assessed in 4 domains: symptoms (New York Heart Association class, Minnesota Living With Heart Failure Questionnaire), functional status (6-minute walk test, peak maximum oxygen consumption), biomarker (N-terminal prohormone brain natriuretic peptide), and left ventricular function/remodeling (left ventricular ejection fraction, left ventricular end-systolic volume), plus clinical outcomes. The primary end point success criteria were prospectively defined as achieving efficacy at 6 months in the group-level (concordant improvement in 7 efficacy parameters and no clinically significant worsening in any parameter), individual-level (total score for predefined clinically meaningful changes in 7 efficacy parameters), or outcome end points (cardiovascular hospitalizations and time to terminal events). Efficacy in 1 analysis had to be associated with at least a positive trend in the other 2 analyses. This combination of requirements resulted in a probability of success by chance alone of 2.7%. The high-dose group versus placebo met the prespecified criteria for success at the group-level, individual-level, and outcome analyses (cardiovascular hospitalizations) at 6 months (confirmed at 12 months) and demonstrated improvement or stabilization in New York Heart Association class, Minnesota Living With Heart Failure Questionnaire, 6-minute walk test, peak maximum oxygen consumption, N-terminal prohormone brain natriuretic peptide levels, and left ventricular end-systolic volume. Significant increases in time to clinical events and decreased frequency of cardiovascular events were observed at 12 months (hazard ratio=0.12; P=0.003), and mean duration of cardiovascular hospitalizations over 12 months was substantially decreased (0.4 versus 4.5 days; P=0.05) on high-dose treatment versus placebo. There were no untoward safety findings. CONCLUSIONS: The Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) study demonstrated safety and suggested benefit of adeno-associated virus type 1/sarcoplasmic reticulum Ca(2+)-ATPase in advanced heart failure, supporting larger confirmatory trials. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT00454818.

Extracorporeal shock wave lithotripsy effectively fragments urinary calculi in the upper urinary tract and upper ureter. These fragments pass completely by 3 months in 77.4 per cent of the patients with single stones. Risk of obstruction, increased postoperative pain, need for additional urological operations and retained fragments are low for stones less than 1 cm. in size. As the number of stones treated or single stone size increases above 1 cm. the risk for these factors increases. Adjunctive urological surgical management is required in 9 per cent of the patients preoperatively and 8 per cent postoperatively. Only 0.6 per cent of the patients require some type of open operation to resolve the stone problems after extracorporeal shock wave lithotripsy. Hemorrhage, obstruction by fragments, severe pain and urinary infection all constitute known complications and require careful urological management of all patients. Hospitalization averages 2 days after treatment and patients usually return to work within a few days after they are discharged from the hospital.

Recent studies have provided new information regarding the optimal surveillance protocols for low-risk patients with differentiated thyroid cancer (DTC). This article summarizes the main issues brought out in a consensus conference of thyroid cancer specialists who analyzed and discussed this new data. There is growing recognition of the value of serum thyroglobulin (Tg) as part of routine surveillance. An undetectable serum Tg measured during thyroid hormone suppression of TSH (THST) is often misleading. Eight studies show that 21% of 784 patients who had no clinical evidence of tumor with baseline serum Tg levels usually below 1 micro g/liter during THST had, in response to recombinant human TSH (rhTSH), a rise in serum Tg to more than 2 micro g/liter. When this happened, 36% of the patients were found to have metastases (36% at distant sites) that were identified in 91% by an rhTSH-stimulated Tg above 2 micro g/liter. Diagnostic whole body scanning, after either rhTSH or thyroid hormone withdrawal, identified only 19% of the cases of metastases. Ten studies comprising 1599 patients demonstrate that a TSH-stimulated Tg test using a Tg cutoff of 2 micro g/liter (either after thyroid hormone withdrawal or 72 h after rhTSH) is sufficiently sensitive to be used as the principal test in the follow-up management of low-risk patients with DTC and that the routine use of diagnostic whole body scanning in follow-up should be discouraged. On the basis of the foregoing, we propose a surveillance guideline using TSH-stimulated Tg levels for patients who have undergone total or near-total thyroidectomy and (131)I ablation for DTC and have no clinical evidence of residual tumor with a serum Tg below 1 micro g/liter during THST.

PURPOSE: Allogeneic hematopoietic cell transplantation (HCT) is curative but is associated with life-threatening complications. Most deaths occur within the first 2 years after transplantation. In this report, we examine long-term survival in 2-year survivors in the largest cohort ever studied. PATIENTS AND METHODS: Records of 10,632 patients worldwide reported to the Center for International Blood and Marrow Transplant Research who were alive and disease free 2 years after receiving a myeloablative allogeneic HCT before 2004 for acute myelogenous or lymphoblastic leukemia, myelodysplastic syndrome, lymphoma, or severe aplastic anemia were reviewed. RESULTS: Median follow-up was 9 years, and 3,788 patients had been observed for 10 or more years. The probability of being alive 10 years after HCT was 85%. The chief risk factors for late death included older age and chronic graft-versus-host disease (GVHD). For patients who underwent transplantation for malignancy, relapse was the most common cause of death. The greatest risk factor for late relapse was advanced disease at transplantation. Principal risk factors for nonrelapse deaths were older age and GVHD. When compared with age, sex, and nationality-matched general population, late deaths remained higher than expected for each disease, with the possible exception of lymphoma, although the relative risk generally receded over time. CONCLUSION: The prospect for long-term survival is excellent for 2-year survivors of allogeneic HCT. However, life expectancy remains lower than expected. Performance of HCT earlier in the course of disease, control of GVHD, enhancement of immune reconstitution, less toxic regimens, and prevention and early treatment of late complications are needed.

The throwing shoulder in pitchers frequently exhibits a paradox of glenohumeral joint motion, in which excessive external rotation is present at the expense of decreased internal rotation. The object of this study was to determine the role of humeral head retroversion in relation to increased glenohumeral external rotation. Glenohumeral joint range of motion and laxity along with humeral head and glenoid version of the dominant versus nondominant shoulders were studied in 25 professional pitchers and 25 nonthrowing subjects. Each subject underwent a computed tomography scan to determine bilateral humeral head and glenoid version. The throwing group demonstrated a significant increase in the dominant shoulder versus the nondominant shoulder in humeral head retroversion, glenoid retroversion, external rotation at 90 degrees, and external rotation in the scapular plane. Internal rotation was decreased in the dominant shoulder. Total range of motion, anterior glenohumeral laxity, and posterior glenohumeral laxity were found to be equal bilaterally. The nonthrowing group demonstrated no significant difference in humeral head retroversion, glenoid retroversion, external rotation at 90 degrees or external rotation in the scapular plane between shoulders, and no difference in internal rotation at 90 degrees, total motion, or laxity. A comparison of the dominant shoulders of the two groups indicated that both external rotation at 90 degrees and humeral head retroversion were significantly greater in the throwing group.

INTRODUCTION: Renal transplant recipients with elevated body mass index (BMI) have been shown to have inferior patient survival as compared to patients with lower BMI. However, previous studies could not establish a link between increased BMI and decreased death censored graft survival. Obesity in nontransplant patients has been associated with hypertension, hyperlipidemia, type II diabetes, proteinuria and glomerulopathy. Given this evidence it is possible that renal transplant recipients with an elevated BMI may have worse long term graft survival. To investigate this hypothesis we retrospectively analyzed 51,927 primary, adult renal transplants registered in the USRDS. METHODS: BMI at date of transplant was calculated for all patients using BMI=body weight (in kg)=.stature (height, in meters) squared. BMI values were further categorized into 11 categories: below 18, from 18 to 36 at 2 unit increments, and above 36 kg/m2. Primary study end points were graft and patient survival. Secondary study end points were death censored graft survival, chronic allograft failure, delayed graft function, and acute rejection (AR). Cox proportional hazard and logistic regression models investigated the link between categorized BMI and the study end points correcting for potential confounding variables. RESULTS: BMI showed a very strong association with outcomes after renal transplantation. The extremes of very high and very low BMI were associated with significantly worse patient and graft survival. The same was true for death censored graft survival and chronic allograft failure. Elevated BMI was also associated with an increased risk for delayed graft function while lower BMI was significantly protective. Acute rejection did not show any significant association with BMI. CONCLUSIONS: BMI has a very strong association with outcomes after renal transplantation independent of most of the known risk factors for patient and graft survival. The extremes of very high and very low BMI before renal transplantation are important risk factors for patient and graft survival. It is important to note that elevated BMI was significantly associated with worse graft survival independent of patient survival. Whether prospective weight adjustment before renal transplantation can favorably affect posttransplant risk needs to be assessed by further studies.

Parkinson's disease (PD) is a common neurodegenerative disorder caused by genetic and environmental factors that results in degeneration of the nigrostriatal dopaminergic pathway in the brain. We analyzed neural cells generated from induced pluripotent stem cells (iPSCs) derived from PD patients and presymptomatic individuals carrying mutations in the PINK1 (PTEN-induced putative kinase 1) and LRRK2 (leucine-rich repeat kinase 2) genes, and compared them to those of healthy control subjects. We measured several aspects of mitochondrial responses in the iPSC-derived neural cells including production of reactive oxygen species, mitochondrial respiration, proton leakage, and intraneuronal movement of mitochondria. Cellular vulnerability associated with mitochondrial dysfunction in iPSC-derived neural cells from familial PD patients and at-risk individuals could be rescued with coenzyme Q(10), rapamycin, or the LRRK2 kinase inhibitor GW5074. Analysis of mitochondrial responses in iPSC-derived neural cells from PD patients carrying different mutations provides insight into convergence of cellular disease mechanisms between different familial forms of PD and highlights the importance of oxidative stress and mitochondrial dysfunction in this neurodegenerative disease.

Transplant recipients have been reported to have an increased risk of solid cancers but most studies are small and have limited ability to evaluate the interaction of host, disease, and treatment-related factors. In the largest study to date to evaluate risk factors for solid cancers, we studied a multi-institutional cohort of 28 874 allogeneic transplant recipients with 189 solid malignancies. Overall, patients developed new solid cancers at twice the rate expected based on general population rates (observed-to-expected ratio 2.1; 95% confidence interval 1.8-2.5), with the risk increasing over time (P trend < .001); the risk reached 3-fold among patients followed for 15 years or more after transplantation. New findings showed that the risk of developing a non-squamous cell carcinoma (non-SCC) following conditioning radiation was highly dependent on age at exposure. Among patients irradiated at ages under 30 years, the relative risk of non-SCC was 9 times that of nonirradiated patients, while the comparable risk for older patients was 1.1 (P interaction < .01). Chronic graft-versus-host disease and male sex were the main determinants for risk of SCC. These data indicate that allogeneic transplant survivors, particularly those irradiated at young ages, face increased risks of solid cancers, supporting strategies to promote lifelong surveillance among these patients.

To assess the effect of venovenous extracorporeal membrane oxygenation (ECMO) compared to conventional management in patients with severe acute respiratory distress syndrome (ARDS). We conducted a systematic review and individual patient data meta-analysis of randomised controlled trials (RCTs) performed after Jan 1, 2000 comparing ECMO to conventional management in patients with severe ARDS. The primary outcome was 90-day mortality. Primary analysis was by intent-to-treat. We identified two RCTs (CESAR and EOLIA) and combined data from 429 patients. On day 90, 77 of the 214 (36%) ECMO-group and 103 of the 215 (48%) control group patients had died (relative risk (RR), 0.75, 95% confidence interval (CI) 0.6–0.94; P = 0.013; I2 = 0%). In the per-protocol and as-treated analyses the RRs were 0.75 (95% CI 0.6–0.94) and 0.86 (95% CI 0.68–1.09), respectively. Rescue ECMO was used for 36 (17%) of the 215 control patients (35 in EOLIA and 1 in CESAR). The RR of 90-day treatment failure, defined as death for the ECMO-group and death or crossover to ECMO for the control group was 0.65 (95% CI 0.52–0.8; I2 = 0%). Patients randomised to ECMO had more days alive out of the ICU and without respiratory, cardiovascular, renal and neurological failure. The only significant treatment-covariate interaction in subgroups was lower mortality with ECMO in patients with two or less organs failing at randomization. In this meta-analysis of individual patient data in severe ARDS, 90-day mortality was significantly lowered by ECMO compared with conventional management.

Birds have evolved alternate physiologic strategies to contend with dehydration, starvation, malnutrition, and reproduction. Basic anatomic and functional differences between birds and mammals impact clinical chemistry values and their evaluation. Interpretation of the results of standard biochemical analyses, including BUN, alanine aminotransferase, aspartate aminotransferase, creatine kinase, gamma glutamyltransferase, bilirubin, ammonia, alkaline phosphatase, cholesterol, bile acids, glucose, albumin, globulins, calcium, phosphorus, prealbumin (transthyretin), fibrinogen, iron, and ferritin, is reviewed and discussed in relation to these physiological differences. The use and interpretation of alternative analytes appropriate for avian species, such as uric acid, biliverdin, glutamate dehydrogenase, and galactose clearance, also are reviewed. Normal avian urine and appropriate use of urinalysis, an integral part of laboratory diagnosis in mammalian species that frequently is omitted from avian diagnostic protocols, is discussed.

Disclaimer: The Extracorporeal Life Support Organization (ELSO) Coronavirus Disease 2019 (COVID-19) Guidelines have been developed to assist existing extracorporeal membrane oxygenation (ECMO) centers to prepare and plan provision of ECMO during the ongoing pandemic. The recommendations have been put together by a team of interdisciplinary ECMO providers from around the world. Recommendations are based on available evidence, existing best practice guidelines, ethical principles, and expert opinion. This is a living document and will be regularly updated when new information becomes available. ELSO is not liable for the accuracy or completeness of the information in this document. These guidelines are not meant to replace sound clinical judgment or specialist consultation but rather to strengthen provision and clinical management of ECMO specifically, in the context of the COVID-19 pandemic.

OBJECTIVE: This study was undertaken to create an imaging-based classification for the lymph nodes of the neck that will be readily accepted by clinicians, result in consistent nodal classification, and be easily used by radiologists. SUBJECTS AND METHODS: Over an 18-month period, the necks of 50 patients with cervical lymphadenopathy were scanned with CT, MR imaging, or both. Imaging anatomic landmarks were sought that would create a nodal classification of these necks similar to the clinically based nodal classifications of the American Joint Committee on Cancer and the American Academy of Otolaryngology-Head and Neck Surgery. Each nodal level was defined to ensure consistent nodal classification and eliminate areas of confusion existing in the clinically based classifications. RESULTS: Necks were classified using the imaging-based classification and then compared with the classification of the same necks using the most common clinically based classifications. The imaging-based nodal classifications of the superficial nodes were the same as the clinically based classifications; however, the deep nodes of eight patients were found only by imaging. The anatomic precision and the level definition afforded by sectional imaging allowed the radiologists to use the imaging-based classification in a consistent manner. CONCLUSION: This imaging-based classification has been endorsed by clinicians who specialize in head and neck cancer. The boundaries of the nodal levels were easily discerned by radiologists and yielded consistent nodal classifications. The reproducibility of this classification will allow it to become an essential component of future classifications of metastatic neck disease.

Mobility disability is becoming prevalent in the obese older population (> or = 60 years of age). We included a total of 13 cross-sectional and 15 longitudinal studies based on actual physical assessments of mobility in the obese older population in this review. We systematically examined existing evidence of which adiposity estimate best predicted mobility disability. Cross-sectional studies (82-4000 participants) showed poorer lower extremity mobility with increasing obesity severity in both men and women. All longitudinal studies (1-22 years) except for one, reported relationships between adiposity and declining mobility. While different physical tests made interpretation challenging, a consistent finding was that walking, stair climbing and chair rise ability were compromised with obesity, especially if the body mass index (BMI) exceeded 35 kg m(-2). More studies found that obese women were at an increased risk for mobility impairment than men. Existing evidence suggests that BMI and waist circumference are emerging as the more consistent predictors of the onset or worsening of mobility disability. Limited interventional evidence shows that weight loss is related with increased mobility and lower extremity function. Additional longitudinal studies are warranted that address overall body composition fat and muscle mass or change on future disability.

High mobility group box 1 (HMGB), a ubiquitous DNA-binding protein, has been implicated as a proinflammatory cytokine and late mediator of lethal endotoxemia. HMGB1 is released by activated macrophages. It amplifies and extends the inflammatory response by inducing cytokine release and mediating acute lung injury, anorexia, and the inflammatory response to tissue necrosis. The kinetics of HMGB1 release provide a wide therapeutic window for endotoxemia because extracellular levels of HMGB1 begin to increase 12 to 24 h after exposure to inflammatory stimuli. Here, we demonstrate that a DNA-binding domain of HMGB1, the B box, recapitulates the cytokine activity of full length HMGB1 and efficiently activates macrophages to release tumor necrosis factor (TNF) and other proinflammatory cytokines. Truncation of the B box revealed that the TNF-stimulating activity localizes to 20 amino acids (HMGB1 amino acids 89 to 108). Passive immunization of mice with antibodies raised against B box conferred significant protection against lethal endotoxemia or sepsis, induced by cecal perforation. These results indicate that a proinflammatory domain of HMGB1 maps to the highly conserved DNA-binding B box, making this primary sequence a suitable target in the design of therapeutics.

Myeloid-derived suppressor cells (MDSCs) are a heterogenous population of immature myeloid cells whose numbers dramatically increase in chronic and acute inflammatory diseases, including cancer, autoimmune disease, trauma, burns and sepsis. Studied originally in cancer, these cells are potently immunosuppressive, particularly in their ability to suppress antigen-specific CD8(+) and CD4(+) T-cell activation through multiple mechanisms, including depletion of extracellular arginine, nitrosylation of regulatory proteins, and secretion of interleukin 10, prostaglandins and other immunosuppressive mediators. However, additional properties of these cells, including increased reactive oxygen species and inflammatory cytokine production, as well as their universal expansion in nearly all inflammatory conditions, suggest that MDSCs may be more of a normal component of the inflammatory response ("emergency myelopoiesis") than simply a pathological response to a growing tumor. Recent evocative data even suggest that the expansion of MDSCs in acute inflammatory processes, such as burns and sepsis, plays a beneficial role in the host by increasing immune surveillance and innate immune responses. Although clinical efforts are currently underway to suppress MDSC numbers and function in cancer to improve antineoplastic responses, such approaches may not be desirable or beneficial in other clinical conditions in which immune surveillance and antimicrobial activities are required.

Joubert syndrome is characterized by episodic hyperpnea and apnea, developmental delay, hypotonia, truncal ataxia, ophthalmologic abnormalities, and vermian dysgenesis. We studied 15 patients with the diagnosis of Joubert syndrome to (1) more fully define the syndrome's clinical features, and (2) correlate the clinical features with magnetic resonance imaging (MRI) findings. Eight of 15 patients had a history of episodic hyperpnea and apnea. All patients had developmental delay and hypotonia. Of the 13 patients receiving detailed neuro-ophthalmologic evaluations, three had optic nerve dysplasia, pendular nystagmus, and gaze-holding nystagmus. All 13 patients had a normal vestibulo-ocular reflex based on head thrust, but had absent to poor ability to cancel the vestibulo-ocular reflex horizontally and vertically. Twelve of 13 patients had impaired smooth pursuit. Twelve of 13 patients had defects in initiation of saccades and quick phases. Two of the most consistent radiologic features were absent or hypoplastic posterior cerebellar vermis, and deformed midbrain and pontomesencephalic junction, which based on ocular motor physiology correlate with the vestibulo-ocular reflex cancellation/ pursuit defect and saccade initiation defect, respectively. As a result of midbrain, vermian, and superior cerebellar peduncle abnormalities, axial neuroimaging showed a unique "molar tooth" appearance of these structures. These results indicate that Joubert syndrome results from maldevelopment of the midbrain and cerebellar vermis, producing a pathognomonic sign on MRI.

In a sample of 60 schizophrenic patients encompassing all grades of severity and chronicity memory impairment was found to be prevalent, often substantial, and disproportionate to the overall level of intellectual impairment. The deficits were not easily attributable to poor cooperation, attention or motivation; nor were they related to neuroleptic or anticholinergic medication. Memory impairment was significantly associated with severity and chronicity of illness and also with negative symptoms and formal thought disorder. There was evidence from the sample as a whole, and from a more detailed examination of five patients with relatively isolated deficits, that schizophrenic memory impairment conformed to the pattern seen in the classical amnesic syndrome. Additionally, there was preliminary evidence for a marked deficit in semantic memory.