University of Toledo Medical Center

Transforming growth factor-beta (TGF-beta) is a potent inhibitor of epithelial cell growth. Human colon cancer cell lines with high rates of microsatellite instability were found to harbor mutations in the type II TGF-beta receptor (RII) gene. Eight such examples, due to three different mutations, were identified. The mutations were clustered within small repeated sequences in the RII gene, were accompanied by the absence of cell surface RII receptors, and were usually associated with small amounts of RII transcript. RII mutation, by inducing the escape of cells from TGF-beta-mediated growth control, links DNA repair defects with a specific pathway of tumor progression.

An antioxidant fraction of Chinese green tea (green tea antioxidant; GTA), containing several catechins, has been previously shown to inhibit 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced tumor promotion in mouse skin. In the present study, GTA was shown to have antioxidative activity toward hydrogen peroxide (H2O2) and the superoxide radical (O2-). GTA also prevented oxygen radical and H2O2-induced cytotoxicity and inhibition of intercellular communication in cultured B6C3F1 mouse hepatocytes and human keratinocytes (NHEK cells). GTA (0.05-50 micrograms/ml) prevented the killing of hepatocytes (measured by lactate dehydrogenase release) by paraquat (1-10 mM) and glucose oxidase (0.8-40 micrograms/ml) in a concentration-dependent fashion. GTA (50 micrograms/ml) also prevented the inhibition of hepatocyte intercellular communication by paraquat (5 mM), glucose oxidase (0.8 micrograms/ml), and phenobarbital (500 micrograms/ml). In addition, GTA (50 micrograms/ml) prevented the inhibition of intercellular communication in human keratinocytes by TPA (100 ng/ml). Cytotoxicity and inhibition of intercellular communication, two possible mechanisms by which tumor promoters may produce their promoting effects were therefore prevented by GTA. The inhibition of these two effects of pro-oxidant compounds may suggest a mechanism by which GTA inhibits tumor promotion in vivo.

OBJECTIVE: Tonsillectomy is one of the most common surgical procedures in the United States, with more than 530,000 procedures performed annually in children younger than 15 years. Tonsillectomy is defined as a surgical procedure performed with or without adenoidectomy that completely removes the tonsil including its capsule by dissecting the peritonsillar space between the tonsil capsule and the muscular wall. Depending on the context in which it is used, it may indicate tonsillectomy with adenoidectomy, especially in relation to sleep-disordered breathing. This guideline provides evidence-based recommendations on the preoperative, intraoperative, and postoperative care and management of children 1 to 18 years old under consideration for tonsillectomy. In addition, this guideline is intended for all clinicians in any setting who interact with children 1 to 18 years of age who may be candidates for tonsillectomy. PURPOSE: The primary purpose of this guideline is to provide clinicians with evidence-based guidance in identifying children who are the best candidates for tonsillectomy. Secondary objectives are to optimize the perioperative management of children undergoing tonsillectomy, emphasize the need for evaluation and intervention in special populations, improve counseling and education of families of children who are considering tonsillectomy for their child, highlight the management options for patients with modifying factors, and reduce inappropriate or unnecessary variations in care. RESULTS: The panel made a strong recommendation that clinicians should administer a single, intraoperative dose of intravenous dexamethasone to children undergoing tonsillectomy. The panel made a strong recommendation against clinicians routinely administering or prescribing perioperative antibiotics to children undergoing tonsillectomy. The panel made recommendations for (1) watchful waiting for recurrent throat infection if there have been fewer than 7 episodes in the past year or fewer than 5 episodes per year in the past 2 years or fewer than 3 episodes per year in the past 3 years; (2) assessing the child with recurrent throat infection who does not meet criteria in statement 2 for modifying factors that may nonetheless favor tonsillectomy, which may include but are not limited to multiple antibiotic allergy/intolerance, periodic fever, aphthous stomatitis, pharyngitis and adenitis, or history of peritonsillar abscess; (3) asking caregivers of children with sleep-disordered breathing and tonsil hypertrophy about comorbid conditions that might improve after tonsillectomy, including growth retardation, poor school performance, enuresis, and behavioral problems; (4) counseling caregivers about tonsillectomy as a means to improve health in children with abnormal polysomnography who also have tonsil hypertrophy and sleep-disordered breathing; (5) counseling caregivers that sleep-disordered breathing may persist or recur after tonsillectomy and may require further management; (6) advocating for pain management after tonsillectomy and educating caregivers about the importance of managing and reassessing pain; and (7) clinicians who perform tonsillectomy should determine their rate of primary and secondary posttonsillectomy hemorrhage at least annually. The panel offered options to recommend tonsillectomy for recurrent throat infection with a frequency of at least 7 episodes in the past year or at least 5 episodes per year for 2 years or at least 3 episodes per year for 3 years with documentation in the medical record for each episode of sore throat and 1 or more of the following: temperature >38.3°C, cervical adenopathy, tonsillar exudate, or positive test for group A β-hemolytic streptococcus.

BACKGROUND: Despite significant differences in ligand binding between the two known isoforms of the human membrane folate receptor (FR), designated herein as FR-beta (placenta) and FR-alpha (placenta, KB cells), little is known about their tissue specificities, and there is no report on the relative expression of FR-beta in any tissue other than in placenta. METHODS: The mRNA for each FR isoform in a wide variety of normal fetal and adult tissue explants, primary normal cell cultures, malignant tumor explants, and established tumor cell lines was estimated by a polymerase chain reaction assay. Total receptor levels were estimated by a [3H] folic acid binding assay. RESULTS: Both the FR isoforms were expressed in fetal as well as adult tissues. Normal tissues generally expressed low to moderate amounts of FR-beta. FR-alpha alone was expressed in normal epithelial cells and was frequently strikingly elevated in a variety of carcinomas, with the exception of squamous cell carcinomas of the head and neck. In contrast, a variety of malignant tissues of nonepithelial origin generally expressed elevated levels of FR-beta alone. Established tumor cell lines expressed FR-alpha virtually alone and did not reflect FR expression patterns in vivo. KB cells and JEG-3 cells grown at low folate concentrations further up-regulated FR-alpha but not FR-beta. CONCLUSIONS: Although FR-beta is the more common isoform, FR-alpha and FR-beta are differentially regulated in normal tissues, carcinomas, nonepithelial malignancies, and immortalized cells or in response to changes in extracellular folate concentrations. The tissue specificity of FR isoforms and their elevation in malignant tissues may be a significant factor in FR-mediated folate uptake, in tissue responsiveness to promising novel antifolates, and in FR-related immunodiagnosis/immunotherapy.

Curcuminoids, a group of phenolic compounds isolated from the roots of Curcuma longa (Zingiberaceae), exhibit a variety of beneficial effects on health and on events that help in preventing certain diseases. A vast majority of these studies were carried out with curcumin (diferuloyl methane), which is a major curcuminoid. The most detailed studies using curcumin include anti-inflammatory, antioxidant, anticarcinogenic, antiviral, and antiinfectious activities. In addition, the wound healing and detoxifying properties of curcumin have also received considerable attention. As a result of extensive research on the therapeutic properties of curcumin, some understanding on the cellular, molecular, and biochemical mechanism of action of curcumin is emerging. These findings are summarized in this review.

OBJECTIVE: To provide a multidimensional analysis of the learning curve in major laparoscopic colonic and rectal surgery and compare outcomes between right-sided versus left-sided resections. SUMMARY BACKGROUND DATA: The laparoscopic learning curve is known to vary between surgeons, may be influenced by the patient selection and operative complexity, and requires appropriate case-mix adjustment. METHODS: This is a descriptive single-center study using routinely collected clinical data from 900 patients undergoing laparoscopic surgery between November 1991 and April 2003. Outcome measures included operation time, conversion rate (CR), and readmission and postoperative complication rates. Multifactorial logistic regression analysis was used to identify patient-, surgeon-, and procedure-related factors associated with conversion of laparoscopic to open surgery. A risk-adjusted Cumulative Sum (CUSUM) model was used for evaluating the learning curve for right and left-sided resections. RESULTS: The conversion rate for right-sided colonic resections was 8.1% (n = 457) compared with 15.3% for left-sided colorectal resections (n = 443). Independent predictors of conversion of laparoscopic to open surgery were the body mass index (BMI) (odds ratio [OR] = 1.07 per unit increase), ASA grade (OR = 1.63 per unit increase), type of resection (left colorectal versus right colonic procedures, OR = 1.5), presence of intra-abdominal abscess (OR = 5.0) or enteric fistula (OR = 4.6), and surgeon's experience (OR 0.9 per 10 additional cases performed). Having adjusted for case-mix, the CUSUM analysis demonstrated a learning curve of 55 cases for right-sided colonic resections versus 62 cases for left-sided resections. Median operative time declined with operative experience (P<0.001). Readmission rates and postoperative complications remained unchanged throughout the series and were not dependent on operative experience. CONCLUSIONS: Conversion rates for laparoscopic colectomy are dependent on a multitude of factors that require appropriate adjustment including the learning curve (operative experience) for individual surgeons. The laparoscopic model described can be used as the basis for performance monitoring between or within institutions.

The metabolic response to injury and illness as manifested by increases in energy expenditure and nitrogen losses makes it difficult for the clinician to evaluate calorie and protein needs. A method for determining daily calorie needs in hospitalized patients is presented. Average increases in resting metabolic expenditure for a group of patients following elective operation, skeletal trauma, skeletal trauma with head injury, blunt trauma, sepsis and burns were determined by indirect calorimetry and protein need by urinary nitrogen losses over extended time periods. Total daily calorie needs were then calculated, using the Harris-Benedict equation and adjusting this value upward using a previously measured activity and injury factor to arrive at the daily needs. Protein requirements may be determined on periodic 24 hour urine samples analyzed for the urinary urea nitrogen and adjusting this to a total nitrogen or protein equivalent. This approach to estimating the calorie nitrogen needs of the hospitalized patient under various degrees of stress more closely approximates the patient's variable needs at the height of the catabolic response and during convalescence.

In Brief Objective: The HepatAssist liver support system is an extracorporeal porcine hepatocyte-based bioartificial liver (BAL). The safety and efficacy of the BAL were evaluated in a prospective, randomized, controlled, multicenter trial in patients with severe acute liver failure. Summary Background Data: In experimental animals with acute liver failure, we demonstrated beneficial effects of the BAL. Similarly, Phase I trials of the BAL in acute liver failure patients yielded promising results. Methods: A total of 171 patients (86 control and 85 BAL) were enrolled. Patients with fulminant/subfulminant hepatic failure and primary nonfunction following liver transplantation were included. Data were analyzed with and without accounting for the following confounding factors: liver transplantation, time to transplant, disease etiology, disease severity, and treatment site. Results: For the entire patient population, survival at 30 days was 71% for BAL versus 62% for control (P = 0.26). After exclusion of primary nonfunction patients, survival was 73% for BAL versus 59% for control (n = 147; P = 0.12). When survival was analyzed accounting for confounding factors, in the entire patient population, there was no difference between the 2 groups (risk ratio = 0.67; P = 0.13). However, survival in fulminant/subfulminant hepatic failure patients was significantly higher in the BAL compared with the control group (risk ratio = 0.56; P = 0.048). Conclusions: This is the first prospective, randomized, controlled trial of an extracorporeal liver support system, demonstrating safety and improved survival in patients with fulminant/subfulminant hepatic failure. A prospective randomized trial of the HepatAssist bioartificial liver support system was carried out in patients with fulminant/subfulminant hepatic failure and primary nonfunction following liver transplantation. Treated fulminant/subfulminant hepatic failure patients had improved survival compared with controls when the effect of confounding factors was accounted for in the data analysis.

In humans, the strong statistical association between fitness and survival suggests a link between impaired oxygen metabolism and disease. We hypothesized that artificial selection of rats based on low and high intrinsic exercise capacity would yield models that also contrast for disease risk. After 11 generations, rats with low aerobic capacity scored high on cardiovascular risk factors that constitute the metabolic syndrome. The decrease in aerobic capacity was associated with decreases in the amounts of transcription factors required for mitochondrial biogenesis and in the amounts of oxidative enzymes in skeletal muscle. Impairment of mitochondrial function may link reduced fitness to cardiovascular and metabolic disease.

Coronaviruses are a family of enveloped, plus-stranded RNA viruses with helical nucleocapsids and extraordinarily large genomes.The hallmark of coronavirus transcription is

We read with interest the study by Luo et al1 that evaluates the efficacy of tocilizumab (antibody against interleukin-6 [IL-6]) in patients with coronavirus disease 2019 (COVID-19). The authors shared an encouraging experience of utilizing this medication, particularly in patients at risk of developing chemokine storm secondary to COVID-19.1 IL-6, a chemokine, is an important biomarker of inflammation and has been shown in studies as an important predictor of severe COVID-19.2, 3 IL-6 is responsible for elevation of acute phase reactants, such as C-reactive protein, serum amyloid A, fibrinogen, and hepcidin, and inhibition of albumin synthesis. The dysregulated production of IL-6 has been attributed to autoimmunity and chronic inflammation.4 We performed a systematic review and meta-analysis to compare IL-6 in severe and nonsevere patients. An extensive literature search of PubMed/Medline, Embase, Cochrane, and Web of Sciences was conducted on 20 April 2020 to include all published studies. Two independent reviewers (MA and RF) screened and finalized articles, and performed data extraction. Any discrepancy during these steps was resolved through a mutual discussion. Severe COVID-19 was defined as either respiratory distress (rate ≥ 30/min, oxygen saturation ≤ 93% at rest, and/or PaO2/FiO2 ≤ 300 mm Hg),5 ICU admission, and/or death. Continuous variables (using mean serum levels and standard deviation) were compared and mean difference (MD) was estimated with 95% confidence interval (CI), and P value less than .05 was considered as statistically significant. DerSimonian Laird method/random effects meta-analysis using Open Meta Analyst (CEBM, University of Oxford, Oxford, UK) was performed. Meta-regression was attempted if studies did not give a direct comparison between groups of interest. Coefficient (Q), 95% CI, P value (<.05 was considered statistically significant), and scatter plot were generated for regression analysis. A total of nine studies with laboratory-confirmed 1426 patients (mean age: 53.0 ± 6.4 years, females: 46.6%) were included. All studies originated from China, and study duration ranged from 1 January to 28 February 2020. A comparison of mean serum IL-6 for severe COVID-19 and nonsevere COVID-19 was performed in seven studies. The mean serum IL-6 was 56.8 (41.4-72.3 pg/mL) and 17.3 pg/mL (13.5-21.1 pg/mL) for severe and nonsevere COVID-19 group, respectively. This was statistically significant (MD: 38.6 pg/mL, 95% CI: 24.3-52.9 pg/mL; P < .001, I2 = 98.5%) (Figure 1A). The results of leave-one-out meta-analysis, with point estimate (MD) ranging between 31.9 and 43.9 pg/mL, were consistent. A subgroup analysis of studies using a strict definition of respiratory distress for severe COVID-19 also showed consistent results (MD: 26.5 pg/mL, 95% CI: 17.2-35.8 pg/mL; P < .001, I2 = 95.7%) (Figure 1B). A total of five studies reported data on overall mortality and serum IL-6 in COVID-19 patients. The pooled prevalence of mortality across these studies was 2.9% (95% CI: 1.8%-4.0%). Meta-regression demonstrated that increasing mean IL-6 on admission was associated with an increased likelihood of mortality (Q: 0.01, 95% CI: 0.01-0.03; P = .03) (Figure 2). Several limitations exist within our meta-analysis; the most important is the observational nature of studies and significant heterogeneity in study results. This can be explained on the basis of different patient population, difference in underlying comorbidities, variation in follow-up, and the presence of coinfection. Despite the limitations, our results remained consistent across both sensitivity and subgroup analysis, demonstrating the importance of obtaining serum IL-6. Although the studies did not stratify data based on mortality, we were able to demonstrate the association of elevated serum IL-6 and increased mortality rates using meta-regression. Another important limitation to note is the variability in laboratory assay when assessing serum IL-6, as local laboratories have different normal ranges based on local data.6 This confounding variable can somewhat undermine our results and our data should be interpreted as such, keeping in mind this important limitation. Based on our analysis, we suggest a cut-off of more than 55 pg/mL for identifying patients at high risk of severe COVID-19. Only one study directly compared mean serum IL-6 level for survivors and nonsurvivors.5 Based on this, a cut-off of more than 80 pg/mL can be used for identifying patients at high risk of mortality. The elevation of IL-6 has been previously demonstrated in inflammatory state for multiple conditions.3 The pathophysiological hallmark of COVID-19 is the severe inflammation and chemokine storm, which explains the elevation of IL-6.7, 8 The importance of identifying this elevated biomarker also lies in the potential use of antibody against IL-6 such as tociluzumab, which is currently undergoing a clinical trial.9 Tociluzumab has previously shown efficacy against autoimmune and inflammatory conditions such as rheumatoid arthritis, systemic juvenile idiopathic arthritis,Castleman's disease, neuromyelitis optica, giant cell arteritis, and cytokine release syndrome.10, 11 Based on our results, IL-6 is an important marker of inflammation and can guide the clinicians in recognizing patients with severe COVID-19 early in the disease course. Furthermore, researchers should develop a scoring system including IL-6 to assist clinicians in early recognition of patients at risk for developing severe disease.

OBJECTIVES: The systemic inflammatory response syndrome (SIRS) is the massive inflammatory reaction resulting from systemic mediator release that may lead to multiple organ dysfunction. The objective of this review article is to analyze the roles of cytokines, cytokine production, and the relationship of cytokine production to the development of SIRS. DATA SOURCES: Previous research and clinical studies related to cytokines and their relationship to SIRS. STUDY SELECTION: From the studies reviewed, three critical questions are addressed. First, what is the definition of increased cytokine concentrations? Second, what other systemic illnesses besides sepsis can alter cytokine concentrations? Third, what are the right cytokines to measure? DATA SYNTHESIS: This article postulates a three-stage development of SIRS, in which stage 1 is a local production of cytokines in response to an injury or infection. Stage 2 is the protective release of a small amount of cytokines into the body's circulation. Stage 3 is the massive systemic reaction where cytokines turn destructive by compromising the integrity of the capillary walls and flooding end organs. CONCLUSIONS: While cytokines are generally viewed as a destructive development in the patient that generally leads to multiple organ dysfunction, cytokines also protect the body when localized. It will be necessary to study the positive effects of cytokines while also studying their role in causing SIRS. It will also be important to investigate the relationship between cytokines and their blockers in SIRS.

Na(+)/K(+)-ATPase as an energy transducing ion pump has been studied extensively since its discovery in 1957. Although early findings suggested a role for Na(+)/K(+)-ATPase in regulation of cell growth and expression of various genes, only in recent years the mechanisms through which this plasma membrane enzyme communicates with the nucleus have been studied. This research, carried out mostly on cardiac myocytes, shows that in addition to pumping ions, Na(+)/K+-ATPase interacts with neighboring membrane proteins and organized cytosolic cascades of signaling proteins to send messages to the intracellular organelles. The signaling pathways that are rapidly elicited by the interaction of ouabain with Na(+)/K(+)-ATPase, and are independent of changes in intracellular Na(+) and K(+) concentrations, include activation of Src kinase, transactivation of the epidermal growth factor receptor by Src, activation of Ras and p42/44 mitogen-activated protein kinases, and increased generation of reactive oxygen species by mitochondria. In cardiac myocytes, the resulting downstream events include the induction of some early response proto-oncogenes, activation of the transcription factors, activator protein-1 and nuclear factor kappa-B, regulation of a number of cardiac growth-related genes, and stimulation of protein synthesis and myocyte hypertrophy. For these downstream events, the induced reactive oxygen species and rise in intracellular Ca(2+) are essential second messengers. In cells other than cardiac myocytes, the proximal pathways linked to Na(+)/K(+)-ATPase through protein-protein interactions are similar to those reported in myocytes, but the downstream events and consequences may be significantly different. The likely extracellular physiological stimuli for the signal transducing function of Na+/K+-ATPase are the endogenous ouabain-like hormones, and changes in extracellular K+ concentration.

BACKGROUND: Despite current therapies, diffuse cutaneous systemic sclerosis (scleroderma) often has a devastating outcome. We compared myeloablative CD34+ selected autologous hematopoietic stem-cell transplantation with immunosuppression by means of 12 monthly infusions of cyclophosphamide in patients with scleroderma. METHODS: We randomly assigned adults (18 to 69 years of age) with severe scleroderma to undergo myeloablative autologous stem-cell transplantation (36 participants) or to receive cyclophosphamide (39 participants). The primary end point was a global rank composite score comparing participants with each other on the basis of a hierarchy of disease features assessed at 54 months: death, event-free survival (survival without respiratory, renal, or cardiac failure), forced vital capacity, the score on the Disability Index of the Health Assessment Questionnaire, and the modified Rodnan skin score. RESULTS: In the intention-to-treat population, global rank composite scores at 54 months showed the superiority of transplantation (67% of 1404 pairwise comparisons favored transplantation and 33% favored cyclophosphamide, P=0.01). In the per-protocol population (participants who received a transplant or completed ≥9 doses of cyclophosphamide), the rate of event-free survival at 54 months was 79% in the transplantation group and 50% in the cyclophosphamide group (P=0.02). At 72 months, Kaplan-Meier estimates of event-free survival (74% vs. 47%) and overall survival (86% vs. 51%) also favored transplantation (P=0.03 and 0.02, respectively). A total of 9% of the participants in the transplantation group had initiated disease-modifying antirheumatic drugs (DMARDs) by 54 months, as compared with 44% of those in the cyclophosphamide group (P=0.001). Treatment-related mortality in the transplantation group was 3% at 54 months and 6% at 72 months, as compared with 0% in the cyclophosphamide group. CONCLUSIONS: Myeloablative autologous hematopoietic stem-cell transplantation achieved long-term benefits in patients with scleroderma, including improved event-free and overall survival, at a cost of increased expected toxicity. Rates of treatment-related death and post-transplantation use of DMARDs were lower than those in previous reports of nonmyeloablative transplantation. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health; ClinicalTrials.gov number, NCT00114530 .).

Abstract The fine structure and micropinocytotic capabilities of epithelial cells closely associated with lymphoid follicles in the chicken bursa of Fabricius, rabbit appendix, and mouse Peyer's patch were compared. Epithelial cells capable of transporting ferritin and India ink tracers from the lumen were demonstrated in all three locations. Epithelial cells not associated with lymphoid follicles in the bursa and appendix did not express pinocytotic activity. Lymphoid cells were identified in bursal epithelium of chick embryos as early as the twelfth day of incubation. These lymphoid cells were smaller than typical bursal lymphocytes, had dense cytoplasm, numerous cytoplasmic projections, and prominent nucleoli. The small lymphoid cells were first demonstrable at a time in incubation during which lymphoid stem cells have been shown to migrate into the bursal epithelium. Lymphoid cells were seen earlier than the specialized follicle‐associated epithelium. It is concluded that specialized pinocytotic follicle‐associated epithelium does not induce initial migration of stem cells into areas along the intestinal tract, but that this transepithelial pinocytotic flow of intestinal contents after birth may provide a significant stimulus for attraction, proliferation and egression of lymphocytes.

BACKGROUND: Numerous studies have compared the outcomes of two competing interventions for multivessel coronary artery disease: coronary-artery bypass grafting (CABG) and coronary stenting. However, little information has become available since the introduction of drug-eluting stents. METHODS: We identified patients with multivessel disease who received drug-eluting stents or underwent CABG in New York State between October 1, 2003, and December 31, 2004, and we compared adverse outcomes (death, death or myocardial infarction, or repeat revascularization) through December 31, 2005, after adjustment for differences in baseline risk factors among the patients. RESULTS: In comparison with treatment with a drug-eluting stent, CABG was associated with lower 18-month rates of death and of death or myocardial infarction both for patients with three-vessel disease and for patients with two-vessel disease. Among patients with three-vessel disease who underwent CABG, as compared with those who received a stent, the adjusted hazard ratio for death was 0.80 (95% confidence interval [CI], 0.65 to 0.97) and the adjusted survival rate was 94.0% versus 92.7% (P=0.03); the adjusted hazard ratio for death or myocardial infarction was 0.75 (95% CI, 0.63 to 0.89) and the adjusted rate of survival free from myocardial infarction was 92.1% versus 89.7% (P<0.001). Among patients with two-vessel disease who underwent CABG, as compared with those who received a stent, the adjusted hazard ratio for death was 0.71 (95% CI, 0.57 to 0.89) and the adjusted survival rate was 96.0% versus 94.6% (P=0.003); the adjusted hazard ratio for death or myocardial infarction was 0.71 (95% CI, 0.59 to 0.87) and the adjusted rate of survival free from myocardial infarction was 94.5% versus 92.5% (P<0.001). Patients undergoing CABG also had lower rates of repeat revascularization. CONCLUSIONS: For patients with multivessel disease, CABG continues to be associated with lower mortality rates than does treatment with drug-eluting stents and is also associated with lower rates of death or myocardial infarction and repeat revascularization.

BACKGROUND: The reverse-transcriptase inhibitor lamivudine has in vitro synergy with zidovudine against the human immunodeficiency virus (HIV). We studied the activity and safety of lamivudine plus zidovudine as compared with either drug alone as treatment for patients with HIV infection, most of whom had not previously received zidovudine. METHODS: Three hundred sixty-six patients with 200 to 500 CD4+ cells per cubic millimeter who had received zidovudine for four weeks or less were randomly assigned to treatment with one of four regimens: 300 mg of lamivudine every 12 hours; 200 mg of zidovudine every 8 hours; 150 mg of lamivudine every 12 hours plus zidovudine; or 300 mg of lamivudine every 12 hours plus zidovudine. The study was double-blind and lasted 24 weeks, with an extension phase for another 28 weeks. RESULTS: Over the 24-week period, the low-dose and high-dose regimens combining lamivudine and zidovudine were associated with greater increases in the CD4+ cell count (P = 0.002 and P = 0.015, respectively) and the percentage of CD4+ cells (P < 0.001 for both) and with greater decreases in plasma levels of HIV-1 RNA (P < 0.001 for both) than was treatment with zidovudine alone. Combination therapy was also more effective than lamivudine alone in lowering plasma HIV-1 RNA levels and increasing the percentage of CD4+ cells (P < 0.001 for all comparisons), and these advantages persisted through 52 weeks. Adverse events were no more frequent with combination therapy than with zidovudine alone. CONCLUSIONS: In HIV-infected patients with little or no prior antiretroviral therapy, treatment with a combination of lamivudine and zidovudine is well tolerated over a one-year period and produces more improvement in immunologic and virologic measures than does treatment with either agent alone.

OBJECTIVE: Bell's palsy, named after the Scottish anatomist, Sir Charles Bell, is the most common acute mono-neuropathy, or disorder affecting a single nerve, and is the most common diagnosis associated with facial nerve weakness/paralysis. Bell's palsy is a rapid unilateral facial nerve paresis (weakness) or paralysis (complete loss of movement) of unknown cause. The condition leads to the partial or complete inability to voluntarily move facial muscles on the affected side of the face. Although typically self-limited, the facial paresis/paralysis that occurs in Bell's palsy may cause significant temporary oral incompetence and an inability to close the eyelid, leading to potential eye injury. Additional long-term poor outcomes do occur and can be devastating to the patient. Treatments are generally designed to improve facial function and facilitate recovery. There are myriad treatment options for Bell's palsy, and some controversy exists regarding the effectiveness of several of these options, and there are consequent variations in care. In addition, numerous diagnostic tests available are used in the evaluation of patients with Bell's palsy. Many of these tests are of questionable benefit in Bell's palsy. Furthermore, while patients with Bell's palsy enter the health care system with facial paresis/paralysis as a primary complaint, not all patients with facial paresis/paralysis have Bell's palsy. It is a concern that patients with alternative underlying etiologies may be misdiagnosed or have unnecessary delay in diagnosis. All of these quality concerns provide an important opportunity for improvement in the diagnosis and management of patients with Bell's palsy. PURPOSE: The primary purpose of this guideline is to improve the accuracy of diagnosis for Bell's palsy, to improve the quality of care and outcomes for patients with Bell's palsy, and to decrease harmful variations in the evaluation and management of Bell's palsy. This guideline addresses these needs by encouraging accurate and efficient diagnosis and treatment and, when applicable, facilitating patient follow-up to address the management of long-term sequelae or evaluation of new or worsening symptoms not indicative of Bell's palsy. The guideline is intended for all clinicians in any setting who are likely to diagnose and manage patients with Bell's palsy. The target population is inclusive of both adults and children presenting with Bell's palsy. ACTION STATEMENTS: The development group made a strong recommendation that (a) clinicians should assess the patient using history and physical examination to exclude identifiable causes of facial paresis or paralysis in patients presenting with acute-onset unilateral facial paresis or paralysis, (b) clinicians should prescribe oral steroids within 72 hours of symptom onset for Bell's palsy patients 16 years and older, (c) clinicians should not prescribe oral antiviral therapy alone for patients with new-onset Bell's palsy, and (d) clinicians should implement eye protection for Bell's palsy patients with impaired eye closure. The panel made recommendations that (a) clinicians should not obtain routine laboratory testing in patients with new-onset Bell's palsy, (b) clinicians should not routinely perform diagnostic imaging for patients with new-onset Bell's palsy, (c) clinicians should not perform electrodiagnostic testing in Bell's palsy patients with incomplete facial paralysis, and (d) clinicians should reassess or refer to a facial nerve specialist those Bell's palsy patients with (1) new or worsening neurologic findings at any point, (2) ocular symptoms developing at any point, or (3) incomplete facial recovery 3 months after initial symptom onset. The development group provided the following options: (a) clinicians may offer oral antiviral therapy in addition to oral steroids within 72 hours of symptom onset for patients with Bell's palsy, and (b) clinicians may offer electrodiagnostic testing to Bell's palsy patients with complete facial paralysis. The development group offered the following no recommendations: (a) no recommendation can be made regarding surgical decompression for patients with Bell's palsy, (b) no recommendation can be made regarding the effect of acupuncture in patients with Bell's palsy, and (c) no recommendation can be made regarding the effect of physical therapy in patients with Bell's palsy.

Urease catalyzes the hydrolysis of urea to ammonia and carbamate and has been found to be an important pathogenic factor for certain bacteria. Cryptococcus neoformans is a significant human pathogenic fungus that produces large amounts of urease; thus we wanted to investigate the importance of urease in the pathogenesis of cryptococcosis. We cloned and sequenced the genomic locus containing the single-copy C. neoformans urease gene (URE1) and used this to disrupt the native URE1 in the serotype A strain H99. The ure1 mutant strains were found to have in vitro growth characteristics, phenoloxidase activity, and capsule size similar to those of the wild type. Comparison of a ure1 mutant with H99 after intracisternal inoculation into corticosteroid-treated rabbits revealed no significant differences in colony counts recovered from the cerebrospinal fluid. However, when these two strains were compared in both the murine intravenous and inhalational infection models, there were significant differences in survival. Mice infected with a ure1 strain lived longer than mice infected with H99 in both models. The ure1 strain was restored to urease positivity by complementation with URE1, and two resulting transformants were significantly more pathogenic than the ure1 strain. Our results suggest that urease activity is involved in the pathogenesis of cryptococcosis but that the importance may be species and/or infection site specific.

The concentration of oxytocin receptors increased in the myometrium of pregnant women and reached maximum levels in early labor. Concentrations of oxytocin receptors were also high in the decidua and reached a maximum at parturition. In vitro, prostaglandin production by the decidua, but not by the myometrium, was increased by the addition of oxytocin. Oxytocin may therefore stimulate uterine contractions by acting both directly on the myometrium and indirectly on decidual prostaglandin production. Oxytocin receptors are probably crucial for the onset of human labor, and the stimulus for the increase in uterine prostaglandins may be oxytocin originating from the fetus.