MetroHealth Medical Center

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis in the absence of a history of significant alcohol use or other known liver disease. Nonalcoholic steatohepatitis (NASH) is the progressive form of NAFLD. The Pathology Committee of the NASH Clinical Research Network designed and validated a histological feature scoring system that addresses the full spectrum of lesions of NAFLD and proposed a NAFLD activity score (NAS) for use in clinical trials. The scoring system comprised 14 histological features, 4 of which were evaluated semi-quantitatively: steatosis (0-3), lobular inflammation (0-2), hepatocellular ballooning (0-2), and fibrosis (0-4). Another nine features were recorded as present or absent. An anonymized study set of 50 cases (32 from adult hepatology services, 18 from pediatric hepatology services) was assembled, coded, and circulated. For the validation study, agreement on scoring and a diagnostic categorization ("NASH," "borderline," or "not NASH") were evaluated by using weighted kappa statistics. Inter-rater agreement on adult cases was: 0.84 for fibrosis, 0.79 for steatosis, 0.56 for injury, and 0.45 for lobular inflammation. Agreement on diagnostic category was 0.61. Using multiple logistic regression, five features were independently associated with the diagnosis of NASH in adult biopsies: steatosis (P = .009), hepatocellular ballooning (P = .0001), lobular inflammation (P = .0001), fibrosis (P = .0001), and the absence of lipogranulomas (P = .001). The proposed NAS is the unweighted sum of steatosis, lobular inflammation, and hepatocellular ballooning scores. In conclusion, we present a strong scoring system and NAS for NAFLD and NASH with reasonable inter-rater reproducibility that should be useful for studies of both adults and children with any degree of NAFLD. NAS of > or =5 correlated with a diagnosis of NASH, and biopsies with scores of less than 3 were diagnosed as "not NASH."

These pediatric hypertension guidelines are an update to the 2004 "Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents." Significant changes in these guidelines include (1) the replacement of the term "prehypertension" with the term "elevated blood pressure," (2) new normative pediatric blood pressure (BP) tables based on normal-weight children, (3) a simplified screening table for identifying BPs needing further evaluation, (4) a simplified BP classification in adolescents ≥13 years of age that aligns with the forthcoming American Heart Association and American College of Cardiology adult BP guidelines, (5) a more limited recommendation to perform screening BP measurements only at preventive care visits, (6) streamlined recommendations on the initial evaluation and management of abnormal BPs, (7) an expanded role for ambulatory BP monitoring in the diagnosis and management of pediatric hypertension, and (8) revised recommendations on when to perform echocardiography in the evaluation of newly diagnosed hypertensive pediatric patients (generally only before medication initiation), along with a revised definition of left ventricular hypertrophy. These guidelines include 30 Key Action Statements and 27 additional recommendations derived from a comprehensive review of almost 15 000 published articles between January 2004 and July 2016. Each Key Action Statement includes level of evidence, benefit-harm relationship, and strength of recommendation. This clinical practice guideline, endorsed by the American Heart Association, is intended to foster a patient- and family-centered approach to care, reduce unnecessary and costly medical interventions, improve patient diagnoses and outcomes, support implementation, and provide direction for future research.

BACKGROUND: Carotid-artery stenting and carotid endarterectomy are both options for treating carotid-artery stenosis, an important cause of stroke. METHODS: We randomly assigned patients with symptomatic or asymptomatic carotid stenosis to undergo carotid-artery stenting or carotid endarterectomy. The primary composite end point was stroke, myocardial infarction, or death from any cause during the periprocedural period or any ipsilateral stroke within 4 years after randomization. RESULTS: For 2502 patients over a median follow-up period of 2.5 years, there was no significant difference in the estimated 4-year rates of the primary end point between the stenting group and the endarterectomy group (7.2% and 6.8%, respectively; hazard ratio with stenting, 1.11; 95% confidence interval, 0.81 to 1.51; P=0.51). There was no differential treatment effect with regard to the primary end point according to symptomatic status (P=0.84) or sex (P=0.34). The 4-year rate of stroke or death was 6.4% with stenting and 4.7% with endarterectomy (hazard ratio, 1.50; P=0.03); the rates among symptomatic patients were 8.0% and 6.4% (hazard ratio, 1.37; P=0.14), and the rates among asymptomatic patients were 4.5% and 2.7% (hazard ratio, 1.86; P=0.07), respectively. Periprocedural rates of individual components of the end points differed between the stenting group and the endarterectomy group: for death (0.7% vs. 0.3%, P=0.18), for stroke (4.1% vs. 2.3%, P=0.01), and for myocardial infarction (1.1% vs. 2.3%, P=0.03). After this period, the incidences of ipsilateral stroke with stenting and with endarterectomy were similarly low (2.0% and 2.4%, respectively; P=0.85). CONCLUSIONS: Among patients with symptomatic or asymptomatic carotid stenosis, the risk of the composite primary outcome of stroke, myocardial infarction, or death did not differ significantly in the group undergoing carotid-artery stenting and the group undergoing carotid endarterectomy. During the periprocedural period, there was a higher risk of stroke with stenting and a higher risk of myocardial infarction with endarterectomy. (ClinicalTrials.gov number, NCT00004732.)

BACKGROUND: Understanding the epidemiology and clinical course of multisystem inflammatory syndrome in children (MIS-C) and its temporal association with coronavirus disease 2019 (Covid-19) is important, given the clinical and public health implications of the syndrome. METHODS: We conducted targeted surveillance for MIS-C from March 15 to May 20, 2020, in pediatric health centers across the United States. The case definition included six criteria: serious illness leading to hospitalization, an age of less than 21 years, fever that lasted for at least 24 hours, laboratory evidence of inflammation, multisystem organ involvement, and evidence of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) based on reverse-transcriptase polymerase chain reaction (RT-PCR), antibody testing, or exposure to persons with Covid-19 in the past month. Clinicians abstracted the data onto standardized forms. RESULTS: We report on 186 patients with MIS-C in 26 states. The median age was 8.3 years, 115 patients (62%) were male, 135 (73%) had previously been healthy, 131 (70%) were positive for SARS-CoV-2 by RT-PCR or antibody testing, and 164 (88%) were hospitalized after April 16, 2020. Organ-system involvement included the gastrointestinal system in 171 patients (92%), cardiovascular in 149 (80%), hematologic in 142 (76%), mucocutaneous in 137 (74%), and respiratory in 131 (70%). The median duration of hospitalization was 7 days (interquartile range, 4 to 10); 148 patients (80%) received intensive care, 37 (20%) received mechanical ventilation, 90 (48%) received vasoactive support, and 4 (2%) died. Coronary-artery aneurysms (z scores ≥2.5) were documented in 15 patients (8%), and Kawasaki's disease-like features were documented in 74 (40%). Most patients (171 [92%]) had elevations in at least four biomarkers indicating inflammation. The use of immunomodulating therapies was common: intravenous immune globulin was used in 144 (77%), glucocorticoids in 91 (49%), and interleukin-6 or 1RA inhibitors in 38 (20%). CONCLUSIONS: Multisystem inflammatory syndrome in children associated with SARS-CoV-2 led to serious and life-threatening illness in previously healthy children and adolescents. (Funded by the Centers for Disease Control and Prevention.).

Insulin sensitivity (euglycemic clamp, insulin infusion rate: 40 mU. m(-2). min(-1)) was studied in 30 subjects with biopsy-proven nonalcoholic fatty liver disease (NAFLD), normal glucose tolerance, and a BMI <30 kg/m(2). Of those 30 subjects, 9 had pure fatty liver and 21 had evidence of steatohepatitis. In addition, 10 patients with type 2 diabetes under good metabolic control and 10 healthy subjects were studied. Most NAFLD patients had central fat accumulation, increased triglycerides and uric acid, and low HDL cholesterol, irrespective of BMI. Glucose disposal during the clamp was reduced by nearly 50% in NAFLD patients, as well as in patients with normal body weight, to an extent similar to that of the type 2 diabetic patients. Basal free fatty acids were increased, whereas insulin-mediated suppression of lipolysis was less effective (-69% in NAFLD vs. -84% in control subjects; P = 0.003). Postabsorptive hepatic glucose production (HGP), measured by [6,6-(2)H(2)]glucose, was normal. In response to insulin infusion, HGP decreased by only 63% of basal in NAFLD vs. 84% in control subjects (P = 0.002). Compared with type 2 diabetic patients, NAFLD patients were characterized by lower basal HGP, but with similarly reduced insulin-mediated suppression of HGP. There was laboratory evidence of iron overload in many NAFLD patients, but clinical, histological, and biochemical data (including insulin sensitivity) were not correlated with iron status. Four subjects were heterozygous for mutation His63Asp of the HFE gene of familiar hemochromatosis. We concluded that NAFLD, in the presence of normoglycemia and normal or moderately increased body weight, is characterized by clinical and laboratory data similar to those found in diabetes and obesity. NAFLD may be considered an additional feature of the metabolic syndrome, with specific hepatic insulin resistance.

<h3>Objective.</h3> —To examine the association between the use of right heart catheterization (RHC) during the first 24 hours of care in the intensive care unit (ICU) and subsequent survival, length of stay, intensity of care, and cost of care. <h3>Design.</h3> —Prospective cohort study. <h3>Setting.</h3> —Five US teaching hospitals between 1989 and 1994. <h3>Subjects.</h3> —A total of 5735 critically ill adult patients receiving care in an ICU for 1 of 9 prespecified disease categories. <h3>Main Outcome Measures.</h3> —Survival time, cost of care, intensity of care, and length of stay in the ICU and hospital, determined from the clinical record and from the National Death Index. A propensity score for RHC was constructed using multivariable logistic regression. Case-matching and multivariable regression modeling techniques were used to estimate the association of RHC with specific outcomes after adjusting for treatment selection using the propensity score. Sensitivity analysis was used to estimate the potential effect of an unidentified or missing covariate on the results. <h3>Results.</h3> —By case-matching analysis, patients with RHC had an increased 30-day mortality (odds ratio, 1.24; 95% confidence interval, 1.03-1.49). The mean cost (25th, 50th, 75th percentiles) per hospital stay was $49300 ($17000, $30500, $56600) with RHC and $35700 ($11 300, $20600, $39200) without RHC. Mean length of stay in the ICU was 14.8 (5,9, 17) days with RHC and 13.0 (4,7, 14) days without RHC. These findings were all confirmed by multivariable modeling techniques. Subgroup analysis did not reveal any patient group or site for which RHC was associated with improved outcomes. Patients with higher baseline probability of surviving 2 months had the highest relative risk of death following RHC. Sensitivity analysis suggested that a missing covariate would have to increase the risk of death 6-fold and the risk of RHC 6-fold for a true beneficial effect of RHC to be misrepresented as harmful. <h3>Conclusion.</h3> —In this observational study of critically ill patients, after adjustment for treatment selection bias, RHC was associated with increased mortality and increased utilization of resources. The cause of this apparent lack of benefit is unclear. The results of this analysis should be confirmed in other observational studies. These findings justify reconsideration of a randomized controlled trial of RHC and may guide patient selection for such a study.

The AASLD/EASL Practice Guideline Subcommittee on Hepatic Encephalopathy are: Jayant A. Talwalkar (Chair, AASLD), Hari S. Conjeevaram, Michael Porayko, Raphael B. Merriman, Peter L.M. Jansen, and Fabien Zoulim. This guideline has been approved by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver and represents the position of both associations. These recommendations provide a data-supported approach. They are based on the following: (1) formal review and analysis of the recently published world literature on the topic; (2) guideline policies covered by the American Association for the Study of Liver Diseases/European Association for the Study of the Liver (AASLD/EASL) Policy on the Joint Development and Use of Practice Guidelines; and (3) the experience of the authors in the specified topic. Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic, and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. To more fully characterize the available evidence supporting the recommendations, the AASLD/EASL Practice Guidelines Subcommittee has adopted the classification used by the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) workgroup, with minor modifications (Table 1). The classifications and recommendations are based on three categories: the source of evidence in levels I through III; the quality of evidence designated by high (A), moderate (B), or low quality (C); and the strength of recommendations classified as strong (1) or weak (2). The literature databases and search strategies are outlined below. The resulting literature database was available to all members of the writing group (i.e., the authors). They selected references within their field of expertise and experience and graded the references according to the GRADE system.1 The selection of references for the guideline was based on a validation of the appropriateness of the study design for the stated purpose, a relevant number of patients under study, and confidence in the participating centers and authors. References on original data were preferred and those that were found unsatisfactory in any of these respects were excluded from further evaluation. There may be limitations in this approach when recommendations are needed on rare problems or problems on which scant original data are available. In such cases, it may be necessary to rely on less-qualified references with a low grading. As a result of the important changes in the treatment of complications of cirrhosis (renal failure, infections, and variceal bleeding [VB]), studies performed more than 30 years ago have generally not been considered for these guidelines. Hepatic encephalopathy (HE) is a frequent complication and one of the most debilitating manifestations of liver disease, severely affecting the lives of patients and their caregivers. Furthermore, cognitive impairment associated with cirrhosis results in utilization of more health care resources in adults than other manifestations of liver disease.2 Progress in the area has been hindered by the complex pathogenesis that is not yet fully elucidated. Apart from such biological factors, there remains the larger obstacle that there are no universally accepted standards for the definition, diagnosis, classification, or treatment of HE, mostly as a result of insufficient clinical studies and standardized definitions. Clinical management tends to be dependent on local standards and personal views. This is an unfavorable situation for patients and contrasts with the severity of the condition and the high level of standardization in other complications of cirrhosis. The lack of consistency in the nomenclature and general standards renders comparisons among studies and patient populations difficult, introduces bias, and hinders progress in clinical research for HE. The latest attempts to standardize the nomenclature were published in 2002 and suggestions for the design of HE trials in 2011. Because there is an unmet need for recommendations on the clinical management of HE, the EASL and the AASLD jointly agreed to create these practice guidelines. It is beyond the scope of these guidelines to elaborate on the theories of pathogenesis of HE, as well as the management of encephalopathy resulting from acute liver failure (ALF), which has been published as guidelines recently. Rather, its aim is to present standardized terminology and recommendations to all health care workers who have patients with HE, regardless of their medical discipline, and focus on adult patients with chronic liver disease (CLD), which is, by far, the most frequent scenario. As these guidelines on HE were created, the authors found a limited amount of high-quality evidence to extract from the existing literature. There are many reasons for this; the elusive character of HE is among them, as well as the lack of generally accepted and utilized terms for description and categorization of HE. This makes a practice guideline all the more necessary for future improvement of clinical studies and, subsequently, the quality of management of patients with HE. With the existing body of evidence, these guidelines encompass the authors' best, carefully considered opinions. Although not all readers may necessarily agree with all aspects of the guidelines, their creation and adherence to them is the best way forward, with future adjustments when there is emergence of new evidence. Advanced liver disease and portosystemic shunting (PSS), far from being an isolated disorder of the liver, have well-known consequences on the body and, notably, on brain functioning. The alterations of brain functioning, which can produce behavioral, cognitive, and motor effects, were termed portosystemic encephalopathy (PSE)3 and later included in the term HE.4 Unless the underlying liver disease is successfully treated, HE is associated with poor survival and a high risk of recurrence.5, 6 Even in its mildest form, HE reduces health-related quality of life and is a risk factor for bouts of severe HE.7-9 Hepatic encephalopathy is a brain dysfunction caused by liver it as a of or from alterations to This definition, in with is based on the that are of brain and that the a to liver The and of HE are to the severity of the underlying liver and In patients with fully HE is an that the of the disease, such as or encephalopathy is in cirrhosis with The of HE may not be an clinical and there are used for its which the in the and The of the of of cirrhosis is in in those with and in patients with portosystemic The that in of those with cirrhosis their clinical and in the in most HE or HE in of patients with The of HE in is not well The risk for the of is within years cirrhosis diagnosis, on the of risk factors, such as other complications to cirrhosis or infections, or and and with a of were found to have a risk of and with have a risk of within 6 Even with cirrhosis and cognitive dysfunction or one of years of the of is and is by the patient selection data were by It an of the frequent of the health care by patients with HE that for in the in the European are not these are to be Furthermore, the of and cirrhosis is and more be to further the of HE. Hepatic encephalopathy a of and In its HE and as well as and other brain As HE such as and may be by the and alterations in and motor of the with are of the is may to and and acute with or and, The for Hepatic Encephalopathy and the of or as the of In patients with HE, motor such as and a can be In may and in can be can are in such as and of and with are in the of to or or is present in the to of HE that or and is, in not a a of of It is by that such as of the with or the of the can be in other such as the and is not of HE it can be in other the cognitive or and motor of HE may not be or not progress in in in the severity of HE. Hepatic is a of HE to by severe motor the of with and of with and or alterations have been and not to may with liver HE may present with with in which brain brain This condition was a term considered this is to and may be more than in patients with liver disease, in of Apart from these manifestations of HE, it is accepted in clinical practice that all of HE and their manifestations are and this is a for treatment research on HE patients and on patients of bouts of on the from those to other may and are later under of may be associated with in and Hepatic encephalopathy be classified according to all of the to the underlying disease, HE is to the severity of The that is HE has been clinical and research a of such is (Table classifications that to aim and and be used to its HE is to the of factors, HE is for standards and expertise lack of or of or or for to to classification, according to or not the patient has liver failure has recently been Although the and this classification is a research The the of of HE in a patient with severe liver who not have of brain The of for HE and the of HE. The the level of (Table Hepatic encephalopathy be classified according to the of underlying disease, severity of and 1). is other that can brain and HE 1). and of HE be and classified according to all factors, and this be relevant according to the clinical The recommendations are in and the severity of HE is as a The strategies in from clinical to and of the are for the The and according to the of the and the of The of is based on a clinical and a clinical Clinical are used to its Specific are needed in study The is the clinical are with limited for I HE, and a lack of can be in clinical In the of and has and are as of or have been used to the severity of In patients with the is and an cognitive dysfunction is not It can be from clinical as well as or The is to them to HE. this remains a of in this patient that is to resulting from of and disease (Table as of other by and for a patient with in HE is encephalopathy and is as the of or clinical of brain dysfunction in patients with who are not or The term that there is no clinical cognitive or of HE. The term and HE. strategies can be and Because the condition of cognitive functioning, which may not be to the the the use of on the local and and with one of the being more accepted as to as a for and is important it can poor quality of life and and patients and the The of and in patients with to be as high as every patient risk be this may be and the consequences of the are not and treatment is not approach may be to patients who have problems with their quality of life or in there are from the patients and their for or HE patients risk for Furthermore, of the available are for the and it is important to patients who not have factors, such as or be by a to that the the result is (i.e., for or in 6 has been of or not that the is a are not to to and are not in the best of both the patient and the local the of patients with HE on the consequences of their and, the is to the have the patient for In cases, the with the that have the expertise to and the to the Although the have been used to for and there is, most a poor them HE is a is with and it is HE a in the of these and of the results for further management need an of the and on the of HE are the of or by of the and one of the following: or or or In the clinical or may use for the severity of HE with which are that data are available and the have been for use in this patient levels not any diagnostic, or in HE patients with in an level is in a patient with and it is the of HE is in of may be to the There may be to which be is in or the relevant be are be when standards for or or other not or information. the risk of is in this patient and the may be a brain is of the of HE and on clinical of other Hepatic encephalopathy be as a from cognitive with through 1). The of HE is through of other of brain dysfunction 1). Hepatic encephalopathy be of the of and the need for care 1). encephalopathy is by clinical and can be graded according the and the 1). The and of and can be and that be performed by 1). for and be used in patients who most from such as those with quality of life or on or not any diagnostic, or for HE in patients with for 1). this is encephalopathy and as its is not on clinical and is by outlined in the its and can have a on a can there may be an to such a patient impairment in quality of or cognitive Liver is under the treatment recommendations for treatment of the following: of or be 1). an for HE is 1). for of of is not in patients with cirrhosis with a high risk to HE with liver failure, is an for approach to management of HE is of care for patients with of be and of and their of HE treatment with of HE who are risk or to their need more and are in an care of encephalopathy are not in patients with cirrhosis. other of encephalopathy are the of encephalopathy may not be termed HE. In the clinical is treatment of both HE and in the management of is of of patients can be with of the to this is the of HE In to the other of the approach to treatment of HE, treatment is of the have not been by studies and are utilized based on These such as and such as such as and other have been In the a can be used to in patients who are to or have an is generally used as treatment for of data not as a for treatment of for it not the and these to be used of of a clinical search for and for the brain it is that the being a that the of in the and of have an beyond the studies have not those In most trials on have been in to the in of In is preferred to based on of In populations with a high of the use of has been the to that and were to was The use of further The of be when the three of the approach are with of every or are the is to to three This be It is a that lack of of of is by larger There is a for of to such as and severe and can has been used for the of HE in a number of it with other and in These trials of that was or to the with with for patients with has been in three trials to and one in cognitive improvement and with patients bouts to the of the of data the use of have been used for treatment of HE, data to their use are or most of these can be used their limited of trials that the manifestations of HE or There is no of on the of These through their as in have been used for treatment of of the for many are available and present as has been for HE, further clinical are was in a on patients who or more of HE in the 6 and who were on The of HE and as well as to clinical studies on the are under way and, may to clinical on patients with HE improvement by in and with is study of or no in patients with cirrhosis who from HE found of HE in the or to were not There was no in of in any of the of the shunting the that may be by the of by the This has its and was used in the for HE it is a As has for its and these for This is not It in improvement on or The may be of in to the may be in by when or when is not have the of and no have been on this on patients on or no on of HE, was to and for HE 1). is the for treatment of 1). is an to for of 1). can be used as an or to patients to can be used as an or to patients to is an for treatment of is an for treatment of There are no trials of for of from it is and of of HE in patients with as of HE to to is the to in patients who have one or more bouts of on treatment their of was to complications of its to the of HE, or HE, was with severe HE as a complication of a a it was to use HE treatment to HE. one study that HE any than selection has the of severe HE it can the original for may important with to the of low a of can to HE, as There is a lack of on to aim to by or The is associated with more bouts of It is used to HE as with other of HE, the that be by of bouts of HE in patients with liver to a search for of such as can be successfully with of HE in a of patients in a liver the risk for is for of of HE the 1). as an to is for of of HE the 1). or is not for the of HE 1). There is a to treatment it has successfully a of The may be that the for is patients are high risk for This risk to as liver are bouts of from a well-known of a factor can be such as or variceal HE may not be a risk and HE can be Even more on the risk for further bouts of is liver and body patients a amount of liver and from the bouts of may well be to HE There are data on this for or HE patients risk for HE. the have been well (i.e., and or liver or may be Although it is not to for and studies have been performed of The of studies have been for than 6 and not the of the the from trials to studies from and studies have an improvement in the underlying cognitive the of has among of studies used relevant It was in an that can of the of the study to be in a larger study in a recommendations can be and have improvement in quality of and in have been the and of and them to as this Because of the used to and treatment and used in trials to treatment for is not this be on a that are approved for for patients with and I HE. of and is not from a 1). of is to the management of all of HE, and are guidelines for of patients with HE are is and of patients with HE from with of and is are than that of patients and are risk of and of is a risk factor for of HE and other cirrhosis has been to be an important in patients with HE patients an of by a with data and strength as of In the is to the the and are and Although body is the may be as well as the such as are for clinical The patient a by a or other The of HE patients for The is by moderate as below. the and a be with of may be the most available not be utilized as the be to patients that can by to patients who the and to other The be and The use of a is generally there are no data on the of and Specific is there are and is considered when HE. is of be and any of of be as to of in patients with cirrhosis. severe is this be There is that be for patients with HE. of may be in the of not be of or or with is to of may be used to HE and generally the of patients with for an of HE has no The studies on the of have been more and by a of the of these may to have more important on of of body than a on HE. be body 1). be 1). or the and a be 1). may to be and in patients of Liver remains the treatment for HE that not on any other is not its The management of these as in the has been published and European guidelines are under Hepatic encephalopathy by is not considered an for associated with poor liver HE severely the quality of life and be medical and who may be liver may and HE, be and considered or the severe be Hepatic encephalopathy it is important to HE from other of such as disease and and of the brain be and the patient be by an in and The and health be that may brain impairment and that not all manifestations of HE are fully by and not is the of a in the The search of the is difficult, and the may have with liver disease and those with HE are of are a frequent associated with and levels in of may be to associated with a search for or are not and the be from a clinical As outlined under the of HE is and more of HE be with being to for HE and to The patients with HE in the in of utilization for this group of patients is as a result of of and more complex and as well as a of There are no by from the be the and the and These are an care, and and the on the or were not The of is to in it from to and are by the the can the of based on that are as of and from in patients with or the of other to be the most The manifestations of HE are have to be considered as an source of dysfunction in any patient with important are and is bleeding and is an risk factor for of HE in patients with The of HE and the to with has been as a risk factor for of HE, in patients with the may be in other cirrhosis risk to HE has been in patients with cirrhosis with of the severity of cirrhosis. are in of patients with cirrhosis with and in of those with with cirrhosis not from patients cirrhosis their risk to brain dysfunction with it is that and with to the of HE. in patients with may as a of in cirrhosis of any The of and be as being the result of or by clinical In any of be the of the underlying liver disease on brain are for and difficult, may be the result of Even patients with disorder and no clinical disease have been to in and and and motor The cognitive dysfunction is more in those patients with disorder who are risk of encephalopathy as a result of or of the it remains the of brain in patients with is the result of HE, or There is evidence that is present and within the of patients chronic of the of their liver and patients with liver disease cognitive and patients with cirrhosis and may have severe and impairment of and of the of liver Because HE with all and underlying it is in the to the of HE and those resulting from other In cases, the and to may be the best of HE. As a level in a patient of HE for of the used present has been for their to HE and other of brain The not be by or may changes to those with HE in of or are to are to for these have been for their use in HE, the results are brain be in every patient with and of brain to In rare cases, by may be a for HE, the be This with research the management of HE. such research be based on research the of HE. It is necessary to more which liver are for of which alterations in and failure of these liver which brain are to the of the and, which this that result in the emergence of HE or the research and clinical management in result in new and treatment that need and clinical There is a severe and unmet need for clinical trials on treatment on all the of HE. clinical studies are the number of patients and their utilization is There are no data on which and patients the and research is needed to the of there is an insufficient for resources and policies management of HE. that were for HE ago were a of care is study of treatment for HE be or the of care. It is to to and The of recently is in the of and there is a need for trials on HE. There is an unmet need for research that is necessary to a for clinical The of and has it is not to results among studies and the be It may be to and HE that the of liver failure and with more than one important area of is the term which was to I of is and This to be by a approach. the isolated liver failure and HE be by clinical and brain brain is and are needed to the of that can be in patients with liver be more classified and based on and to the of clinical practice and studies in They be on the of HE on and to use and the in clinical (Table on and among on aspects on and with treatment studies on that can which patients may from Development of to when and to the on (i.e., and use on on for and of dysfunction on who from the for to and on cognitive improvement on to and be the to new which have been and are not a for studies The existing literature from a lack of and this makes of data or to consistency the field have been published by is a of the

Research on hepatic encephalopathy is hampered by the imprecise definition of this disabling complication of liver disease. Under this light, the Organisation Mondiale de Gastroentérologie commissioned a Working Party to reach a consensus in this area and to present it at the 11th World Congress of Gastroenterology in Vienna (1998). The Working Party continued its work thereafter and now present their final report. In summary, the Working Party has suggested a modification of current nomenclature for clinical diagnosis of hepatic encephalopathy; proposed guidelines for the performance of future clinical trials in hepatic encephalopathy; and felt the need for a large study to redefine neuropsychiatric abnormalities in liver disease, which would allow the diagnosis of minimal (subclinical) encephalopathy to be made on firm statistical grounds. In the interim, it proposes the use of a psychometric hepatic encephalopathy score, based on the result of 5 neuropsychologic tests. Finally, the need for a careful evaluation of the newer neuroimaging modalities for the diagnosis of hepatic encephalopathy was stressed.

C-reactive protein (CRP) is a phylogenetically highly conserved plasma protein, with homologs in vertebrates and many invertebrates, that participates in the systemic response to inflammation. Its plasma concentration increases during inflammatory states, a characteristic that has long been employed for clinical purposes. CRP is a pattern recognition molecule, binding to specific molecular configurations that are typically exposed during cell death or found on the surfaces of pathogens. Its rapid increase in synthesis within hours after tissue injury or infection suggests that it contributes to host defense and that it is part of the innate immune response. Recently, an association between minor CRP elevation and future major cardiovascular events has been recognized, leading to the recommendation by the Centers for Disease Control and the American Heart Association that patients at intermediate risk of coronary heart disease might benefit from measurement of CRP. This review will largely focus on our current understanding of the structure of CRP, its ligands, the effector molecules with which it interacts, and its apparent functions.

Foot infections are a common and serious problem in persons with diabetes. Diabetic foot infections (DFIs) typically begin in a wound, most often a neuropathic ulceration. While all wounds are colonized with microorganisms, the presence of infection is defined by ≥2 classic findings of inflammation or purulence. Infections are then classified into mild (superficial and limited in size and depth), moderate (deeper or more extensive), or severe (accompanied by systemic signs or metabolic perturbations). This classification system, along with a vascular assessment, helps determine which patients should be hospitalized, which may require special imaging procedures or surgical interventions, and which will require amputation. Most DFIs are polymicrobial, with aerobic gram-positive cocci (GPC), and especially staphylococci, the most common causative organisms. Aerobic gram-negative bacilli are frequently copathogens in infections that are chronic or follow antibiotic treatment, and obligate anaerobes may be copathogens in ischemic or necrotic wounds. Wounds without evidence of soft tissue or bone infection do not require antibiotic therapy. For infected wounds, obtain a post-debridement specimen (preferably of tissue) for aerobic and anaerobic culture. Empiric antibiotic therapy can be narrowly targeted at GPC in many acutely infected patients, but those at risk for infection with antibiotic-resistant organisms or with chronic, previously treated, or severe infections usually require broader spectrum regimens. Imaging is helpful in most DFIs; plain radiographs may be sufficient, but magnetic resonance imaging is far more sensitive and specific. Osteomyelitis occurs in many diabetic patients with a foot wound and can be difficult to diagnose (optimally defined by bone culture and histology) and treat (often requiring surgical debridement or resection, and/or prolonged antibiotic therapy). Most DFIs require some surgical intervention, ranging from minor (debridement) to major (resection, amputation). Wounds must also be properly dressed and off-loaded of pressure, and patients need regular follow-up. An ischemic foot may require revascularization, and some nonresponding patients may benefit from selected adjunctive measures. Employing multidisciplinary foot teams improves outcomes. Clinicians and healthcare organizations should attempt to monitor, and thereby improve, their outcomes and processes in caring for DFIs.

OBJECTIVE: To examine the association between the use of right heart catheterization (RHC) during the first 24 hours of care in the intensive care unit (ICU) and subsequent survival, length of stay, intensity of care, and cost of care. DESIGN: Prospective cohort study. SETTING: Five US teaching hospitals between 1989 and 1994. SUBJECTS: A total of 5735 critically ill adult patients receiving care in an ICU for 1 of 9 prespecified disease categories. MAIN OUTCOME MEASURES: Survival time, cost of care, intensity of care, and length of stay in the ICU and hospital, determined from the clinical record and from the National Death Index. A propensity score for RHC was constructed using multivariable logistic regression. Case-matching and multivariable regression modeling techniques were used to estimate the association of RHC with specific outcomes after adjusting for treatment selection using the propensity score. Sensitivity analysis was used to estimate the potential effect of an unidentified or missing covariate on the results. RESULTS: By case-matching analysis, patients with RHC had an increased 30-day mortality (odds ratio, 1.24; 95% confidence interval, 1.03-1.49). The mean cost (25th, 50th, 75th percentiles) per hospital stay was $49 300 ($17 000, $30 500, $56 600) with RHC and $35 700 ($11 300, $20 600, $39 200) without RHC. Mean length of stay in the ICU was 14.8 (5, 9, 17) days with RHC and 13.0 (4, 7, 14) days without RHC. These findings were all confirmed by multivariable modeling techniques. Subgroup analysis did not reveal any patient group or site for which RHC was associated with improved outcomes. Patients with higher baseline probability of surviving 2 months had the highest relative risk of death following RHC. Sensitivity analysis suggested that a missing covariate would have to increase the risk of death 6-fold and the risk of RHC 6-fold for a true beneficial effect of RHC to be misrepresented as harmful. CONCLUSION: In this observational study of critically ill patients, after adjustment for treatment selection bias, RHC was associated with increased mortality and increased utilization of resources. The cause of this apparent lack of benefit is unclear. The results of this analysis should be confirmed in other observational studies. These findings justify reconsideration of a randomized controlled trial of RHC and may guide patient selection for such a study.

In order to describe the outcomes of patients hospitalized with an acute exacerbation of severe chronic obstructive pulmonary disease (COPD) and determine the relationship between patient characteristics and length of survival, we studied a prospective cohort of 1,016 adult patients from five hospitals who were admitted with an exacerbation of COPD and a PaCO2 of 50 mm Hg or more. Patient characteristics and acute physiology were determined. Outcomes were evaluated over a 6 mo period. Although only 11% of the patients died during the index hospital stay, the 60-d, 180-d, 1-yr, and 2-yr mortality was high (20%, 33%, 43%, and 49%, respectively). The median cost of the index hospital stay was $7,100 ($4,100 to $16,000; interquartile range). The median length of the index hospital stay was 9 d (5 to 15 d). After discharge, 446 patients were readmitted 754 times in the next 6 mo. At 6 mo, only 26% of the cohort were both alive and able to report a good, very good, or excellent quality of life. Survival time was independently related to severity of illness, body mass index (BMI), age, prior functional status, PaO2/FI(O2), congestive heart failure, serum albumin, and the presence of cor pulmonale. Patients and caregivers should be aware of the likelihood of poor outcomes following hospitalization for exacerbation of COPD associated with hypercarbia.

Obesity is the most common medical condition in women of reproductive age. Obesity during pregnancy has short term and long term adverse consequences for both mother and child. Obesity causes problems with infertility, and in early gestation it causes spontaneous pregnancy loss and congenital anomalies. Metabolically, obese women have increased insulin resistance in early pregnancy, which becomes manifest clinically in late gestation as glucose intolerance and fetal overgrowth. At term, the risk of cesarean delivery and wound complications is increased. Postpartum, obese women have an increased risk of venous thromboembolism, depression, and difficulty with breast feeding. Because 50-60% of overweight or obese women gain more than recommended by Institute of Medicine gestational weight guidelines, postpartum weight retention increases future cardiometabolic risks and prepregnancy obesity in subsequent pregnancies. Neonates of obese women have increased body fat at birth, which increases the risk of childhood obesity. Although there is no unifying mechanism responsible for the adverse perinatal outcomes associated with maternal obesity, on the basis of the available data, increased prepregnancy maternal insulin resistance and accompanying hyperinsulinemia, inflammation, and oxidative stress seem to contribute to early placental and fetal dysfunction. We will review the pathophysiology underlying these data and try to shed light on the specific underlying mechanisms.

BACKGROUND: Hepatic encephalopathy is a chronically debilitating complication of hepatic cirrhosis. The efficacy of rifaximin, a minimally absorbed antibiotic, is well documented in the treatment of acute hepatic encephalopathy, but its efficacy for prevention of the disease has not been established. METHODS: In this randomized, double-blind, placebo-controlled trial, we randomly assigned 299 patients who were in remission from recurrent hepatic encephalopathy resulting from chronic liver disease to receive either rifaximin, at a dose of 550 mg twice daily (140 patients), or placebo (159 patients) for 6 months. The primary efficacy end point was the time to the first breakthrough episode of hepatic encephalopathy. The key secondary end point was the time to the first hospitalization involving hepatic encephalopathy. RESULTS: Rifaximin significantly reduced the risk of an episode of hepatic encephalopathy, as compared with placebo, over a 6-month period (hazard ratio with rifaximin, 0.42; 95% confidence interval [CI], 0.28 to 0.64; P<0.001). A breakthrough episode of hepatic encephalopathy occurred in 22.1% of patients in the rifaximin group, as compared with 45.9% of patients in the placebo group. A total of 13.6% of the patients in the rifaximin group had a hospitalization involving hepatic encephalopathy, as compared with 22.6% of patients in the placebo group, for a hazard ratio of 0.50 (95% CI, 0.29 to 0.87; P=0.01). More than 90% of patients received concomitant lactulose therapy. The incidence of adverse events reported during the study was similar in the two groups, as was the incidence of serious adverse events. CONCLUSIONS: Over a 6-month period, treatment with rifaximin maintained remission from hepatic encephalopathy more effectively than did placebo. Rifaximin treatment also significantly reduced the risk of hospitalization involving hepatic encephalopathy. (ClinicalTrials.gov number, NCT00298038.)

tricarboxylic acid cycle phosphoenolpyruvate carboxykinase phosphoenolpyruvate The oxidation of acetyl-CoA to CO2by the TCA1 cycle is the central process in energy metabolism. However, the TCA cycle also functions in biosynthetic pathways in which intermediates leave the cycle to be converted primarily to glucose, fatty acids, or non-essential amino acids. If TCA cycle anions are removed from the cycle they must be replaced to permit its continued function. This process is termed anaplerosis. Pyruvate carboxylase, which generates oxalacetate directly in the mitochondria, is the major anaplerotic enzyme. Conversely, 4- and 5-carbon intermediates enter the TCA cycle during the catabolism of amino acids. Because the TCA cycle cannot fully oxidize 4- and 5-carbon compounds, these intermediates must be removed from the cycle by a process termedcataplerosis. Cataplerosis may be linked to biosynthetic processes such as gluconeogenesis in the liver and kidney cortex, fatty acid synthesis in the liver, and glyceroneogenesis in adipose tissue. Cataplerotic enzymes present in many mammalian tissues include P-enolpyruvate carboxykinase (PEPCK), glutamate dehydrogenase, aspartate aminotransferase, and citrate lyase. In this review we have evaluated the roles of anaplerosis and cataplerosis in whole body metabolism. The expression anaplerotic sequences was a term used in biochemistry by Sir Hans Kornberg (1Kornberg H.L. Essays Biochem. 1966; 2: 1-31Crossref Scopus (359) Google Scholar) to describe a series of enzymatic reactions or pathways that replenish the pools of metabolic intermediates in the TCA cycle. These intermediates are critical for the functioning of the TCA cycle, the primary role of which is the oxidation of acetyl-CoA to carbon dioxide. The pool of TCA cycle intermediates is sufficient to sustain the oxidative carbon flux over a fairly wide range, so that during high energy consumption (e.g. exercise) or during lower energy consumption (e.g. fasting), there is not a large change in the pool size of TCA intermediates (2Graham T.E. Gibala M.J. Richter E.A. Galbo H. Kiens B. Saltin B. Skeletal Muscle Metabolism in Exercise and Diabetes. Plenum Press, New York1998: 271-286Google Scholar). However, in several physiological states, there is a large influx (anaplerosis) of 4- and 5-carbon intermediates into the TCA cycle. Because the TCA cycle cannot act as a carbon sink, anaplerosis must be coupled with the exit of intermediates from the cycle via cataplerosis. The importance of anaplerotic reactions for cellular metabolism is thus apparent. However, the coupling of this process with cataplerosis and the roles that both pathways play in the regulation of amino acid, glucose, and fatty acid metabolism have not been emphasized to a sufficient extent. The terms anaplerosis and cataplerosis describe reciprocal and correlative reactions involved in the function of the TCA cycle. The enzymatic steps in these processes have long been known, but the overall concept of a linkage between anaplerosis and cataplerosis should be underscored, because the balance between these two processes controls the entry and exit of TCA cycle anions. Anaplerotic and cataplerotic reactions are involved in the ultimate disposal of all metabolic intermediates. The metabolic role of anaplerosis and cataplerosis in amino acid metabolism varies with specific organs and is dependent on the nutritional/metabolic status of the individual. During feeding, the intestine is an important site of catabolism of enterally derived amino acids, whereas in the starved state amino acid catabolism occurs primarily in the kidney, liver, and muscle. The catabolism of amino acids produces gluconeogenic or ketogenic precursors (Table I). The disposal of gluconeogenic anions in the TCA cycle employs anaplerotic and cataplerotic pathways for their terminal oxidation. The only known pathway for the terminal oxidation of leucine is through acetoacetate to acetyl-CoA and subsequent oxidation in the TCA cycle. However, other amino acids also have for their disposal alternate ketogenic pathways for terminal oxidation. Thus, the ketogenic amino acids from proteolysis can be terminally oxidized in muscle, whereas the gluconeogenic amino acids are dependent upon anaplerosis and cataplerosis for conversion to glucose in the liver and kidney before oxidation to CO2 and H2O.Table IMetabolic fates of amino acids in the TCA cycle1. Amino acids converted to pyruvate Alanine, serine, glycine, threonine, cysteine, tryptophan2. Amino acids converted to oxaloacetate Aspartate, asparagine3. Amino acids converted to α-ketoglutarate Glutamate, glutamine, proline, histidine, arginine4. Amino acids converted to fumarate Phenylalanine, tyrosine5. Amino acids converted to succinyl-CoA Methionine, isoleucine, valine6. Amino acids converted to acetyl-CoA Leucine, isoleucine, lysine, phenylalanine, tyrosine, tryptophan, threonine Open table in a new tab The first reaction of the TCA cycle, citrate synthase, catalyzes the condensation of oxalacetate with acetyl-CoA; the oxalacetate is subsequently regenerated by the reactions of the cycle and condenses with another molecule of acetyl-CoA. However, the TCA cycle also functions in biosynthetic processes in which intermediates are removed from the cycle; this necessitates anaplerotic reactions to replenish TCA cycle intermediates to ensure its continued function. Pyruvate carboxylase, which synthesizes oxalacetate from pyruvate in the mitochondrial matrix, is the archetypical anaplerotic enzyme. The activity of this enzyme is high in many tissues (e.g. 10–12 units/g of liver); acetyl-CoA is a positive allosteric regulator of the enzyme. Anaplerosis is obligatory during both gluconeogenesis and lipogenesis when malate (gluconeogenesis) or citrate (lipogenesis) leaves the mitochondria and is further metabolized to form glucose or fatty acids, respectively. If intermediates can be added to the TCA cycle, it is equally important to remove them to avoid the accumulation of anions in the mitochondrial matrix. Cataplerosis describes reactions involved in the disposal of TCA cycle intermediates. There are several cataplerotic enzymes; these include PEPCK, aspartate aminotransferase, and glutamate dehydrogenase. Each of these reactions has as substrate a TCA cycle anion that is converted to a product that effectively removes intermediates from the cycle. In the liver and kidney, the role of PEPCK in cataplerosis is of special importance because it is a common route for the generation of PEP from oxalacetate to be used for gluconeogenesis. Alternatively, in muscle, PEP can be converted to pyruvate that can be decarboxylated to acetyl-CoA for subsequent oxidation to CO2 in the TCA cycle. The regulation of anaplerosis and cataplerosis depends upon the metabolic and physiologic state and the specific tissue/organ involved. For example, during starvation, cataplerosis via phosphoenolpyruvate to support gluconeogenesis may be regulatory in the liver, whereas in the kidney anaplerosis via uptake of glutamine may be regulatory. Anaplerotic and cataplerotic intermediates entering and exiting the TCA cycle are shown in Fig. 1. A detailed and elegant analysis of amino acid metabolism can be found in a review by Jungas et al. (3Jungas R.L. Halperin M.L. Brosnan J.T. Physiol. Rev. 1992; 72: 419-448Crossref PubMed Scopus (234) Google Scholar). The interplay between anaplerotic and cataplerotic reactions in humans was demonstrated by renal metabolism during total, prolonged starvation (4Owen O.E. Felig P. Morgan A.P. Wahren J. Cahill Jr., G.F. J. Clin. Invest. 1969; 48: 584-594Crossref PubMed Scopus (569) Google Scholar). Arteriovenous concentration differences of metabolites across the kidneys coupled with urinary nitrogen losses showed that the kidney extracted glutamine and produced urinary ammonium (5Van Slyke D.D. Phillips R.A. Hamilton P.B. Archibald R.M. Futcher P.H. Hiller A. J. Biol. Chem. 1943; 150: 481-482Abstract Full Text PDF Google Scholar). Concurrently, the kidney released glucose into the blood. It was initially recognized that renal ammoniagenesis was related to ketonuria during prolonged starvation when there is an increase in ketogenesis (6Sapir D.G. Owen O.E. Cheng J.T. Ginsberg R. Boden G. Walker W.G. J. Clin. Invest. 1972; 51: 2093-2102Crossref PubMed Scopus (26) Google Scholar). However, it was not generally appreciated that the entry (anaplerosis) and removal (cataplerosis) of intermediates into and out of the TCA cycle as related to renal ammoniagenesis and gluconeogenesis had to be balanced. This fundamental principle is poorly understood and is the foundation of this paper. During prolonged starvation glutamine is transported from muscle to the kidney where the amino and amide groups are used for ammonia formation. The ammonia released from the renal cells serves to titrate the acidity of the tubular urine created by the disassociation of organic acids, primarily β-hydroxybutyric and acetoacetic acids. For ammonia generation to continue, glutamine undergoes anaplerotic reactions to form α-ketoglutarate that enters the TCA cycle and is sequentially converted to malate that leaves the mitochondria. Malate is oxidized in the cytosol to oxalacetate that is subsequently converted to PEP and then to glucose. Thus, anaplerotic and cataplerotic reactions are essential and balanced during renal ammoniagenesis and gluconeogenesis. The heightened ketonuria that occurs with ketonemia is related to the need for the kidney to generate glucose during total starvation when renal gluconeogenesis accounts for about 50% of the net glucose synthesis (4Owen O.E. Felig P. Morgan A.P. Wahren J. Cahill Jr., G.F. J. Clin. Invest. 1969; 48: 584-594Crossref PubMed Scopus (569) Google Scholar, 7Owen O.E. Smalley K.J. D'Alessio D.A. Mozzoli M.A. Dawson E.K. Am. J. Clin. Nutr. 1998; 68: 12-34Crossref PubMed Scopus (90) Google Scholar). Thus, renal ammoniagenesis and gluconeogenesis are tightly interlocked and dependent upon balanced anaplerotic reactions to replenish the α-ketoglutarate in the TCA cycle and cataplerotic reactions to drain remnant 4-carbon metabolic intermediates from the cycle to synthesize glucose (7Owen O.E. Smalley K.J. D'Alessio D.A. Mozzoli M.A. Dawson E.K. Am. J. Clin. Nutr. 1998; 68: 12-34Crossref PubMed Scopus (90) Google Scholar). In addition, there is a metabolic bonus when the kidneys excrete urinary ammonium during starvation. The caloric value of protein is greater when amino acid nitrogen is lost in the urine as ammonium rather than urea because it requires four molecules of ATP to generate a molecule of urea via the urea cycle. In addition, energy is required for the synthesis of creatine and uric acid. Despite the relatively slow rate of turnover of skeletal muscle protein, it represents the largest reservoir of amino acids because of its large mass. Following an overnight fast, there is a net release of amino acids from skeletal muscle; however, the amino acids released do not reflect the amino acid composition of the skeletal muscle proteins (3Jungas R.L. Halperin M.L. Brosnan J.T. Physiol. Rev. 1992; 72: 419-448Crossref PubMed Scopus (234) Google Scholar, 8Felig P. Bergman M. Felig P. Baxter J.D. Frohman L.A. Endocrinology and Metabolism. 3rd Ed. McGraw-Hill, Inc., New York1995: 1107-1250Google Scholar). This suggests that there is local metabolism and interconversion of amino acids in the muscle. Specifically, alanine and glutamine represent a disproportionately larger fraction of amino acids released by the skeletal muscle when compared with the amino acid composition of skeletal muscle proteins. The relative proportion of these amino acids released by muscle also changes with the metabolic status, such as prolonged starvation or diabetes, or in response to administration of insulin or glucagon (3Jungas R.L. Halperin M.L. Brosnan J.T. Physiol. Rev. 1992; 72: 419-448Crossref PubMed Scopus (234) Google Scholar, 8Felig P. Bergman M. Felig P. Baxter J.D. Frohman L.A. Endocrinology and Metabolism. 3rd Ed. McGraw-Hill, Inc., New York1995: 1107-1250Google Scholar, 9Reeds P.J. Fjeld C.R. Jahoor F. J. Nutr. 1994; 124: 906-910Crossref PubMed Scopus (282) Google Scholar, 10Castillo C.E. Katz A. Spencer M.K. Yan Z. Nyomba B.L. Am. J. Physiol. 1991; 261: E598-E605PubMed Google Scholar, 11Gibala M.J. MacLean D.A. Graham T.E. Saltin B. Am. J. Physiol. 1998; 275: E235-E242PubMed Google Scholar). These data suggest that a local metabolism of amino acids occurs in the skeletal muscle that results in the de novo synthesis of certain non-essential amino acids, primarily alanine and glutamine. Arteriovenous concentration differences across skeleton muscles show net uptake and/or release of lactate, ammonia, alanine, glutamine, and glutamate at rest and during exercise (11Gibala M.J. MacLean D.A. Graham T.E. Saltin B. Am. J. Physiol. 1998; 275: E235-E242PubMed Google Scholar). In addition, during exercise there is an increase in the TCA cycle intermediates; however, the increase in concentration is not equal in all the TCA intermediates (Table II).Table IIIntramuscular concentrations of individual TCA cycle intermediates at rest and during exerciseRest5 min10 minCitrate0.362 ± 0.0470.658 ± 0.0772-ap ≤ 0.05versus rest.0.631 ± 0.0522-ap ≤ 0.05versus rest.Isocitrate0.085 ± 0.0130.194 ± 0.0222-ap ≤ 0.05versus rest.0.200 ± 0.0222-ap ≤ 0.05versus rest.α-Ketoglutarate0.050 ± 0.0040.036 ± 0.0052-ap ≤ 0.05versus rest.0.038 ± 0.0052-ap ≤ 0.05versus rest.Succinate0.368 ± 0.0760.567 ± 0.1150.609 ± 0.118Fumarate0.087 ± 0.0060.198 ± 0.0292-ap ≤ 0.05versus rest.0.195 ± 0.0322-ap ≤ 0.05versus rest.Malate0.365 ± 0.0371.163 ± 0.2032-ap ≤ 0.05versus rest.1.182 ± 0.1602-ap ≤ 0.05versus rest.Oxalacetate0.012 ± 0.0030.030 ± 0.0052-ap ≤ 0.05versus rest.0.027 ± 0.0062-ap ≤ 0.05versus rest.2-a p ≤ 0.05versus rest. Open table in a new tab During caloric restriction, amino acids also provide a source of energy. Amino acids yield part of their energy during oxidative deamination, but their carbon skeleton must undergo subsequent catabolism to be fully metabolized. Although most amino acids enter the TCA cycle as 4- or 5-carbon compounds, only acetyl-CoA produced from their catabolism can be fully oxidized in the cycle. Recent data from studies in humans have shown that only a small increase in the concentration of TCA intermediates (mostly 4-carbon) occurs during fasting or exercise, thus confirming the concept that only small changes in the amounts of these intermediates are required to adapt to the need for energy (12Sahlin K. Katz A. Broberg S. Am. J. Physiol. 1990; 259: C834-C841Crossref PubMed Google Scholar, 13Garber A.J. Karl I.E. Kipnis D.M. J. Biol. Chem. 1976; 251: 826-835Abstract Full Text PDF PubMed Google Scholar). The removal (cataplerosis) of TCA cycle anions generated from the entry of amino acids occurs via the action of PEPCK, glutamate dehydrogenase, or aspartate aminotransferase. Alanine and glutamine are synthesized from other amino acids and released into the circulation. Alanine is generated by the transamination of pyruvate via alanine aminotransferase. The possible sources of pyruvate are glucose and lactate, or PEP via PEPCK, using as a substrate the oxalacetate generated in the TCA cycle (cataplerosis) (13Garber A.J. Karl I.E. Kipnis D.M. J. Biol. Chem. 1976; 251: 826-835Abstract Full Text PDF PubMed Google Scholar). The carbon skeleton for the synthesis of glutamine can be generated from the TCA cycle intermediates formed by the catabolism of gluconeogenic amino acids such as aspartate and asparagine (14Chang T.W. Goldberg A.L. J. Biol. Chem. 1978; 253: 3685-3695Abstract Full Text PDF PubMed Google Scholar). These amino acids are capable of generating intermediates that can be converted by forward flow of the TCA cycle to the α-ketoglutarate required for glutamate synthesis. Transamination of α-ketoglutarate, using the branched-chain amino acids as the source of the amino groups, accounts for the synthesis of glutamate, which is then converted to glutamine by glutamine synthase using ammonia generated in muscle by the purine nucleotide cycle. In light of the concept of balanced anaplerosis and cataplerosis, branched-chain amino acid metabolism in muscle needs to be studied further. Another paradigm for the metabolic roles of anaplerosis and cataplerosis is the oxidation of glutamine to CO2 in the small intestine. In this case, the α-ketoglutarate formed from glutamine is converted to malate by the TCA cycle; the malate leaves the mitochondria and is oxidized in the cytosol to oxalacetate by NAD:malate dehydrogenase. The oxalacetate is decarboxylated to PEP by PEPCK, and the PEP is converted to pyruvate by pyruvate kinase. The pyruvate re-enters the mitochondria where it is decarboxylated to acetyl-CoA by the pyruvate dehydrogenase complex; the acetyl-CoA is then oxidized by the TCA cycle. Alternately, a fraction of the pyruvate may be transaminated to alanine in the cytosol (Fig.2). Recent research on the metabolism of glutamine in human adults and infants illustrates the critical role of anaplerosis and cataplerosis in amino acid metabolism in the gut. In normal healthy adults, almost 74% of the enterally administered glutamine was extracted by the splanchnic compartment during the first pass (15Matthews D.E. Marano M.A. Campbell R.G. Am. J. Physiol. 1993; 264: E848-E854PubMed Google Scholar), whereas 70–80% of enterally administered [13C]glutamine tracer was found in respiratory CO2 (16Haisch M. Fukagawa N.K. Matthews D.E. Am. J. Physiol. 2000; 278: E593-E602Crossref PubMed Google Scholar). Other data from studies of newborn infants also show that enterally administered glutamine is rapidly metabolized in the gut as an energy source for the enterocytes, resulting in increased urea production (17Devapatla S. Parimi P. O'Brien A. Gruca L. Kalhan S. Pediatr. Res. 2002; 51: 286AGoogle Scholar). The majority of the glutamine is metabolized by the small intestine and not the liver, because there is no observed dilution of parenterally administered [15N]glutamine. This suggests that the carbon skeleton of dietary glutamine is oxidized by the small intestine (not the liver) as a source of energy. The metabolism of glutamine by the small intestine illustrates the importance of both anaplerosis and cataplerosis in the metabolism of the 5-carbon intermediates formed from the catabolism of the carbon skeletons of amino acids. For the carbon skeleton of glutamine to be metabolized to CO2 in the TCA cycle, the α-ketoglutarate formed from glutamate (originally from the deamination of glutamine) must be converted to acetyl-CoA for full oxidation. As shown in Fig. 2, the removal of carbon from the TCA cycle involves the cataplerotic activity of PEPCK in the small intestine, which synthesizes PEP from the oxalacetate generated from the oxidation of α-ketoglutarate. The synthesis of triglyceride in adipose tissue during starvation is another example of cataplerosis linked to a biosynthetic pathway. There is a net breakdown of triglyceride in adipose tissue during fasting (lipolysis) that is stimulated by cAMP and inhibited by insulin. During starvation when the rates of lipolysis are highest, a major fraction (up to 30%) of the free fatty acids generated from triglyceride breakdown is re-esterified back to triglyceride in adipose tissue (18Elia M. Zed C. Neale G. Livesey G. Metabolism. 1987; 36: 251-255Abstract Full Text PDF PubMed Scopus (89) Google Scholar, 19Miyoshi H. Shulman G.I. Peters E.J. Wolfe M.H. Elahi D. Wolfe R.R. J. Clin. Invest. 1988; 81: 1545-1555Crossref PubMed Scopus (117) Google Scholar, 20Patel D. Kalhan S. Pediatr. Res. 1992; 31: 52-58Crossref PubMed Scopus (66) Google Scholar, 21Vaughan M. J. Biol. Chem. 1962; 237: 3354-3361Abstract Full Text PDF PubMed Google Scholar). This process requires a source of 3-glycerol phosphate, which is generally supplied by glucose via glycolysis. However, during prolonged starvation glucose utilization by adipose tissue is curtailed to spare glucose as a fuel for the brain and red blood cells. An alternative source of 3-glycerol phosphate is provided by glyceroneogenesis, an abbreviated version of gluconeogenesis, which provides the glyceride glycerol in triglyceride in adipose tissue (Fig.3) (22Ballard F.J. Hanson R.W. Leveille G.A. J. Biol. Chem. 1967; 242: 2746-2750Abstract Full Text PDF PubMed Google Scholar, 23Reshef L. Hanson R.W. Ballard F.J. J. Biol. Chem. 1970; 245: 5979-5984Abstract Full Text PDF PubMed Google Scholar). Rats fed a high protein, carbohydrate-free diet synthesize up to 80% of their glyceride glycerol in white adipose tissue by glyceroneogenesis (24Botion L.M. Brito M.N. Brito N.A. Brito S.R. Kettelhut Metabolism. 1998; Full Text PDF PubMed Scopus Google Scholar). is also an important pathway for the synthesis of triglyceride during It has been that of the fatty acids up by the liver during fasting is converted to triglyceride and released as (7Owen O.E. Smalley K.J. D'Alessio D.A. Mozzoli M.A. Dawson E.K. Am. J. Clin. Nutr. 1998; 68: 12-34Crossref PubMed Scopus (90) Google Scholar). is a major pathway for the synthesis of the 3-glycerol phosphate that is required to support triglyceride synthesis in the by et al. (24Botion L.M. Brito M.N. Brito N.A. Brito S.R. Kettelhut Metabolism. 1998; Full Text PDF PubMed Scopus Google Scholar) have that glyceroneogenesis in the of fed a high protein, carbohydrate-free diet 80% of the glyceride glycerol in In humans have for of the glyceride glycerol is derived from glyceroneogenesis and only from glycerol S. L. Hanson R.W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The TCA cycle is balanced between the and of intermediates for metabolic The of the TCA cycle as a needs in light of its role in The cycle as a on a in which the flow of into the must be balanced by the flow out or the be with In this we have several metabolic in which the two anaplerosis and cataplerosis, to ensure the balance of carbon flow into and out of the TCA cycle. The of this fundamental is in its and in its It is as in

BACKGROUND: The perinatal and maternal consequences of induction of labor at 39 weeks among low-risk nulliparous women are uncertain. METHODS: In this multicenter trial, we randomly assigned low-risk nulliparous women who were at 38 weeks 0 days to 38 weeks 6 days of gestation to labor induction at 39 weeks 0 days to 39 weeks 4 days or to expectant management. The primary outcome was a composite of perinatal death or severe neonatal complications; the principal secondary outcome was cesarean delivery. RESULTS: A total of 3062 women were assigned to labor induction, and 3044 were assigned to expectant management. The primary outcome occurred in 4.3% of neonates in the induction group and in 5.4% in the expectant-management group (relative risk, 0.80; 95% confidence interval [CI], 0.64 to 1.00). The frequency of cesarean delivery was significantly lower in the induction group than in the expectant-management group (18.6% vs. 22.2%; relative risk, 0.84; 95% CI, 0.76 to 0.93). CONCLUSIONS: Induction of labor at 39 weeks in low-risk nulliparous women did not result in a significantly lower frequency of a composite adverse perinatal outcome, but it did result in a significantly lower frequency of cesarean delivery. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ARRIVE ClinicalTrials.gov number, NCT01990612 .).

THE LAST 3 decades have witnessed profound changes in the management of patients with thalassemia major. Regular red blood cell (RBC) transfusions eliminate the complications of anemia and compensatory bone marrow (BM) expansion, permit normal development throughout childhood, and extend survival.[1

OBJECTIVES: This study analyzed whether inadequate functional health literacy is an independent risk factor for hospital admission. METHODS: We studied a prospective cohort of 3260 Medicare managed care enrollees. RESULTS: Of the participants, 29.5% were hospitalized. The crude relative risk (RR) of hospitalization was higher for individuals with inadequate literacy (n = 800; RR = 1.43; 95% confidence interval [CI] = 1.24, 1.65) and marginal literacy (n = 366; RR = 1.33; 95% CI = 1.09, 1.61) than for those with adequate literacy (n = 2094). In multivariate analysis, the adjusted relative risk of hospital admission was 1.29 (95% CI = 1.07, 1.55) for individuals with inadequate literacy and 1.21 (95% CI = 0.97, 1.50) for those with marginal literacy. CONCLUSIONS: Inadequate literacy was an independent risk factor for hospital admission among elderly managed care enrollees.

Chicago Classification v4.0 (CCv4.0) is the updated classification scheme for esophageal motility disorders using metrics from high-resolution manometry (HRM). Fifty-two diverse international experts separated into seven working subgroups utilized formal validated methodologies over two-years to develop CCv4.0. Key updates in CCv.4.0 consist of a more rigorous and expansive HRM protocol that incorporates supine and upright test positions as well as provocative testing, a refined definition of esophagogastric junction (EGJ) outflow obstruction (EGJOO), more stringent diagnostic criteria for ineffective esophageal motility and description of baseline EGJ metrics. Further, the CCv4.0 sought to define motility disorder diagnoses as conclusive and inconclusive based on associated symptoms, and findings on provocative testing as well as supportive testing with barium esophagram with tablet and/or functional lumen imaging probe. These changes attempt to minimize ambiguity in prior iterations of Chicago Classification and provide more standardized and rigorous criteria for patterns of disorders of peristalsis and obstruction at the EGJ.

OBJECTIVE: To determine associations of gestational diabetes mellitus (GDM) and obesity with adverse pregnancy outcomes in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. RESEARCH DESIGN AND METHODS: Participants underwent a 75-g oral glucose tolerance test (OGTT) between 24 and 32 weeks. GDM was diagnosed post hoc using International Association of Diabetes and Pregnancy Study Groups criteria. Neonatal anthropometrics and cord serum C-peptide were measured. Adverse pregnancy outcomes included birth weight, newborn percent body fat, and cord C-peptide >90th percentiles, primary cesarean delivery, preeclampsia, and shoulder dystocia/birth injury. BMI was determined at the OGTT. Multiple logistic regression was used to examine associations of GDM and obesity with outcomes. RESULTS: Mean maternal BMI was 27.7, 13.7% were obese (BMI ≥33.0 kg/m(2)), and GDM was diagnosed in 16.1%. Relative to non-GDM and nonobese women, odds ratio for birth weight >90th percentile for GDM alone was 2.19 (1.93-2.47), for obesity alone 1.73 (1.50-2.00), and for both GDM and obesity 3.62 (3.04-4.32). Results for primary cesarean delivery and preeclampsia and for cord C-peptide and newborn percent body fat >90th percentiles were similar. Odds for birth weight >90th percentile were progressively greater with both higher OGTT glucose and higher maternal BMI. There was a 339-g difference in birth weight for babies of obese GDM women, compared with babies of normal/underweight women (64.2% of all women) with normal glucose based on a composite OGTT measure of fasting plasma glucose and 1- and 2-h plasma glucose values (61.8% of all women). CONCLUSIONS: Both maternal GDM and obesity are independently associated with adverse pregnancy outcomes. Their combination has a greater impact than either one alone.