Memorial Hospital

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is thatthere is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the completeprocess including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increasedautophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in manycases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as forreviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multipleassays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagyrelated protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

An inquiry has been made into conditions which may influence the viability of 1×1 cm areas of biopsied rabbit skin during refrigeration at 0° and 6-8°C. Since the availability of oxygen, as well as the nature of the storage medium, had an, important influence on the preservation of viability at these two temperatures, these relationships may be of interest to those wishing to store or ship tissues for surgical and other purposes. Tissues separated from the circulation rapidly become anoxemic and necrotic at room or body temperatures. This condition may be prevented in uterine or intestinal strips by oxygenation or by chilling., The survival of ligated limbs and of the cells in whole embryos, or organs, is optimal (among the widely spaced temperatures which have been studied) at 0°. At this temperature respiration is minimal, while oxygen solubility in water is twice that at 30°. Though Lambert Carrel, and Hetherington and Craig found 0 to 7° favorable for preserving the small masses of crowded cells in embryonic tissue fragments, there is considerable evidence that the thin perimeter of migrating and dividing cells in established tissue cultures has maximal longevity around 30° and are unable to re-establish growth after refrigeration for a few days., , Upon considering the fact that large tissues are killed more rapidly at higher temperatures and small groups of thinly spread cells at low temperatures, it seemed not unlikely that one of the common denominators might be a question of oxygen supply and demand. Methods. After shaving and scrubbing, the chosen area of rabbit skin was covered for 2 minutes with a wet pack of tincture of iodine diluted 1:2 in water, and again scrubbed with alcohol. The strips of biopsied skin, either full- or half-skin depth were cut into 1×1 cm pieces.

Importance: Combining biologic monoclonal antibodies with chemotherapeutic cytotoxic drugs provides clinical benefit to patients with advanced or metastatic colorectal cancer, but the optimal choice of the initial biologic therapy in previously untreated patients is unknown. Objective: To determine if the addition of cetuximab vs bevacizumab to the combination of leucovorin, fluorouracil, and oxaliplatin (mFOLFOX6) regimen or the combination of leucovorin, fluorouracil, and irinotecan (FOLFIRI) regimen is superior as first-line therapy in advanced or metastatic KRAS wild-type (wt) colorectal cancer. Design, Setting, and Participants: Patients (≥18 years) enrolled at community and academic centers throughout the National Clinical Trials Network in the United States and Canada (November 2005-March 2012) with previously untreated advanced or metastatic colorectal cancer whose tumors were KRAS wt chose to take either the mFOLFOX6 regimen or the FOLFIRI regimen as chemotherapy and were randomized to receive either cetuximab (n = 578) or bevacizumab (n = 559). The last date of follow-up was December 15, 2015. Interventions: Cetuximab vs bevacizumab combined with either mFOLFOX6 or FOLFIRI chemotherapy regimen chosen by the treating physician and patient. Main Outcomes and Measures: The primary end point was overall survival. Secondary objectives included progression-free survival and overall response rate, site-reported confirmed or unconfirmed complete or partial response. Results: Among 1137 patients (median age, 59 years; 440 [39%] women), 1074 (94%) of patients met eligibility criteria. As of December 15, 2015, median follow-up for 263 surviving patients was 47.4 months (range, 0-110.7 months), and 82% of patients (938 of 1137) experienced disease progression. The median overall survival was 30.0 months in the cetuximab-chemotherapy group and 29.0 months in the bevacizumab-chemotherapy group with a stratified hazard ratio (HR) of 0.88 (95% CI, 0.77-1.01; P = .08). The median progression-free survival was 10.5 months in the cetuximab-chemotherapy group and 10.6 months in the bevacizumab-chemotherapy group with a stratified HR of 0.95 (95% CI, 0.84-1.08; P = .45). Response rates were not significantly different, 59.6% vs 55.2% for cetuximab and bevacizumab, respectively (difference, 4.4%, 95% CI, 1.0%-9.0%, P = .13). Conclusions and Relevance: Among patients with KRAS wt untreated advanced or metastatic colorectal cancer, there was no significant difference in overall survival between the addition of cetuximab vs bevacizumab to chemotherapy as initial biologic treatment. Trial Registration: clinicaltrials.gov identifier: NCT00265850.

Department of Anaesthesia; Orillia Soldiers' Memorial Hospital; Orillia, Ontario, Canada L3V 1Y2; E-mail: oyston@oyston.comJames C. Eisenach, M.D., EditorURL: http://www3.ncbi.nlm.nih.gov/Omim/Sponsor: Johns Hopkins University, Baltimore, MarylandAuthor: Dr. Victor A. McKusick and colleaguesWeb Version: National Center for Biotechnology InformationReaders of this column may be interested in Online Mendelian Inheritance in Man (OMIM) for two reasons: Firstly, some patients have genetic conditions that must be considered when planning anesthesia. Secondly, it is an excellent demonstration of the use of the Internet to make a vast amount of medical information widely available in a format that is more convenient to use and more up-to-date than would be possible in any other way.OMIM is a database with 9,145 entries, each reviewing a specific genetic disease, which is continually being updated at the rate of 60 new entries and 500 revisions per month by Dr. Victor A. McKusick and his colleagues at Johns Hopkins University and elsewhere. It has been made freely available on the Web by the National Center for Biotechnology Information. The site begins with a warning: "OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine. Non-medical users are strongly urged to seek the assistance of an expert in the interpretation of OMIM text and images."The site consists of plain text with small link buttons. Animations, Java, frames, plug-ins, and multimedia are not used. Unfortunately, a link to the Cedars-Sinai Medical Center Genetics Image Archive was not available at the time of this review.For anesthesiologists, the most important feature is the search engine. Type in almost any variation of any name for an inherited disease, and, if spelling is correct, a link will be provided to the appropriate entry for that disease. Because many genetic syndromes have various names, this is more convenient than most textbook indices. A facility that offers alternative spelling when a search produces no results would be a useful addition.Each disease entry is presented as a Web page. A Table ofcontents provides shortcuts to sections that typically include "Clinical Features," "Diagnosis," "Clinical Management," and "References," and several sections that would only interest a geneticist, such as "Population Genetics." A clinical synopsis is sometimes available as a separate Web page.Each entry is referenced heavily, with links from the text to the relevant PubMed abstract. The full text can be ordered online through "Loansome Doc." There are extensive links to MEDLINE and to other genetics resources. Each page has a link to a form that can be used to add comments or new information.I compared OMIM to two standard anesthetic textbooks, Anesthesia and Co-Existing Disease, 3rd edition, 1993, by Stoelting and Dierdorf, and Anesthesia and Uncommon Diseases, 4th edition, 1998, by Benumof. I searched each resource for information about five genetic conditions of interest to anesthetists, which I saw recently in the preadmission clinic.The anesthetic textbooks both had extensive and detailed accounts of this condition, indexed under both words. OMIM has 11 pages about "hyperthermia of anesthesia." This contains a good history of the disease from the first case report in 1962 to recent developments, but no practical information for anesthesiologists. There was no link to clinical resources such as the Malignant Hyperthermia Association of the United States Emergency Hotline.The anesthetic texts mentioned pseudocholinesterase only in the context of liver disease. OMIM had no relevant information. Perhaps an inherited enzyme deficiency is not really a disease, but it was surprising that none of the resources mentioned this condition.Both anesthetic textbooks had more than a page of information, although Anesthesia and Uncommon Diseases indexed acute intermittent porphyria under "H" for "hepatic porphyrias." Both textbooks listed safe and unsafe anesthetic drugs. OMIM has 23 pages of text with 82 references. Although the section about clinical features mentions that attacks can be precipitated by barbiturates or sulfonamides, there was not enough information to plan a safe anesthetic.Both anesthetic texts had brief entries that mentioned difficult tracheal intubation and the risk of malignant hyperthermia. OMIM produced five pages of information, including 26 references (compared with five between the two textbooks), but none of the references were to anesthesia journals, and there was no mention of difficult tracheal intubation or malignant hyperthermia.Anesthesia and Co-Existing Disease had 134 words, half of which was about anesthetic implications, indexed under both names, whereas Anesthesia and Uncommon Diseases provided 118 words, indexed only under "Osler-Weber-Rendu." Each had one reference. OMIM had 16 pages and 82 references. An extensive history section included fascinating nuggets, including the correct pronunciation ("OHz-ler, ren-DYU, and VAY-ber"), with a note that Weber "pronounced his name in the Germanic manner even though he was born in England."OMIM is an invaluable resource for physicians dealing with patients with genetic diseases. It uses the Web to make medical information accessible in a way that should inspire other specialties to develop similar resources. Although it does not contain enough anesthesia-related information to act as a sole source of information about genetic conditions for anesthesiologists, it would be of great benefit to any anesthesiologist writing a consult note, preparing rounds, or publishing a case report about a patient with an inheritable condition.John Oyston, M.B., B.S., F.F.A.R.C.S.Department of Anaesthesia; Orillia Soldiers' Memorial Hospital; Orillia, Ontario, Canada L3V 1Y2; E-mail: oyston@oyston.com

Sixty-six cases of aneurysmal bone cyst were reviewed clinically, pathologically and radiologically. Different therapies, including curettage, block excision, amputation and radiation therapy, and a new treatment, cryosurgery, were employed. Cryosurgery, which avoids the growth and neoplastic complications of radiation therapy and the loss of bone with block excision, had an extremely low rate of recurrence when compared to simple curettage. In manometric studies of 6 cysts, 3 had elevated vascular pressures as high as arteriolar levels. Thirty-two percent of the aneurysmal bone cysts had an accompanying benign primary lesion of bone. Based on these findings, a new hypothesis for the etiology and pathogenesis of aneurysmal bone cysts was proposed: a primary lesion of bone initiates an osseous, arteriovenous fistula and thereby creates, via its hemodynamic forces, the secondary reactive lesion of bone, which we term aneurysmal bone cyst.

Optimal management of neuropathic pain is a major clinical challenge. We investigated the involvement of c-Jun N-terminal kinase (JNK) in neuropathic pain produced by spinal nerve ligation (SNL) (L5). SNL induced a slow (>3 d) and persistent (>21 d) activation of JNK, in particular JNK1, in GFAP-expressing astrocytes in the spinal cord. In contrast, p38 mitogen-activated protein kinase activation was found in spinal microglia after SNL, which had fallen to near basal level by 21 d. Intrathecal infusion of a JNK peptide inhibitor, D-JNKI-1, did not affect normal pain responses but potently prevented and reversed SNL-induced mechanical allodynia, a major symptom of neuropathic pain. Intrathecal D-JNKI-1 also suppressed SNL-induced phosphorylation of the JNK substrate, c-Jun, in spinal astrocytes. However, SNL-induced upregulation of GFAP was not attenuated by spinal D-JNKI-1 infusion. Furthermore, SNL induced a rapid (<12 h) but transient activation of JNK in the L5 (injured) but not L4 (intact) DRG. JNK activation in the DRG was mainly found in small-sized C-fiber neurons. Infusion of D-JNKI-1 into the L5 DRG prevented but did not reverse SNL-induced mechanical allodynia. Finally, intrathecal administration of an astroglial toxin, l-alpha-aminoadipate, reversed mechanical allodynia. Our data suggest that JNK activation in the DRG and spinal cord play distinct roles in regulating the development and maintenance of neuropathic pain, respectively, and that spinal astrocytes contribute importantly to the persistence of mechanical allodynia. Targeting the JNK pathway in spinal astroglia may present a new and efficient way to treat neuropathic pain symptoms.

BACKGROUND: Elderly patients (ages 70 yr and older) are among the fastest-growing group starting renal-replacement therapy in the United States. The outcomes of elderly patients who receive a kidney transplant have not been well studied compared with those of their peers on the waiting list. METHODS: Using the Scientific Registry of Transplant Recipients, we analyzed data from 5667 elderly renal transplant candidates who initially were wait-listed from January 1, 1990 to December 31, 2004. Of these candidates, 2078 received a deceased donor transplant, and 360 received a living donor transplant by 31 December 2005. Time-to-death was studied using Cox regression models with transplant as a time-dependent covariate. Mortality hazard ratios (RRs) of transplant versus waiting list were adjusted for recipient age, sex, race, ethnicity, blood type, panel reactive antibody, year of placement on the waiting list, dialysis modality, comorbidities, donation service area, and time from first dialysis to first placement on the waiting list. RESULTS: Elderly transplant recipients had a 41% lower overall risk of death compared with wait-listed candidates (RR=0.59; P<0.0001). Recipients of nonstandard, that is, expanded criteria donor, kidneys also had a significantly lower mortality risk (RR=0.75; P<0.0001). Elderly patients with diabetes and those with hypertension as a cause of end-stage renal disease also experienced a large benefit. CONCLUSIONS: Transplantation offers a significant reduction in mortality compared with dialysis in the wait-listed elderly population with end-stage renal disease.

BACKGROUND: The purposes of this retrospective study were to review the results of isolated subtalar arthrodesis in adults and to identify factors influencing the union rate. The hypotheses were that (1) the overall outcome is acceptable but is not as favorable as previously reported, (2) complication rates, especially the nonunion rate, are higher than previously reported, and (3) factors contributing to a less favorable union rate can be identified. METHODS: Between January 1988 and July 1995, 184 consecutive isolated subtalar arthrodeses were performed in 174 adults (115 men and fifty-nine women) whose average age was forty-three years (range, eighteen to seventy-nine years). Eighty patients (46 percent) were smokers. The indications for the procedure included posttraumatic arthritis after a fracture of the calcaneus (109 feet), a fracture of the talus (thirteen feet), or a subtalar dislocation (thirteen feet); primary subtalar arthritis (thirteen feet); failure of a previous subtalar arthrodesis (twenty-eight feet); and residual congenital deformity (eight feet). Rigid internal fixation with one or two screws was used for all feet. Bone graft was used in 145 feet; the types of graft material included cancellous autograft (ninety-four feet), structural autograft (twenty-nine feet), cancellous allograft (seventeen feet), and structural allograft (five feet). Bone graft was not used in the remaining thirty-nine feet. RESULTS: Clinical and radiographic follow-up examinations were performed for 148 (80 percent) of the 184 feet at an average of fifty-one months (range, twenty-four to 130 months) postoperatively. The average ankle-hindfoot score according to the modified scale of the American Orthopaedic Foot and Ankle Society (maximum possible score, 94 points) improved from 24 points preoperatively to 70 points at follow-up. Thirty feet had clinical evidence of nonunion. The union rate was 84 percent (154 of 184) overall, 86 percent (134 of 156) after primary arthrodesis, and 71 percent (twenty of twenty-eight) after revision arthrodesis. The union rate was 92 percent (ninety-three of 101 feet) for nonsmokers and 73 percent (sixty-one of eighty-three feet) for smokers (p < 0.05). Intraoperative inspection revealed that 42 percent (seventy-eight) of the 184 feet had evidence of more than two millimeters of avascular bone at the subtalar joint; all thirty nonunions occurred in this group (p < 0.05). A nonunion occurred in three of the five feet that had been treated with structural allograft and in two of the six feet in which the subtalar arthrodesis had been performed adjacent to the site of a previous ankle arthrodesis. After elimination of the subgroups of feet in patients who smoked, those that had had a failure of a previous subtalar arthrodesis, those that had been treated with a structural graft, and those that had had the subtalar arthrodesis adjacent to the site of a previous ankle arthrodesis, the union rate improved to 96 percent (seventy-three of seventy-six). Complications other than nonunion included prominent hardware requiring screw removal (thirty-six of 184 feet; 20 percent), lateral impingement (fifteen of 148 feet; 10 percent), symptomatic valgus malalignment (five of 148 feet; 3 percent), symptomatic varus malalignment (four of 148 feet; 3 percent), and infection (five of 184 feet; 3 percent). CONCLUSIONS: To the best of our knowledge, the present study includes the largest reported series of isolated subtalar arthrodeses in adults. Our results suggest that the outcome following isolated subtalar arthrodesis is not as favorable as has been reported in previous studies. The rate of union was significantly diminished by smoking, the presence of more than two millimeters of avascular bone at the arthrodesis site, and the failure of a previous subtalar arthrodesis (p < 0.05 for all). Other factors that probably affect the union rate include the use of structural allograft and performance of the arthrodesis adjac

BACKGROUND AND PURPOSE: This prospective clinical investigation examined the effects of a multidimensional exercise program on balance, mobility, and risk for falls in community-dwelling older adults with a history of falling. Factors used to predict adherence and a successful response to exercise were identified. SUBJECTS: A total of 105 community-dwelling older adults (> or = 65 years of age) with a history of two or more falls in the previous 6 months (no neurologic diagnosis) participated. They were classified into (1) a control group of fallers (n = 21), (2) a fully adherent exercise group (n = 52), and (3) a partially adherent exercise group (n = 32). METHODS: Following evaluation, each patient received an individualized exercise program addressing the impairments and functional disabilities identified during the assessment. The control group received no intervention. Changes in performance on five clinical tests of balance and mobility and fall risk were compared among groups. RESULTS: Both exercise groups scored better than the control group on all measures of balance and mobility. Although both exercise groups showed a reduction in fall risk compared with the control group, the greatest reduction was found in the fully adherent exercise group. Factors associated with successful response to exercise included degree of adherence to exercise program and pretest score on the Tinetti Mobility Assessment. CONCLUSION AND DISCUSSION: Exercise can improve balance and mobility function and reduce the likelihood for falls among community-dwelling older adults with a history of falling. The amount of exercise needed to achieve these results, however, could not be determined from this study.

The incretin system has become an important target in the treatment of type 2 diabetes in recent years, and glucagon-like peptide 1 (GLP-1) is of particular interest for its glucose-lowering effects. The physiological response to oral ingestion of nutrients, involving the incretin system, is reduced in some patients with type 2 diabetes but may be augmented by administration of GLP-1 receptor agonists. The GLP-1 receptor agonists currently approved in the United States for the treatment of type 2 diabetes include exenatide (administered twice daily), liraglutide and lixisenatide (administered once daily), and the once-weekly agents exenatide extended-release, albiglutide, and dulaglutide. These agents have been shown to reduce A1C (by ∼0.8-1.6%), body weight (by ∼1-3 kg), blood pressure, and lipids. GLP-1 receptor agonists are associated with a low risk of hypoglycemia, and the most common adverse effects are gastrointestinal. Proper patient selection and education can assist in achieving positive treatment outcomes.

Summary and conclusionsDifferentiation between life and death in unicellular beings should be based upon criteria which are more convenient and fundamental than measurements of capacity for growth. The principle of ion (eosin) exclusion has been substantiated as a simple, rapid tool for this purpose. The conditions for valid observations in cell and tissue cultures have been delineated in respect to: eosin, serum and electrolyte concentrations. These simplified methods have replaced cultivation procedures in studies on: the effects of exposure to pancreatin and to drying, and the exposure of sensitive cells to tuberculin; storage of stock suspensions of cells without renewal of medium; and use of such methods for investigating nutritional or metabolic requirements.

The laser sheath uses optical fibers, delivering pulsed ultraviolet excimer laser light, to vaporize fibrotic tissue binding intravenous cardiac leads to the vein or heart wall during lead extraction from the implant vein. The total investigational experience with laser sheaths is reported. During the period from October 1995 to December 1999, 2,561 pacing and defibrillator leads were treated in 1,684 patients at 89 sites in the United States with three sizes of laser sheath. Endpoints were complete removal of the lead, partial removal (leaving the tip behind), or failure (abandoning the lead, onset of complications, change to transfemoral or transatrial approach). Minimal follow-up at 30 days was recorded. Of the leads, 90% were completely removed, 3% were partially removed, and the balance were failures. Major perioperative complications (tamponade, hemothorax, pulmonary embolism, lead migration, and death) were observed in 1.9% of patients with in hospital death in 13 (0.8%). Minor complications were seen in an additional 1.4% of patients. Multivariate analysis showed that implant duration was the only preoperative independent predictor of failure; female sex was the only multivariate predictor of complications. Success and complications were not dependent on laser sheath size. At follow-up, various extraction related complications were observed in 2% of patients. The learning curve showed a trend toward fewer complications with experience. Lead extraction with the laser sheath can be safely practiced with high success rates. Success is independent of laser sheath size. Major complications can be expected in < 2% of patients, and occur more often during an investigator's early experience.

From December 1988 to April 1994, the extraction of 2,195 intravascular pacing leads from 1,299 patients was attempted at 193 centers. Indications were: infection (54%, including 10% septicemia), pacemaker reoperation with removal of nonfunctional or incompatible leads (40%), and other causes (6%). Extraction was attempted via the implant vein using locking stylets and dilator sheaths, via the femoral vein using snares, retrieval baskets, and sheaths, or via both approaches. Leads had been implanted for 0.2 months to 24 years (mean 56 months). At the conclusion of the intravascular procedure, 86.8% of the leads were completely removed, 7.5% were partially removed, and 5.7% were not removed. For physicians performing their first case, 12% of leads were not removed; for physicians who had performed more than 10 cases, only 2% of leads were not removed. Of the 189 leads where extraction attempts had previously failed, 75.1% were completely removed, 14.8% were partially removed, and 10.1% were not removed. Scar tissue increased in severity with implant duration, was a complicating factor, and was the main cause of failure to remove leads. Use of the femoral approach increased with implant duration (5% of leads implanted 12 months or less, 11% of leads 13 months to 3 years, 20% of leads 4-7 years, and 31% of leads 8-24 years), primarily because of increasingly abundant scarring and prior lead damage. Fatal and near fatal complications occurred in 2.5%, including 8 (0.6%) deaths (3 hemopericardium/tamponade, 1 hemothorax, 3 pulmonary embolus, 1 stroke).(ABSTRACT TRUNCATED AT 250 WORDS)

BACKGROUND: Mobile stroke units (MSUs) are ambulances with staff and a computed tomographic scanner that may enable faster treatment with tissue plasminogen activator (t-PA) than standard management by emergency medical services (EMS). Whether and how much MSUs alter outcomes has not been extensively studied. METHODS: In an observational, prospective, multicenter, alternating-week trial, we assessed outcomes from MSU or EMS management within 4.5 hours after onset of acute stroke symptoms. The primary outcome was the score on the utility-weighted modified Rankin scale (range, 0 to 1, with higher scores indicating better outcomes according to a patient value system, derived from scores on the modified Rankin scale of 0 to 6, with higher scores indicating more disability). The main analysis involved dichotomized scores on the utility-weighted modified Rankin scale (≥0.91 or <0.91, approximating scores on the modified Rankin scale of ≤1 or >1) at 90 days in patients eligible for t-PA. Analyses were also performed in all enrolled patients. RESULTS: We enrolled 1515 patients, of whom 1047 were eligible to receive t-PA; 617 received care by MSU and 430 by EMS. The median time from onset of stroke to administration of t-PA was 72 minutes in the MSU group and 108 minutes in the EMS group. Of patients eligible for t-PA, 97.1% in the MSU group received t-PA, as compared with 79.5% in the EMS group. The mean score on the utility-weighted modified Rankin scale at 90 days in patients eligible for t-PA was 0.72 in the MSU group and 0.66 in the EMS group (adjusted odds ratio for a score of ≥0.91, 2.43; 95% confidence interval [CI], 1.75 to 3.36; P<0.001). Among the patients eligible for t-PA, 55.0% in the MSU group and 44.4% in the EMS group had a score of 0 or 1 on the modified Rankin scale at 90 days. Among all enrolled patients, the mean score on the utility-weighted modified Rankin scale at discharge was 0.57 in the MSU group and 0.51 in the EMS group (adjusted odds ratio for a score of ≥0.91, 1.82; 95% CI, 1.39 to 2.37; P<0.001). Secondary clinical outcomes generally favored MSUs. Mortality at 90 days was 8.9% in the MSU group and 11.9% in the EMS group. CONCLUSIONS: In patients with acute stroke who were eligible for t-PA, utility-weighted disability outcomes at 90 days were better with MSUs than with EMS. (Funded by the Patient-Centered Outcomes Research Institute; BEST-MSU ClinicalTrials.gov number, NCT02190500.).

While investigating the systemic effects of hista- mine in man, Weiss and his co-workers (1, 2) ob-

INFECTION with Toxoplasma gondii exists in chronic asymptomatic form in approximately 50 per cent of the population in the United States. T. gondii is clinically important in the adult for three major reasons: it may cause lymphadenopathy; as an opportunist, it may cause a lethal infection in the immunologically compromised host; and it is responsible for at least 3000 congenitally infected infants in the United States yearly, thus making correct interpretation of serologic tests in the woman who is pregnant (or thinking of becoming so) an urgent matter.1 , 2 Life CycleThe protozoan T. gondii is found throughout the world in . . .

IT is the purpose of this report to describe the clinical and functional aspects of the renal disease associated with potassium depletion in man, and to correlate these with the histologic changes found in renal tissue obtained by serial biopsies.It is well known that experimental depletion of potassium produces renal tubular lesions in rats.1 2 3 Although there have been a few recent reports of renal lesions in human subjects dying with potassium deficiency,4 5 6 7 the clinical and physiologic implications of the renal damage have not received attention until recently. A previous report8 described 2 patients in whom marked but apparently reversible . . .

Cell size and number of three adipose depots, epididymal, retroperitoneal, and subcutaneous, were determined during growth of the obese Zucker rat ("fatty") and nonobese Zucker control. Cellularity of these depots in the adult "fatty" was compared with that in nonobese controls and in nonobese Zucker rats made obese by ventromedial hypothalamic lesions. Epididymal and retroperitoneal depots in the nonobese rat grew by cell enlargement and increase in cell number until the 14th wk, when number became fixed; further increase in depot size occurred by cell enlargement. The subcutaneous depot added cells until the 26th wk. In the Zucker "fatty," cell number increased until the 26th wk in all depots, accompanied by extreme cell enlargement. The enlarged adipose depots of the adult Zucker "fatty," when compared with the nonobese control, are the result of both hypertrophy and hyperplasia. Depot enlargement in the lesioned animal is the result of hypertrophy. "Fatties" have more cells in adipose depots than do lesioned rats. Genetic obesity in the Zucker rat is clearly different from the obesity produced by hypothalamic lesioning.

DISORDERS of acid–base equilibrium can be caused by primary disturbances in the pulmonary regulation of the concentration of carbonic acid in body fluids, by changes in the concentration of bicarbonate and other buffer anions induced by metabolic disturbances or by some combination of the two. The degree and direction of primary respiratory disturbances can be evaluated by the determination of carbon dioxide tension (pCO2) in the blood, since this quantity is directly proportional to the actual amount of dissolved carbonic acid. For the assessment of metabolic disturbances, Van Slyke and Cullen1 proposed many years ago that the bicarbonate . . .

Importance: Studies showing that patients with cancer from rural areas have worse outcomes than their urban counterparts have relied on cancer population data and did not account for differences in access to care. Clinical trial patients receive protocol-directed care by design, so large clinical trial databases are ideal for examining the impact of rural vs urban residency on outcomes. Objective: To compare the geographic distribution and survival outcomes for rural vs urban patients with cancer treated in clinical trials. Design, Setting, and Participants: In this comparative effectiveness retrospective cohort analysis, 36 995 patients from all 50 states enrolled in 44 phase 3 and phase 2/3 SWOG (formerly the Southwest Oncology Group) treatment trials from January 1, 1986, to December 31, 2012, were examined. Seventeen different cancer-specific analysis cohorts were constructed. Data through January 30, 2018, were analyzed. Main Outcomes and Measures: Rural vs urban residency was defined using the Rural-Urban Continuum Codes developed by the US Department of Agriculture. Multivariate Cox regression was used to estimate the association of residency with overall survival, progression-free survival, and cancer-specific survival, controlling for major disease-specific prognostic factors and demographic variables and stratifying by study. Different definitions of rurality were examined. The distribution of rural vs urban patients by geographic region was described. Results: Overall, 27.7% of patients were 65 years or older (range across 17 cohort analyses, 7.8%-74.5%), 40.3% were female in the non-sex-specific analyses (range across 17 cohort analyses, 28.1%-45.9%), and 10.8% were black (range across 17 cohort analyses, 1.9%-22.4%). Overall, 19.4% of patients (7184 of 36 995) were from rural locations. Rural patients were more likely to be aged 65 years or older (rural, 30.7% aged ≥65 years vs urban, 27.0% aged ≥65 years; difference, 3.7%; 95% CI, 2.5%-4.9%; P < .001), were less likely to be black (rural, 5.4% vs urban, 12.1%; difference, 6.7%; 95% CI, 6.1%-7.3%; P < .001), were similar with respect to sex (rural, 40.4% female vs urban, 39.7% female; difference, 0.6%; 95% CI, -1.4% to 2.6%; P = .53), and were well represented within major US geographic regions (West, Midwest, South, and Northeast). Clinical prognostic factors were similar. In multivariable regression, rural patients with adjuvant-stage estrogen receptor-negative and progesterone receptor-negative breast cancer had worse overall survival (hazard ratio, 1.27; 95% CI, 1.06-1.51; P = .008) and cancer-specific survival (hazard ratio, 1.26; 95% CI, 1.04-1.52; P = .02). No other statistically significant differences for overall, progression-free, or cancer-specific survival were found. Results were consistent regardless of the definition of rurality. Conclusions and Relevance: Rural and urban patients with uniform access to cancer care through participation in a SWOG clinical trial had similar outcomes. This finding suggests that improving access to uniform treatment strategies for patients with cancer may help resolve the disparity in cancer outcomes between rural and urban patients.