Sinai Grace Hospital

The present review focuses on the hypothesized D1/D2 dopamine (DA) receptor classification, originally based on the form of receptor coupling to adenylate cyclase activity. The pharmacological effects of compounds exhibiting putative selective agonist or antagonist profiles at those DA receptors positively coupled to adenylate cyclase activity (D1 DA receptors) are extensively reviewed. Comparisons are made with the effects of putative selective D2 DA receptor agonists and antagonists, and on the basis of this work, the DA receptor classification is critically evaluated. A variety of biochemical, behavioral, and electrophysiological evidence is presented which supports the view that D1 and D2 DA receptors can interact in both an opposing and synergistic fashion. Particular attention is focused on the possibility that D1 receptor stimulation is required to enable the expression of certain D2 receptor-mediated effects, and the functional consequences of this form of interaction are considered. A hypothetical model is presented which considers how both the opposing and enabling forms of interaction between D1 and D2 DA receptors can control behavioral expression. Finally, the clinical relevance of this work is discussed and the potential use of selective D1 receptor agonists and antagonists in the treatment of psychotic states and Parkinson's disease is considered.

Our laboratory has previously demonstrated that increased malignancy of several histological types of human and animal tumours is associated with increases in their cathepsin B activity, particularly cathepsin B activity associated with plasma-membrane/endosomal vesicles or shed vesicles. Here we report that cathepsin B from normal or tumour tissues degrades purified extracellular-matrix components, type IV collagen, laminin and fibronectin, at both acid pH and neutral pH. The number and sizes of degradation products were analysed by SDS/PAGE. Cathepsin B from both sources exhibited similar activities towards, and similar patterns of cleavage of, the extracellular-matrix proteins. At neutral pH, cathepsin B from both sources appeared to undergo autodegradation, a process that was decreased in the presence of alternative substrates such as the extracellular-matrix proteins. Cathepsin B readily degraded type IV collagen at 25 degrees C, indicating activity towards native type IV collagen. Fibronectin degradation products of 100-200 kDa and of 18 and 22 kDa were observed. A single 70 kDa fragment was released from laminin under non-reducing conditions and multiple fragments ranging from 45 to 200 kDa under reducing conditions. These results suggest that cathepsin B at or near the surface of malignant tumour cells may play a functional role in the focal dissolution of extracellular matrices.

In a randomized series of 70 patients with with colo rectal adenocarcinoma, a comparison of systemic 5-fluorouracil chemotherapy administered as a continuous 120-hours infusion vs. intravenous bolus injection daily for 5 days demonstrated superiority of prolonged intravenous infusion. The most striking advantage of prolonged infusion of 5-FU was the absence of myelotoxicity. Fifteen of the 34 patients treated with infusion and 8 of the 36 patients treated by bolus injection developed objective tumor responses. The difference in response rate at least in part is explainable by unequal distribution of patients with different characteristics between the two treatment groups.

Infections caused by resistant gram-negative bacteria are becoming increasingly prevalent and now constitute a serious threat to public health worldwide because they are difficult to treat and are associated with high morbidity and mortality rates. In the United States, there has been a steady increase since 2000 in rates of extended-spectrum β-lactamase-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and multidrug-resistant strains of Pseudomonas aeruginosa and Acinetobacter baumannii, particularly among hospitalized patients with intraabdominal infections, urinary tract infections, ventilator-associated pneumonia, and bacteremia. Colonization with resistant gram-negative bacteria is common among residents in long-term care facilities (particularly those residents with an indwelling device), and these facilities are considered important originating sources of such strains for hospitals. Antibiotic resistance is associated with a substantial clinical and economic burden, including increased mortality, greater hospital and antibiotic costs, and longer stays in hospitals and intensive care units. Control of resistant gram-negative infections requires a comprehensive approach, including strategies for risk factor identification, detection and identification of resistant organisms, and implementation of infection-control and prevention strategies. In treating resistant gram-negative infections, a review of surveillance data and hospital-specific antibiograms, including resistance patterns within local institutions, and consideration of patient characteristics are helpful in guiding the choice of empiric therapy. Although only a few agents are available with activity against resistant gram-negative organisms, two recently released β-lactam/β-lactamase inhibitor combinations - ceftolozane/tazobactam and ceftazidime/avibactam - have promising activity against these organisms. In this article, we review the epidemiology, risk factors, and antibiotic resistance mechanisms of gram-negative organisms. In addition, an overview of treatment options for patients with these infections is provided.

OBJECTIVES: No single universal definition of emergency department (ED) overcrowding exists. The authors hypothesize that a previously developed site-sampling form for academic ED overcrowding is a valid model to quantify overcrowding in academic institutions and can be used to develop a validated short form that correlates with overcrowding. METHODS: A 23-question site-sampling form was designed based on input from academic physicians at eight medical schools representative of academic EDs nationwide. A total of 336 site-samplings at eight academic medical centers were conducted at 42 computer-generated random times over a three-week period by independent observers at each site. These sampling times ranged from very slow to severely overcrowded. The outcome variable was the degree of overcrowding as assessed by the charge nurse and ED physicians. The full model consisted of objective data that were obtained by counting the number of patients, determining patients' waiting times, and obtaining information from registration, triage, and ancillary services. Specific objective data were indexed to site-specific demographics. The outcome and objective data were compared using a multiple linear regression to determine predictive validity of the full model. A five-question reduced model was calculated using a backward stepdown procedure. Predictive validity and relationships between the outcome and objective data were assessed using a mixed-effects linear regression model, treating center as random effect. RESULTS: Overcrowding occurred 12% to 73% of the time (mean, 35%), with two hospitals being overcrowded more than 50% of the time. Comparison of objective and outcome data resulted in an R(2) of 0.49 (p < 0.001), indicating a good degree of predictive validity. A reduced five-question model predicted the full model with 88% accuracy. CONCLUSIONS: Overcrowding varied widely between academic centers during the study period. Results of a five-question reduced model are valid and accurate in predicting the degree of overcrowding in academic centers.

BACKGROUND: Colistin, originally abandoned due to high rates of nephrotoxicity, has been recently reintroduced due to activity against carbapenem-resistant Gram-negative organisms. Recent literature, largely obtained from outside the United States, suggests a lower rate of nephrotoxicity than historically reported. METHODS: A retrospective cohort of all patients who received colistin for ≥ 48 hours at the Detroit Medical Center over a 5-year period was performed to determine the rate of colistin-associated nephrotoxicity as defined by the RIFLE criteria. RESULTS: Fifty-four (43%) patients in the cohort developed nephrotoxicity. Patients who experienced nephrotoxicity after colistin administration were in the Risk (13%), Injury (17%), or Failure (13%) categories per RIFLE criteria. Patients who developed nephrotoxicity received significantly higher mean doses than those who did not (5.48 mg/kg per day vs 3.95 mg/kg per day; P < .001), and the toxicity occurred in a dose-dependent fashion. Independent predictors for nephrotoxicity were a colistin dose of ≥ 5.0 mg/kg per day of ideal body weight (odds ratio [OR], 23.41; 95% confidence interval [CI], 5.3-103.55), receipt of concomitant rifampin (OR, 3.81; 95% CI, 1.42-10.2), and coadministration of ≥ 3 concomitant nephrotoxins (OR, 6.80; 95% CI, 1.42-32.49). CONCLUSIONS: In this retrospective cohort, nephrotoxicity (as defined by RIFLE criteria) occurred among 43% of treated patients in a dose-dependent manner. Higher colistin doses, similar to those commonly used in the United States, led to a relatively high rate of nephrotoxicity. These data raise important questions regarding the safe use of colistin in the treatment of multidrug-resistant pathogens.

Abstract: The brain requires a ready supply of iron for normal neurological function, but free iron is toxic. Consequently, iron bioavailability must be stringently regulated. Recent evidence has suggested that the brain iron regulatory system is dysfunctional in neurological disorders such as Alzheimer's and Parkinson's diseases (AD and PD, respectively). A key component of the iron regulatory system in the brain is ferritin. Ferritin consists of 24 subunits, which are distinguished as either a heavy‐chain (H) or light‐chain (L) isoform. These peptide subunits are genetically and functionally distinct. Thus, the ability to investigate separately the types of ferritin in brain should provide insight into iron management at both the cellular and the molecular level. In this study, the ratio of isoferritins was determined in select regions of adult elderly AD and PD human brains. The H‐rich ferritin was more abundant in the young brain, except in the globus pallidus where the ratio of H/L ferritin was 1:1. The balance of H/L isoferritins was influenced by age, brain region, and disease state. With normal aging, both H and L ferritin increased; however, the age‐associated increase in isoferritins generally failed to occur in AD and PD brain tissue. The imbalance in H/L isoferritins was disease and region specific. For example, in frontal cortex, there was a dramatic (fivefold) increase in the ratio of H/L ferritin in AD brains but not in PD brains. In PD, caudate and putamen H/L ratios were higher than in AD and the elderly control group. The analysis of isoferritin expression in brain provides insight into regional iron regulation under normal conditions and suggests a loss of ability to maintain iron homeostasis in the two disease states. This latter observation provides further evidence of dysfunction of iron homeostatic mechanisms in AD and PD and may contribute significantly to understanding the underlying pathogenesis of each, particularly in relation to iron‐induced oxidative damage.

OBJECTIVES: To prospectively validate that the inability to decrease procalcitonin levels by more than 80% between baseline and day 4 is associated with increased 28-day all-cause mortality in a large sepsis patient population recruited across the United States. DESIGN: Blinded, prospective multicenter observational clinical trial following an Food and Drug Administration-approved protocol. SETTING: Thirteen U.S.-based emergency departments and ICUs. PATIENTS: Consecutive patients meeting criteria for severe sepsis or septic shock who were admitted to the ICU from the emergency department, other wards, or directly from out of hospital were included. INTERVENTIONS: Procalcitonin was measured daily over the first 5 days. MEASUREMENTS AND MAIN RESULTS: The primary analysis of interest was the relationship between a procalcitonin decrease of more than 80% from baseline to day 4 and 28-day mortality using Cox proportional hazards regression. Among 858 enrolled patients, 646 patients were alive and in the hospital on day 4 and included in the main intention-to-diagnose analysis. The 28-day all-cause mortality was two-fold higher when procalcitonin did not show a decrease of more than 80% from baseline to day 4 (20% vs 10%; p = 0.001). This was confirmed as an independent predictor in Cox regression analysis (hazard ratio, 1.97 [95% CI, 1.18-3.30; p < 0.009]) after adjusting for demographics, Acute Physiology and Chronic Health Evaluation II, ICU residence on day 4, sepsis syndrome severity, antibiotic administration time, and other relevant confounders. CONCLUSIONS: Results of this large, prospective multicenter U.S. study indicate that inability to decrease procalcitonin by more than 80% is a significant independent predictor of mortality and may aid in sepsis care.

BACKGROUND: Sepsis is a common condition encountered by emergency and critical care physicians, with significant costs, both economic and human. Myocardial dysfunction in sepsis is a well-recognized but poorly understood phenomenon. There is an extensive body of literature on this subject, yet results are conflicting and no objective definition of septic cardiomyopathy exists, representing a critical knowledge gap. OBJECTIVES: In this article, we review the pathophysiology of septic cardiomyopathy, covering the effects of key inflammatory mediators on both the heart and the peripheral vasculature, highlighting the interconnectedness of these two systems. We focus on the extant literature on echocardiographic and laboratory assessment of the heart in sepsis, highlighting gaps therein and suggesting avenues for future research. Implications for treatment are briefly discussed. CONCLUSIONS: As a result of conflicting data, echocardiographic measures of left ventricular (systolic or diastolic) or right ventricular function cannot currently provide reliable prognostic information in patients with sepsis. Natriuretic peptides and cardiac troponins are of similarly unclear utility. Heterogeneous classification of illness, treatment variability, and lack of formal diagnostic criteria for septic cardiomyopathy contribute to the conflicting results. Development of formal diagnostic criteria, and use thereof in future studies, may help elucidate the link between cardiac performance and outcomes in patients with sepsis.

IMPORTANCE: The combination of ascorbic acid, corticosteroids, and thiamine has been identified as a potential therapy for septic shock. OBJECTIVE: To determine whether the combination of ascorbic acid, corticosteroids, and thiamine attenuates organ injury in patients with septic shock. DESIGN, SETTING, AND PARTICIPANTS: Randomized, blinded, multicenter clinical trial of ascorbic acid, corticosteroids, and thiamine vs placebo for adult patients with septic shock. Two hundred five patients were enrolled between February 9, 2018, and October 27, 2019, at 14 centers in the United States. Follow-up continued until November 26, 2019. INTERVENTIONS: Patients were randomly assigned to receive parenteral ascorbic acid (1500 mg), hydrocortisone (50 mg), and thiamine (100 mg) every 6 hours for 4 days (n = 103) or placebo in matching volumes at the same time points (n = 102). MAIN OUTCOMES AND MEASURES: The primary outcome was change in the Sequential Organ Failure Assessment (SOFA) score (range, 0-24; 0 = best) between enrollment and 72 hours. Key secondary outcomes included kidney failure and 30-day mortality. Patients who received at least 1 dose of study drug were included in analyses. RESULTS: Among 205 randomized patients (mean age, 68 [SD, 15] years; 90 [44%] women), 200 (98%) received at least 1 dose of study drug, completed the trial, and were included in the analyses (101 with intervention and 99 with placebo group). Overall, there was no statistically significant interaction between time and treatment group with regard to SOFA score over the 72 hours after enrollment (mean SOFA score change from 9.1 to 4.4 [-4.7] points with intervention vs 9.2 to 5.1 [-4.1] points with placebo; adjusted mean difference, -0.8; 95% CI, -1.7 to 0.2; P = .12 for interaction). There was no statistically significant difference in the incidence of kidney failure (31.7% with intervention vs 27.3% with placebo; adjusted risk difference, 0.03; 95% CI, -0.1 to 0.2; P = .58) or in 30-day mortality (34.7% vs 29.3%, respectively; hazard ratio, 1.3; 95% CI, 0.8-2.2; P = .26). The most common serious adverse events were hyperglycemia (12 patients with intervention and 7 patients with placebo), hypernatremia (11 and 7 patients, respectively), and new hospital-acquired infection (13 and 12 patients, respectively). CONCLUSIONS AND RELEVANCE: In patients with septic shock, the combination of ascorbic acid, corticosteroids, and thiamine, compared with placebo, did not result in a statistically significant reduction in SOFA score during the first 72 hours after enrollment. These data do not support routine use of this combination therapy for patients with septic shock. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03389555.

Incidence and distribution of adenomatous polyps of the colon and rectum based on 1,000 autopsy examinations: PDF Only

†Department of Orthopaedics, Grace Hospital, 6071 West Outer Drive, Detroit, Michigan 48235. E-mail address for Dr. Koman: [email protected] ‡Shriners Hospital for Children, 1645 West Eighth Street, Erie, Pennsylvania 16505.

When murine leukemia L1210 cells are exposed to certain porphyrins, in the presence of light, a rapid loss of cell viability occurs. We have examined structure-activity relationships, using a series of porphyrins, and have studied early effects of these agents, to elucidate their mode of action. In the system employed here, only water-soluble porphyrins were cytotoxic. The first step in cytotoxicity involved binding of porphyrin to the cell surface. Porphyrins unable to bind were inactive. An important determinant of drug binding was the partition coefficient of a porphyrin between octanol and water. In the presence of light, presumably via a singlet oxygen intermediate, a variety of effects on the cell surface and cell membrane were then produced. These included inhibition of nucleoside and amino acid transport, perturbation of permeability barriers to actinomycin D uptake, enhanced binding of the fluorescent probe 8-anilino-1-naphthalenesulfonate, inhibition of activity of 5′-nucleotidase, an ectoenzyme, and altered cell-surface properties, measured with a two-phase aqueous polymer system. In the L1210 cell line, the most potent compound tested was deuteroporphyrin IX which produced the effects mentioned above at a 5 × 10(−6) level; this drug level also prevented subsequent cell division. A tenfold higher drug level caused inhibition of intracellular nucleoside kinase activity, along with inhibition of sugar transport and of the fluorogenic interaction between 8-anilino-1-naphthalenesulfonic acid and cell companents. We conclude that the initial site of photoactivated porphyrin toxicity is at or near the cell surface.

Tolcapone is a potent catechol-O-methyltransferase inhibitor that prolongs the plasma half-life of levodopa. This multicenter, double-blind, placebo-controlled study used two 10-hour clinical evaluations to compare the efficacy and safety of three doses of tolcapone (50, 200, and 400 mg tid) with placebo in patients with Parkinson's disease (PD) experiencing motor fluctuations from levodopa/carbidopa. One hundred fifty-one patients completed the study. Clinical evaluations lasting 10 hours were performed on day -1 and day 42 using United Parkinson's Disease Rating Scale motor subscale and "on/off" and dyskinesia assessments every 30 minutes. Tolcapone significantly reduced "off" time an average of 40% and increased total "on" time by about 25% at all dose levels, as compared to placebo treatment. Levodopa/carbidopa dosage and frequency were significantly reduced. Tolcapone was well tolerated, with patients experiencing typical dopaminergic side effects that could be reduced or eliminated by lowering levodopa/carbidopa dosages. Tolcapone was effective at prolonging the clinical benefit of levodopa and reducing total levodopa requirements in PD patients with motor fluctuations.

BACKGROUND: Ceftolozane/tazobactam is a novel cephalosporin/beta-lactamase inhibitor combination that often retains activity against resistant Pseudomonas aeruginosa. The comparative safety and efficacy vs polymyxins or aminoglycosides in this setting remains unknown. METHODS: A retrospective, multicenter, observational cohort study was performed. Patients who received ceftolozane/tazobactam were compared with those treated with either polymyxin or aminoglycoside-based regimens for infections due to drug-resistant P. aeruginosa. Multivariate logistic regression was performed controlling for factors associated with treatment to assess the independent impact of ceftolozane/tazobactam on clinical cure, acute kidney injury (AKI), and in-hospital mortality. RESULTS: A total of 200 patients were included (100 in each treatment arm). The cohort represented an ill population with 69% in the intensive care unit, 63% mechanically ventilated, and 42% in severe sepsis or septic shock at infection onset. The most common infection type was ventilator-associated pneumonia (52%); 7% of patients were bacteremic. Combination therapy was more commonly used in polymyxin/aminoglycoside patients than those who received ceftolozane/tazobactam (72% vs 15%, P < .001). After adjusting for differences between groups, receipt of ceftolozane/tazobactam was independently associated with clinical cure (adjusted odds ratio [aOR], 2.63; 95% confidence interval [CI], 1.31-5.30) and protective against AKI (aOR, 0.08; 95% CI, 0.03-0.22). There was no difference in in-hospital mortality. The number needed to treat for a clinical cure with ceftolozane/tazobactam was 5, and the number needed to harm with AKI with a polymyxin/aminoglycoside was 4. CONCLUSIONS: These data support the preferential use of ceftolozane/tazobactam over polymyxins or aminoglycosides for drug-resistant P. aeruginosa infections.

Although many classification schemes for antiarrhythmic drugs have been proposed, the system introduced by Vaughan Williams and later modified by Harrison has been widely accepted. This classification system is comprised of four categories. Class I agents block sodium channels. Class II agents are Beta blockers. Class III agents prolong the cardiac action potential. Class IV agents are calcium channel blockers. This classification scheme, based largely on clinical observation continues to be useful almost two decades after its introduction. The electrophysiologic bases, strengths and weaknesses of this system are discussed.

Metastasis of cancer via the bloodstream is a major factor in the diagnosis, treatment, and prognosis of patients with cancer. Key events in hematogenous metastasis occur in the microvasculature. This is a brief, selective review of some interactions involving cancer cells and the microvasculature in pathological sequence, specifically: 1) intravasation of cancer cells; 2) the arrest of circulating cancer in the microvasculature; 3) cancer cell trauma associated with arrest; 4) microvascular trauma; 5) the inflammatory and 6) coagulative responses associated with arrest; and 7) the fate of arrested cancer cells. The evidence shows that in addition to providing routes for cancer cell dissemination and arrest sites for cancer cell emboli, the microvasculature, through a series of complex interactions with cancer cells, controls the efficiency of and acts as a rate regulator for the metastatic process.

Due to the results of a 6-year experience with civilian penetrating colon injuries at Mount Carmel/Grace Hospital, in Detroit, Michigan, which had favored primary repair of colon injuries, a prospective randomized study was performed. Seventy-one patients with penetrating colon injuries were entered in a prospective randomized study. Forty-three patients were treated with primary repair or resection and anastomosis, and 28 patients were treated with diversion. The average Penetrating Abdominal Trauma Index score was 25.5 for the primary repair and 23.4 for the diversion groups. The majority of injuries as assessed by the Colon Injury Score (CIS) for the primary repair group were grades 2 (58%) and 3 (28%). The diversion group predominantly had grades 2 (64%) and 3 (25%). There was no significant difference between the two groups. There were 8 (19%) patients with colon and noncolon-related complications in the primary repair group, and 10 (36%) patients with colon, noncolon, and colostomy-related complications in the diversion group. In addition, there were 2 (7%) patients with complications following colostomy reversal. Independent risk factors for adverse outcomes were compared and used to calculate the probability for adverse outcomes with respect to the mode of treatment. The probability for adverse outcomes was statistically greater in the diversion group. An analysis was also made within the primary repair group comparing the subgroups of primary repair with, and without, resection of colon. It appears that the primary repair with resection of colon may have fewer complications; however, this conclusion is based on a statistically insufficient sample size. The authors contend that primary repair or resection with anastomosis is the method of choice for treatment of all penetrating colon injuries in the civilian population despite any associated risk factors for adverse outcomes.

BACKGROUND: Recent evidence suggests that among patients receiving vancomycin, receipt of concomitant piperacillin-tazobactam increases the risk of nephrotoxicity. Well-controlled, adequately powered studies comparing rates of acute kidney injury (AKI) among patients receiving vancomycin + piperacillin-tazobactam (VPT) compared to similar patients receiving vancomycin + cefepime (VC) are lacking. In this study we compared the incidence of AKI among patients receiving combination therapy with VPT to a matched group receiving VC. METHODS: A retrospective, matched, cohort study was performed. Patients were eligible if they received combination therapy for ≥48 hours. Patients were excluded if their baseline serum creatinine was >1.2mg/dL or they were receiving renal replacement therapy. Patients receiving VC were matched to patients receiving VPT based on severity of illness, intensive care unit status, duration of combination therapy, vancomycin dose, and number of concomitant nephrotoxins. The primary outcome was the incidence of AKI. Multivariate modeling was performed using Cox proportional hazards. RESULTS: A total of 558 patients were included. AKI rates were significantly higher in the VPT group than the VC group (81/279 [29%] vs 31/279 [11%]). In multivariate analysis, therapy with VPT was an independent predictor for AKI (hazard ratio = 4.27; 95% confidence interval, 2.73-6.68). Among patients who developed AKI, the median onset was more rapid in the VPT group compared to the VC group (3 vs 5 days P =< .0001). CONCLUSION: The VPT combination was associated with both an increased AKI risk and a more rapid onset of AKI compared to the VC combination.

OBJECTIVE: To determine the Helicobacter pylori IgG serology pattern 12-21 months after successful organism eradication and to assess the usefulness of IgG serology in the long-term follow-up of patients. METHODS: We recruited patients from our 1990-91 study on IgG serology after H. pylori treatment. Forty-three of 45 patients (93%) agreed to participate. They had all been cured of H. pylori infection after triple antibiotic therapy and remained H. pylori negative at 1 yr posttreatment. H. pylori IgG antibody concentrations were measured in serum samples taken at 3-month intervals between 12 and 21 months posttreatment. [13C]-urea breath test was done at each blood draw to ensure continued eradication. Serology was determined by ELISA (Pylori Stat, BioWhittaker, Inc) and expressed as absorbance. RESULTS: All 43 patients (100%) continued to be free of H. pylori and demonstrated a decline in their H. pylori IgG concentration compared with baseline. The overall decline in serology among all 43 patients was approximately 50%. Forty of 43 patients (93%) had a decline of more than 20% in H. pylori IgG concentration compared with baseline. However, 28 of 43 patients (65%) remained seropositive for more than 1 yr after successful H. pylori eradication. CONCLUSION: We conclude that a 20% decline in IgG concentration has an overall sensitivity of 93% for determining H. pylori eradication 12-21 months after H. pylori treatment. Serology is an attractive alternative to endoscopy or urea breath tests in monitoring patients after H. pylori treatment, but serum IgG levels should not be expected to reach seronegative range after successful H. pylori eradication.