Abnormal function of the bone marrow microenvironment in chronic myelogenous leukemia: role of malignant stromal macrophages

The bone marrow microenvironment supports and regulates the proliferation and differentiation of hematopoietic cells. Dysregulated hematopoiesis in chronic myelogenous leukemia (CML) is caused, at least in part, by abnormalities in CML hematopoietic progenitors leading to altered interactions with the marrow microenvironment. The role of the microenvironment itself in CML has not been well characterized. We examined the capacity of CML stroma to support the growth of long-term culture-initiating cells (LTC-IC) obtained from normal and CML marrow. The growth of normal LTC-IC on CML stroma was significantly reduced compared with normal stroma. This did not appear to be related to abnormal production of soluble factors by CML stroma because normal LTC- IC grew equally well in Transwells above CML stroma as in Transwells above normal stroma. In addition, CML and normal stromal supernatants contained similar quantities of both growth-stimulatory (granulocyte colony-stimulating factor (CSF), interleukin-6, stem cell factor, granulocyte-macrophage CSF, and interleukin-1 beta) and growth- inhibitory cytokines (transforming growth factor-beta, macrophage inflammatory protein-1 alpha, and tumor necrosis factor-alpha). The relative proportion of different cell types in CML and normal stroma was similar. However, polymerase chain reaction and fluorescence in situ hybridization studies showed the presence of bcr-abl-positivo cells in CML stroma, which were CD14+ stromal macrophages. To assess the effect of these malignant macrophages on stromal function, CML and normal stromal cells were separated by fluorescence-activated cell sorting into stromal mesenchymal cell (CD14-) and macrophage (CD14+) populations. CML and normal CD14- cells supported the growth of normal LTC-IC equally well. However, the addition of CML macrophages to normal or CML CD14- mesenchymal cells resulted in impaired progenitor support. This finding indicates that the abnormal function of CML bone marrow stroma is related to the presence of malignant macrophages. In contrast to normal LTC-IC, the growth of CML LTC-IC on allogeneic CML stromal layers was not impaired and was significantly better than that of normal LTC-IC cocultured with the same CML stromal layers. These studies demonstrate that, in addition to abnormalities in CML progenitors themselves, abnormalities in the CML marrow microenvironment related to the presence of malignant stromal macrophages may contribute to the selective expansion of leukemic progenitors and suppression of normal hematopoiesis in CML.     

Impact of a Letter-Grade Program on Restaurant Sanitary Conditions and Diner Behavior in New York City

Objectives. We evaluated the impact of the New York City restaurant letter-grading program on restaurant hygiene, food safety practices, and public awareness.Methods. We analyzed data from 43 448 restaurants inspected between 2007 and 2013 to measure changes in inspection score and violation citations since program launch in July 2010. We used binomial regression to assess probability of scoring 0 to 13 points (A-range score). Two population-based random-digit-dial telephone surveys assessed public perceptions of the program.Results. After we controlled for repeated restaurant observations, season of inspection, and chain restaurant status, the probability of scoring 0 to 13 points on an unannounced inspection increased 35% (95% confidence interval [CI] = 31%, 40%) 3 years after compared with 3 years before grading. There were notable improvements in compliance with some specific requirements, including having a certified kitchen manager on site and being pest-free. More than 91% (95% CI = 88%, 94%) of New Yorkers approved of the program and 88% (95% CI = 85%, 92%) considered grades in dining decisions in 2012.Conclusions. Restaurant letter grading in New York City has resulted in improved sanitary conditions on unannounced inspection, suggesting that the program is an effective regulatory tool.Restaurant food safety is increasingly important, with almost half of the US food dollar spent on restaurant food1 and about one third of caloric intake from foods prepared outside the home.2 In New York City (NYC), residents eat out nearly 1 billion times each year.3 Although most diners do not get sick, foodborne pathogens cause millions of preventable illnesses in the United States annually.4 The exact proportion of restaurant-attributable foodborne illness is unknown, but national surveillance in the United States found that two thirds of reported foodborne outbreaks from 1998 through 2008 occurred in the restaurant or deli setting,5 and consumption of food prepared outside the home has been linked to an increased risk of sporadic foodborne diseases.6Regular inspection of restaurants for food safety is a core function of local health authorities, guided by the US Food and Drug Administration (FDA) Food Code.7 Although all states have sanitation codes modeled after the FDA Food Code,8 implementation methods vary by jurisdiction. The NYC Department of Health and Mental Hygiene (hereafter, Health Department) is charged with inspecting restaurants, coffee shops, bars, nightclubs, employee or university cafeterias, bakeries, and fixed-site food stands (hereafter, restaurants). Its inspection program uses a scoring system to measure compliance with the NYC Health Code, which is updated regularly to maintain consistency with the FDA Food Code and the New York State Sanitary Code. Restaurants are entitled to an impartial review of inspection results by an administrative tribunal, which can improve an assigned score and reduce associated monetary fines.Before letter grading, the Health Department aimed to inspect restaurants at least once per year and imposed monetary fines for violations cited at inspections. Inspection results were available on the Health Department Web site. However, financial disincentives and the Web site posting were insufficient to drive improvements across the industry, with most restaurants cited for multiple public health hazards. Mean inspection scores and restaurant sanitary conditions were stagnant (D. Kass, email communication, February 2009).In an effort to improve restaurant food safety and increase transparency of inspection information, the Health Department launched its letter-grade program on July 27, 2010. The program uses public disclosure of inspection scores in the form of letter grades at point of decision-making; a more finely tuned, risk-based inspection schedule; and financial incentives to encourage high food-safety standards. It began after an 18-month planning process that included a public announcement of the intent to begin letter grading; meetings with restaurant industry representatives, food safety experts, and regulators from a jurisdiction with a restaurant sanitary grade program; promulgation of 2 regulations subject to notice and comment; and training and education for restaurateurs. The process was covered by the media, and by July 2010, restaurateurs were aware of the program and anticipating the launch.9,10We evaluated the impact of the restaurant letter-grade program by assessing (1) hygiene and food-safety practices as characterized by inspection outcomes before and after program implementation and (2) public response to the program measured by 2 population-based telephone surveys.     

Malignant peritoneal mesothelioma a clinical and laparoscopic study of ten cases

Summary A retrospective study of 10 cases of malignant peritoneal mesothelioma from two centers is reported. All cases were initially diagnosed between 1967 and 1986 utilizing laparoscopy and the histologic interpretation of laparoscopic biopsy samples. Subsequently, the original diagnosis was confirmed by two independent pathologists employing both histological and histochemical techniques. In five cases immunohistochemical studies were also performed. The clinical findings and course of the disease were similar to other reported series. Laparoscopic findings of mesothelioma were indistinguishible from metastatic peritoneal neoplasms. However, the presence of homogeneous spreading of nodules, plaques, or fleshy masses on both parietal and visceral peritoneum; the absence of direct or indirect signs of other abdominal neoplasms; and the absence of hepatic metastases or the possible presence of nodules or plaques on Glisson's capsule without any parenchymal involvement, when observed, allowed the laparoscopist to suspect the disease in four of 10 cases. Laparoscopy may be useful in detecting mesothelioma. The diagnosis is mainly morphological, but even morphology has its inherent limitations. Further studies are necessary to improve the diagnostic accuracy of this tumor.A part of this study was presented during the 12th International Congress of Gastroenterology and the 5th International Congress of Gastrointestinal Endoscopy in Lisbon, Portugal, September 16–22, 1984.     

Prospective Study on the Hepatitis Safety of Intravenous Immunoglobulin, pH 4.25

Recent reports of transmission by intravenous gamma-globulin preparations of non-A non-B hepatitis (NANBH), including several cases that progressed to severe liver damage and death, have raised concerns about the safety of intravenous gamma-globulin. However, the problem does not seem to be widespread. To assess this issue, we previously reported the results of liver function tests monitored in 41 patients with primary immunodeficiency treated with intravenous immunoglobulin (IGIV), pH 4.25 over periods ranging from 6 to 15 months. Eighteen of these patients at two of the three centers have now had serial serum glutamic pyruvic transaminase (SGPT) levels performed regularly at intervals of 1-5 weeks while continuing monthly intravenous infusions of nonmodified IGIV, pH 4.25 for an additional 14-26 months. The standard dosage was 400 mg per kg body weight IGIV, pH 4.25. Six lots of IGIV, pH 4.25 were used. Transient minor SGPT elevations were observed in 5 of the patients on a total of 8 occasions. None of the elevations was considered indicative of NANBH or of any chronic hepatic disease. All patients remained negative for hepatitis B surface antigen throughout the study.     

Long-term mortality and morbidity of transfusion-associated non-A, non-B, and type C hepatitis: A National Heart, Lung, and Blood Institute collaborative study

Persons with non-A, non-B hepatitis (cases) identified in 5 transfusion studies in the early 1970s have been followed ever since and compared for outcome with matched, transfused, non-hepatitis controls from the same studies. Previously, we reported no difference in all-cause mortality but slightly increased liver-related mortality between these cohorts after 18 years follow-up. We now present mortality and morbidity data after approximately 25 years of follow-up, restricted to the 3 studies with archived original sera. All-cause mortality was 67% among 222 hepatitis C-related cases and 65% among 377 controls (P = NS). Liver-related mortality was 4.1% and 1.3%, respectively (P =.05). Of 129 living persons with previously diagnosed transfusion-associated hepatitis (TAH), 90 (70%) had proven TAH-C, and 39 (30%), non-A-G hepatitis. Follow-up of the 90 TAH-C cases revealed viremia with chronic hepatitis in 38%, viremia without chronic hepatitis in 39%, anti-HCV without viremia in 17%, and no residual HCV markers in 7%. Thirty-five percent of 20 TAH-C patients biopsied for biochemically defined chronic hepatitis displayed cirrhosis, representing 17% of all those originally HCV-infected. Clinically evident liver disease was observed in 86% with cirrhosis but in only 23% with chronic hepatitis alone. Thirty percent of non-A, non-B hepatitis cases were unrelated to hepatitis viruses A,B,C, and G, suggesting another unidentified agent. In conclusion, all-cause mortality approximately 25 years after acute TAH-C is high but is no different between cases and controls. Liver-related mortality attributable to chronic hepatitis C, though low (<3%), is significantly higher among the cases. Among living patients originally HCV-infected, 23% have spontaneously lost HCV RNA.     

Preliminary observation with dronabinol in patients with intractable pruritus secondary to cholestatic liver disease

Pruritus due to cholestatic liver disease can be particularly difficult to manage and frequently is intractable to a variety of medical therapies. The aim of our study is to evaluate the efficacy of delta-9-tetrahydrocannabinol (delta-9-THC) for intractable cholestatic related pruritus (ICRP) that has failed conventional (and unconventional) remedies. Three patients were evaluated for plasmapheresis because of ICRP. All 3 patients had previously been extensively treated with standard therapies for ICRP including: diphenhydramine, chlorpheniramine, cholestyramine, rifampicin, phenobarbital, doxepin, naltrexone, UV therapy, and topical lotions. Even multiple courses of plasmapheresis were performed without any benefit for the intractable pruritus. All patients reported significant decreases in their quality of life, including lack of sleep, depression, inability to work, and suicidal ideations. All patients were started on 5 mg of delta-9-THC (Marinol) at bedtime. All 3 patients reported a decrease in pruritus, marked improvement in sleep, and eventually were able to return to work. Resolution of depression occurred in two of three. Side effects related to the drug include one patient experiencing a disturbance in coordination. Marinol dosage was decreased to 2.5 mg in this patient with resolution of symptoms. The duration of antipruritic effect is approximately 4-6 hrs in all three patients suggesting the need for more frequent dosing. Delta-9-tetrahydrocannabinol may be an effective alternative in patients with intractable cholestatic pruritus.