Resistance to insulin therapy among patients and providers: results of the cross-national Diabetes Attitudes, Wishes, and Needs (DAWN) study

OBJECTIVE: To examine the correlates of patient and provider attitudes toward insulin therapy. RESEARCH DESIGN AND METHODS: Data are from surveys of patients with type 2 diabetes not taking insulin (n = 2,061) and diabetes care providers (nurses = 1,109; physicians = 2,681) in 13 countries in Asia, Australia, Europe, and North America. Multiple regression analysis is used to identify correlates of attitudes toward insulin therapy among patients, physicians, and nurses. RESULTS: Patient and provider attitudes differ significantly across countries, controlling for individual characteristics. Patients rate the clinical efficacy of insulin as low and would blame themselves if they had to start insulin therapy. Self-blame is significantly lower among those who have better diet and exercise adherence and less diabetes-related distress. Patients who are not managing their diabetes well (poor perceived control, more complications, and diabetes-related distress) are significantly more likely to see insulin therapy as potentially beneficial. Most nurses and general practitioners (50-55%) delay insulin therapy until absolutely necessary, but specialists and opinion leaders are less likely to do so. Delay of insulin therapy is significantly less likely when physicians and nurses see their patients as more adherent to medication or appointment regimens, view insulin as more efficacious, and when they are less likely to delay oral diabetes medications. CONCLUSIONS: Patient and provider resistance to insulin therapy is substantial, and for providers it is part of a larger pattern of reluctance to prescribe blood glucose-lowering medication. Interventions to facilitate timely initiation of insulin therapy will need to address factors associated with this resistance.     

Impact of leukapheresis on early death rate in adult acute myeloid leukemia presenting with hyperleukocytosis

BACKGROUND: Patients with acute myeloid leukemia (AML) with hyperleukocytosis of at least 100 x 10(9) per L are at high risk of early death due to pulmonary or cerebral leukostasis. Although the efficacy of leukapheresis in terms of prompt cytoreduction is generally accepted, published data regarding the clinical value of immediate therapeutic leukapheresis are limited and conflicting. STUDY DESIGN AND METHODS: To determine whether leukapheresis has a favorable impact on early mortality, the clinical course of 53 newly diagnosed patients with AML and hyperleukocytosis admitted between 1995 and 2005 was analyzed retrospectively. Before August 2001, 28 patients received chemotherapy without leukoreduction (Cohort A). Thereafter, all AML patients with hyperleukocytosis were scheduled to receive leukapheresis, which was performed in 25 patients (Cohort B). RESULTS: There were no procedure-related adverse events. By Day 21 of therapy, 13 of 53 patients had died, resulting in an overall early death rate of 25 percent. In a multivariate logistic regression model, patients in Cohort B had a significantly lower risk of early death than patients in Cohort A (16% vs. 32%, respectively; p = 0.015). Dyspnea (p = 0.005), elevated creatinine (p = 0.028), and higher lactate dehydrogenase serum levels (p = 0.021) were independent risk factors for early death. With a median follow-up of 24.2 months, the overall survival was similar in both cohorts (Cohort A, 7.5; Cohort B, 6.5 months). Thus, leukapheresis had no impact on patients' long-term survivals. CONCLUSIONS: Our experience suggests that AML patients with hyperleukocytosis receiving leukapheresis had a significantly lower risk for early death by Day 21 than patients treated without leukapheresis. We therefore have adopted leukapheresis as a standard procedure in our department.     

Effect of a multifaceted educational intervention for anti-infectious measures on sepsis mortality: a cluster randomized trial

Purpose

Guidelines recommend administering antibiotics within 1 h of sepsis recognition but this recommendation remains untested by randomized trials. This trial was set up to investigate whether survival is improved by reducing the time before initiation of antimicrobial therapy by means of a multifaceted intervention in compliance with guideline recommendations.

Methods

The MEDUSA study, a prospective multicenter cluster-randomized trial, was conducted from July 2011 to July 2013 in 40 German hospitals. Hospitals were randomly allocated to receive conventional continuous medical education (CME) measures (control group) or multifaceted interventions including local quality improvement teams, educational outreach, audit, feedback, and reminders. We included 4183 patients with severe sepsis or septic shock in an intention-to-treat analysis comparing the multifaceted intervention (n = 2596) with conventional CME (n = 1587). The primary outcome was 28-day mortality.

Results

The 28-day mortality was 35.1% (883 of 2596 patients) in the intervention group and 26.7% (403 of 1587 patients; p = 0.01) in the control group. The intervention was not a risk factor for mortality, since this difference was present from the beginning of the study and remained unaffected by the intervention. Median time to antimicrobial therapy was 1.5 h (interquartile range 0.1–4.9 h) in the intervention group and 2.0 h (0.4–5.9 h; p = 0.41) in the control group. The risk of death increased by 2% per hour delay of antimicrobial therapy and 1% per hour delay of source control, independent of group assignment.

Conclusions

Delay in antimicrobial therapy and source control was associated with increased mortality but the multifaceted approach was unable to change time to antimicrobial therapy in this setting and did not affect survival.

     

Thrittene,homologous with somatostatin-28((1-13)), is a novel peptide in mammalian gut and circulation

Preprosomatostatin is a gene expressed ubiquitously among vertebrates, and at least two duplications of this gene have occurred during evolution. Somatostatin-28 (S-28) and somatostatin-14 (S-14), C-terminal products of prosomatostatin (ProS), are differentially expressed in mammalian neurons, D cells, and enterocytes. One pathway for the generation of S-14 entails the excision of Arg13-Lys14 in S-28, leading to equivalent amounts of S-28((1-12)). Using an antiserum (F-4), directed to the N-terminal region of S-28 that does not react with S-28((1-12)), we detected a peptide, in addition to S-28 and ProS, that was present in human plasma and in the intestinal tract of rats and monkeys. This F-4 reacting peptide was purified from monkey ileum; and its amino acid sequence, molecular mass, and chromatographic characteristics conformed to those of S-28((1-13)), a peptide not described heretofore. When extracts of the small intestine were measured by RIA, there was a discordance in the ratio of peptides reacting with F-4 and those containing the C terminus of ProS, suggesting sites of synthesis for S-28((1-13)) distinct from those for S-14 and S-28. This was supported by immunocytochemistry, wherein F-4 reactivity was localized in gastrointestinal (GI) endocrine cells and a widespread plexus of neurons within the wall of the distal gut while immunoreactivity to C-terminal domains of S-14 and S-28 in these neurons was absent. Further, F-4 immunoreactivity persisted in similar GI endocrine cells and myenteric neurons in mice with a targeted deletion of the preprosomatostatin gene. We believe that these data suggest a novel peptide produced in the mammalian gut, homologous with the 13 residues of the proximal region of S-28 but not derived from the ProS gene. Pending characterization of the gene from which this peptide is derived, its distribution, and function, we have designated this peptide as thrittene. Its localization in both GI endocrine cells and gut neurons suggests that thrittene may function as both a hormone and neurotransmitter.     

The role of plasma-derived factor VIII/von Willebrand factor concentrates in the treatment of hemophilia A patients

Besides preventing bleeding episodes, common goals of the treatment of hemophilia include integrating of patients into a normal social life and optimizing their quality of life. Sufficient amounts of factor VIII (FVIII) concentrates, whether recombinant or plasma-derived, are continuously needed. Guidelines for quality assurance of treatment will be a cornerstone to maintain optimal clinical management of patients especially considering financial aspects. Advances in manufacturing technologies have made possible general availability of modern concentrates for the management of hemophilia A patients. Safety, cost and continuous supply of concentrates must be considered when deciding on a product for replacement therapy. As todays' products have reached an excellent margin of safety with regard to virus transmission, the development and treatment of inhibitors is currently the main concern for physicians and patients. The incidence of inhibitors is influenced by various patient-related factors such as mutation type or severity of the disease. Plasma-derived FVIII concentrates containing von Willebrand factor (VWF) may have clinical advantages over pure FVIII concentrates with regard to inhibitor development and inhibitor eradication. Clinical trials comparing FVIII/VWF concentrates with pure FVIII concentrates are lacking, thus a lower inhibitor incidence has not yet been proven. Data from Germany on immune tolerance induction with FVIII/VWF concentrates indicate higher success rates with these than with pure FVIII concentrates. In addition FVIII/VWF concentrates are the therapy of choice when immune tolerance therapy with pure FVIII products is not successful.     

AML with 11q23/MLL abnormalities as defined by the WHO classification: incidence,partner chromosomes,FAB subtype,age distribution,and prognostic impact in an unselected series of 1897 cytogenetically analyzed AML cases

Acute myeloid leukemia (AML) cases with 11q23 abnormalities involving the MLL gene comprise one category of recurring genetic abnormalities in the WHO classification. In an unselected series of 1897 AML cases, 54 patients with an 11q23/MLL rearrangement were identified, resulting in an incidence of 2.8%. The incidence of AML with MLL rearrangement was significantly higher in therapy-related AML (t-AML) than in de novo AML (9.4% vs 2.6%, P <.0001). The frequency of MLL rearrangements was significantly higher in patients younger than 60 years (5.3% vs 0.8%, P <.0001). While the incidence of MLL rearrangements in AML M4, M5a, and M5b was 4.7%, 33.3%, and 15.9%, respectively, it was found in only 0.9% of all other French-American-British (FAB) subtypes (P <.0001). Compared with AML with intermediate karyotype, AML with 11q23/MLL rearrangement had a worse outcome, which was rather comparable with AML with unfavorable karyotype. Compared with t-AML, the median overall survival (OS) of de novo AML with MLL rearrangement was significantly better (2.5 vs 10 months, P =.0143). No significant differences in median OS were observed between cases with t(9;11) compared with all other MLL rearrangements (10.0 vs 8.9 months, P =.36). In conclusion, the category AML with 11q23/MLL abnormalities accounts for 2.8% of unselected AML, is closely associated with monocytic differentiation, and has a dismal prognosis. (     

Reverse transcriptase/polymerase chain reaction analysis of parathyroid hormone-related protein for the detection of tumor cell dissemination in the peripheral blood and bone marrow of patients with breast cancer

Journal of Cancer Research and Clinical Oncology - Tumor cell dissemination in the bone marrow is an independent prognostic marker for relapse and survival for patients with primary breast cancer....     

Predictive value of Ki67 and p53 in locally advanced rectal cancer：Correlation with thymidylate synthase and histopathological tumor regression after neoadjuvant 5-FU-based chemoradiotherapy

AIM： To investigate the predictive value of Ki67 and p53 and their correlation with thymidylate synthase （TS） gene expression in a rectal cancer patient cohort treated according to a standardized recommended neoadjuvant treatment regimen.METHODS： Formalin fixed, paraffin embedded pre-therapeutical tumor biopsies （n = 22） and post-therapeutical resection specimens （n = 40） from patients with rectal adenocarcinoma （clinical UICC stage Ⅱ/Ⅲ） receiving standardized neoadjuvant 5-fluorouracil （5-FU） based chemoradiotherapy were studied for Ki67 and p53 expression by immunohistochemistry and correlated with TS mRNA expression by quantitative TaqMan real-time PCR after laser microdissection. The results were compared with histopathological tumor regression according to a standardized semiquantitative score grading system.RESULTS： Responders （patients with high tumor regression） showed a significantly lower Ki67 expression than non-responders in the pre-therapeutical tumor biopsies （81.2% vs 16.7%; P 〈 0.05） as well as in the post-therapeutical resection specimens （75.8% vs 14.3%; P 〈 0.01）. High TS mRNA expression was significantly correlated with a high Ki67 index and low TS mRNA expression was significantly correlated with a low Ki67 index in the pre-therapeutical tumor biopsies （corr. coef. = 0.46; P 〈 0.01） as well as in the post-therapeutical resection specimens （corr. coef. = 0.40; P 〈 0.05）. No significant association was found between p53 and TS mRNA expression or tumor regression.CONCLUSION： Ki67 has, like TS, predictive value in rectal cancer patients after neoadjuvant 5-FU based chemoradiotherapy. The close correlation between Ki67 and TS indicates that TS is involved in active cell cycle processes.     

Acute resetting in two functionally different types of carotid baroreceptors.

The presence of two types of carotid sinus baroreceptors, as characterized by two different stimulus-response curves in an earlier study, suggests that each type may play a different role in the regulation of blood pressure. The discontinuous hyperbolic curve of the type I baroreceptors, marked by higher firing rates and greater sensitivity than the sigmoidal curve of type II baroreceptors, suggests that these baroreceptors would contribute more to the buffering of arterial pressure changes than the "tonically" active type II baroreceptors, which fired over greater pressure ranges and generally had spontaneous subthreshold discharge. The firing characteristics of type II baroreceptors suggest that these receptors would contribute more to regulation of tonic, baseline levels of arterial pressure. If this functional differentiation exists, the acute resetting characteristics of the two types of baroreceptors could be different. Resetting is defined as a shift in the response curve of a baroreceptor, marked by shifts in pressure threshold, in the same direction as the change in pressure to which it is exposed. Type I baroreceptors would be more likely to reset in response to a sustained acute change in pressure, since their primary role would be to prevent the initial change in pressure. However, type II baroreceptors would not reset to the acute change in pressure, since their primary role would be to maintain consistent information on the level of existing pressure. Therefore, this study was performed to examine the acute resetting ability of both types of baroreceptors by using a vascularly isolated carotid sinus preparation in the dog.(ABSTRACT TRUNCATED AT 250 WORDS)     

Über die carcinogene Wirkung von 3-Amino-Δ1.3.5(10)-oestratrienen und von 2-Nitroso-fluoren

Zusammenfassung Ölige Suspensionen vergleichbarer Dosen von 3-Acetyl-amino-^1.3.5(10)-oestratrien, N-Acetyl-N[3-^1.3.5(10)-oestratrienyl]-hydroxylamin, 2-Acetylaminofluoren und 2-Nitrosofluoren werden mit der Schlundsonde an Ratten über ca. 42 Wochen verfüttert. Die Oestratrien-Derivate zeigten keinerlei carcinogene Wirkung. 2-Acetylaminofluoren führt in bekannter Weise zu Gehörgangscarcinomen und—bei den männlichen Tieren—zu Leberzellcarcinomen. 2-Nitrosofluoren erzeugt dieselben Carcinomarten wie 2-Acetylaminofluoren, außerdem werden Plattenepithelcarcinome des Vormagens beobachtet. Die Struktur-Wirkungsbeziehungen oestrogener und carcinogener Substanzen sowie das Stoffwechselgeschehen im Hinblick auf mögliche Wirkformen der applizierten Carcinogene werden diskutiert.

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On the carcinogenic activity of 3-Amino-^1.3.5(10)-estratrien and 2-nitrosofluorene

Summary For approximately 42 weeks rats were fed with oily suspensions of comparable doses of 2-acetylamino-^1.3.5(10)-estratrien, N-acetyl-N[3-^1.3.5(10)-estratrienyl]-hydroxylamine, 2-acetylamino-fluorene and 2-nitrosofluorene by stomach tube. The estratrien-derivatives did not show any carcinogenic activity. 2-acetylamino-fluorene produced ear-duct carcinoma and—in the male animals—hepatocellular carcinomas. 2-nitrosofluorene yields the same types of carcinoma as 2-acetylaminofluorene, and in addition, squamous epithelial carcinomas of the forestomach. The relations between chemical structure and biological activity of estrogenic and carcinogenic compounds as well as their metabolism in connection with the possible ultimate carcinogens produced are discussed.

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Herrn Prof. Dr. Drs. mult. A. Butenandt zum 65. Geburtstag in dankbarer Verehrung gewidmet.

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Teil der Dissertation, Traut (1966).

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Herrn Prof. Butenandt danken wir für sein förderndes Interesse an dieser Arbeit. Frl. I. Brachmann, Frl. I. Bahr sowie Frl. A. Kritzler und Frl. U. Romba möchten wir für ihre sorgfältige Mitarbeit bei der Durchführung der Fütterungsversuche danken.