Systemic hematologic effects of PEG-rHuMGDF-induced megakaryocyte hyperplasia in mice

PEG-rHuMGDF injected daily in normal mice causes a rapid dose-dependent increase in megakaryocytes and platelets. At the same time that platelet numbers are increased, the mean platelet volume (MPV) and platelet distribution width (PDW) can be either decreased, normal, or increased depending on the dose and time after administration. Thus, PEG-rHuMGDF at a low dose causes decreases in MPV and PDW, MGDF at an intermediate dose causes an initial increase followed by a decrease in MPV and PDW, and PEG-rHuMGDF at higher doses causes an increase in MPV and PDW followed by a gradual normalization of these platelet indices. In addition to the expected thrombocytosis after 7 to 10 days of daily injection of high doses of PEG-rHuMGDF, a transient decrease in peripheral red blood cell numbers and hemoglobin is noted accompanied in the bone marrow by megakaryocytic hyperplasia, myeloid hyperplasia, erythroid and lymphoid hypoplasia, and deposition of a fine network of reticulin fibers. Splenomegaly, an increase in splenic megakaryocytes, and extramedullary hematopoiesis accompany the hematologic changes in the peripheral blood and marrow to complete a spectrum of pathologic features similar to those reported in patients with myelofibrosis and megakaryocyte hyperplasia. However, all the PEG-rHuMGDF-initiated hematopathology including the increase in marrow reticulin is completely and rapidly reversible upon the cessation of administration of PEG-rHuMGDF. Thus, transient hyperplastic proliferation of megakaryocytes does not cause irreversible tissue injury. Furthermore, PEG-rHuMGDF completely ameliorates carboplatin-induced thrombocytopenia at a low-dose that does not cause the hematopathology associated with myelofibrosis.     

Understanding the Usage of Content in a Mental Health Intervention for Depression: An Analysis of Log Data

Background

Web-based interventions for the early treatment of depressive symptoms can be considered effective in reducing mental complaints. However, there is a limited understanding of which elements in an intervention contribute to effectiveness. For efficiency and effectiveness of interventions, insight is needed into the use of content and persuasive features.

Objective

The aims of this study were (1) to illustrate how log data can be used to understand the uptake of the content of a Web-based intervention that is based on the acceptance and commitment therapy (ACT) and (2) to discover how log data can be of value for improving the incorporation of content in Web-based interventions.

Methods

Data from 206 participants (out of the 239) who started the first nine lessons of the Web-based intervention, Living to the Full, were used for a secondary analysis of a subset of the log data of the parent study about adherence to the intervention. The log files used in this study were per lesson: login, start mindfulness, download mindfulness, view success story, view feedback message, start multimedia, turn on text-message coach, turn off text-message coach, and view text message. Differences in usage between lessons were explored with repeated measures ANOVAs (analysis of variance). Differences between groups were explored with one-way ANOVAs. To explore the possible predictive value of the login per lesson quartiles on the outcome measures, four linear regressions were used with login quartiles as predictor and with the outcome measures (Center for Epidemiologic Studies—Depression [CES-D] and the Hospital Anxiety and Depression Scale—Anxiety [HADS-A] on post-intervention and follow-up) as dependent variables.

Results

A significant decrease in logins and in the use of content and persuasive features over time was observed. The usage of features varied significantly during the treatment process. The usage of persuasive features increased during the third part of the ACT (commitment to value-based living), which might indicate that at that stage motivational support was relevant. Higher logins over time (9 weeks) corresponded with a higher usage of features (in most cases significant); when predicting depressive symptoms at post-intervention, the linear regression yielded a significant model with login quartile as a significant predictor (explained variance is 2.7%).

Conclusions

A better integration of content and persuasive features in the design of the intervention and a better intra-usability of features within the system are needed to identify which combination of features works best for whom. Pattern recognition can be used to tailor the intervention based on usage patterns from the earlier lessons and to support the uptake of content essential for therapy. An adaptable interface for a modular composition of therapy features supposes a dynamic approach for Web-based treatment; not a predefined path for all, but a flexible way to go through all features that have to be used.     

Colorectal cancer extracellular acidosis decreases immune cell killing and is partially ameliorated by pH-modulating agents that modify tumor cell cytokine profiles

Tumor cells upregulate myriad proteins that are important for pH regulation, resulting in the acidification of the extracellular tumor microenvironment (TME). Abnormal pH is known to dampen immune function, resulting in a worsened anti-tumor immune response. Understanding how extrinsic alterations in pH modulate the interactions between immune cells and tumors cells will help elucidate opportunities for new therapeutic approaches. We observed that pH impacts the function of immune cells, both natural killer (NK) and T cells, which is relevant in the context of a highly acidic TME. Decreased NK and T cell activity was correlated with decreasing pH in a co-culture immune cell-mediated tumor cell-killing assay. The addition of pH-modulating drugs cariporide, lansoprazole, and acetazolamide to the co-culture assay was able to partially mitigate this dampened immune cell function. Treatment of colorectal cancer (CRC) cells with NHE1 inhibitor cariporide increased CRC cell-secreted cytokines involved in immune cell recruitment and activation and decreased cytokines involved in epithelial-mesenchymal transition (EMT). Cariporide treatment also decreased CRC cell shed TRAIL-R2, TRAIL-R3, and PD-L1 which is relevant in the context of immunotherapy. These experiments can help inform future investigations into how the pH of the tumor microenvironment may be extrinsically modulated to improve anti-tumor immune response in solid tumors such as colorectal cancer.     

Simultaneous measurement of gallbladder emptying with cholescintigraphy and US during infusion of physiologic doses of cholecystokinin: a comparison

Both ultrasonography (US) and cholescintigraphy are used to study gallbladder dynamics. The present study was undertaken to determine whether the two methods provide the same or different information relating to gallbladder emptying. Emptying was simultaneously studied with both methods during infusion of graded physiologic doses of cholecystokinin (CCK) in six healthy subjects. Infusion of stepwise increasing doses of CCK, ranging from 0.03 to 0.5 Ivy dog units per kilogram of body weight per hour (IDU/kg.h), induced significant dose-related increases in plasma CCK, decreases in gallbladder volume assessed with US, and gallbladder emptying assessed with cholescintigraphy. The threshold dose for inducing significant gallbladder emptying was 0.13 IDU/kg.h, as determined with both techniques, indicating similar detection limits. There was a highly significant correlation between decreases in gallbladder volume and decreases in radioactive counts over the gallbladder region, with a tendency toward greater gallbladder responses at sonography during the early phase of gallbladder contraction and toward greater responses at cholescintigraphy during the later phase of gallbladder contraction. It is concluded that these methods can be used interchangeably for the quantitation of gallbladder emptying.     

The cervico-ocular reflex is increased in whiplash injury patients

Whiplash-associated disorders (WAD) are a major problem in the Western world, which put a formidable financial burden on modern society and which evoke an emerging debate on the true nature of their origin. To date there is no generally accepted test that allows us to diagnose WAD objectively. Because whiplash injury causes dysfunction of proprioception in the neck, we investigated the characteristics of the cervico-ocular reflex (COR) of presumptive WAD patients. These patients and age-matched healthy controls were rotated at different stimulus peak velocities in the dark while their head was fixed in space. The gain values of the COR were significantly increased in the patient population at a wide range of stimulus peak velocities with maximum difference at the lower frequencies (p = 0.037, ANOVA). Hence, although larger numbers of patients should be measured, the COR gain appears to be a parameter that may permit an objective diagnosis of WAD.     

Major motor atrophic patterns in the face and neck: CT evaluation

Cranial nerve deficits from various pathologic processes of the head and neck may result in characteristic patterns of denervation muscular atrophy. Such atrophic patterns may be clues to the location and extent of the lesion, particularly when cranial nerves are involved early in the course of the disease process. Thirty-six patients with computed tomographic (CT) evidence of muscular atrophy secondary to pathologic conditions involving the motor division of cranial nerves were examined. Five characteristic denervation muscular atrophy patterns seen on CT scans were identified. In several patients, identification of the muscular atrophy pattern was the only clue to the presence of a pathologic condition. Recognition of these atrophic patterns can prevent misinterpretation of their CT appearance and direct the CT examination to the course of the compromised cranial nerve from the brainstem to its peripheral innervation.     

脐部给药的多塞平栓研制及应用

目的：研制透皮制剂多塞平栓,考察其治疗各型急、慢性荨麻疹的临床疗效。方法：多塞平以甘油明胶为质,氮酮为促透剂,制成栓剂,经脐部给药,观察５０个病例,与口服多塞平片作对照,观察临床疗效。结果：多塞平栓治疗各型急、慢性荨麻疹,总有效率为９４．０％,经统计学分析,Ｐ〈０．０５,差异具显著性。结论：本品制备工艺可行,疗效确切,用药剂量小,无副作用,具有进一步研究、开发的价值。