Expression of receptor activator of nuclear factor kappaB ligand on bone marrow plasma cells correlates with osteolytic bone disease in patients with multiple myeloma.

PURPOSE: Increased bone resorption is a hallmark of multiple myeloma and is attributable to osteoclast activation. Recent studies showed that the receptor activator of nuclear factor kappaB ligand (RANKL) is the key mediator of osteoclastogenesis and plays a crucial role in bone destruction in malignant bone disease. We found that human myeloma cells express RANKL and analyzed the association of the RANKL expression with the presence of osteolytic bone disease in patients with multiple myeloma. EXPERIMENTAL DESIGN: Flow cytometry was performed on bone marrow samples derived from controls and multiple myeloma patients with or without osteolytic bone lesions on conventional radiography. Plasma cells were identified as CD38++/CD138+ cells. The level of RANKL expression on the surface of bone marrow plasma cells was correlated with the bone status of the patients. RESULTS: The bone marrow plasma cells from controls showed no or only a weak surface expression of RANKL, and the median mean fluorescence index (MFI) was 6. In contrast, expression of RANKL could be detected on bone marrow plasma cells from all of the patients with multiple myeloma, and median MFI was 47. The difference in MFI for RANKL expression of bone marrow plasma cells from controls and myeloma patients was highly significant (P < 0.0005). Myeloma patients with osteolytic bone lesions showed a significantly higher expression of RANKL (median MFI = 60; range, 16-2494) compared with patients without osteolysis (median MFI = 16; range, 6-229; P < 0.0005). CONCLUSIONS: These results show for the first time that the level of RANKL expression by myeloma cells correlates significantly with osteolytic bone disease.     

Inhibition of bone repair in a rat model for chronic and excessive alcohol consumption.

Alcohol abuse is associated with increases in both the incidence of fractures and complications in fracture healing. The purpose of this study was to determine the dose-dependent effects of ethanol on bone repair in a rat model. Three-month-old male Wistar rats were continuously fed liquid diets containing ethanol as either 36% or 26% of total calories or control diets for 6 weeks. Then, a bone repair model was created in all rats. Bone healing and liver metabolism were evaluated 7 weeks after bone injury. For each dose, there were three ethanol-feeding groups receiving (1) ethanol for 13 weeks, (2) control diet for 13 weeks (pair-fed), and (3) ethanol before bone injury and control diet (pair-fed) after injury. Another group was fed ethanol (36%) before injury and given control diet ad libitum after injury. There were also two nutritional controls consuming control diet and standard rat chow ad libitum for 13 weeks. Abnormal liver metabolism was evident at the higher ethanol dose - increases in cytochrome P4502E1 specific activity (5-fold; P < .01), triglyceride content (4-fold; P < .02), and liver weight (25%; P = .05) - compared with pair-fed controls. The higher dose of ethanol resulted in deficient bone repair when compared with rats receiving ethanol-free control diet by pair-feeding: 26% less (P = .02) rigidity of the repaired bone, 41% less (P = .02) intrinsic stiffness, 24% less intrinsic strength (P = .05), and 14% less (P = .001) ash density of the repair tissue. The reduced food consumption of ethanol-fed rats compared with that in the nutritional controls did not contribute to this deficiency. Furthermore, removal of ethanol (as 36% of calories) from the diet after bone injury completely restored normal bone healing and nearly normalized the liver metabolism. The lower ethanol dose (26% of calories) had a minimal effect on liver metabolism and bone repair. We conclude that ethanol (as 36% of calories) in the rat diet, especially during the postinjury period, was solely responsible for the observed inhibition of bone repair.     

Preliminary assessment of an automated surveillance system for infection control.

BACKGROUND AND OBJECTIVE: Rapid identification and investigation of potential outbreaks is key to limiting transmission in the healthcare setting. Manual review of laboratory results remains a cumbersome, time-consuming task for infection control practitioners (ICPs). Computer-automated techniques have shown promise for improving the efficiency and accuracy of surveillance. We examined the use of automated control charts, provided by an automated surveillance system, for detection of potential outbreaks. SETTING: A 656-bed academic medical center. METHODS: We retrospectively reviewed 13 months (November 2001 through November 2002) of laboratory-patient data, comparing an automated surveillance application with standard infection control practices. We evaluated positive predictive value, sensitivity, and time required to investigate the alerts. An ICP created 75 control charts. A standardized case investigation form was developed to evaluate each alert for the likelihood of nosocomial transmission based on temporal and spatial overlap and culture results. RESULTS: The 75 control charts were created in 75 minutes and 18 alerts fired above the 3-sigma level. These were independently reviewed by an ICP and associate hospital epidemiologist. The review process required an average of 20 minutes per alert and the kappa score between the reviewers was 0.82. Eleven of the 18 alerts were determined to be potential outbreaks, yielding a positive predictive value of 0.61. Routine surveillance identified 5 of these 11 alerts during this time period. CONCLUSION: Automated surveillance with user-definable control charts for cluster identification was more sensitive than routine methods and is capable of operating with high specificity and positive predictive value in a time-efficient manner.     

Phase I and pharmacologic study of infusional topotecan and Carboplatin in relapsed and refractory acute leukemia.

PURPOSE: To assess the maximum tolerated dose, toxicities, pharmacokinetics, and antileukemic activity of topotecan and carboplatin in adults with recurrent or refractory acute leukemias. EXPERIMENTAL DESIGN: Patients received topotecan and carboplatin by 5-day continuous infusion at nine dose levels. Patients achieving a complete remission received up to two additional courses for consolidation. Plasma topotecan and ultrafilterable platinum were assayed on days 1 to 5. In addition, pretreatment levels of various polypeptides in leukemic cells were examined by immunoblotting to assess possible correlations with response. RESULTS: Fifty-one patients received a total of 69 courses of therapy. Dose-limiting toxicity consisted of grade 4/5 typhlitis and grade 3/4 mucositis after one course of therapy or grade 4 neutropenia and thrombocytopenia lasting >50 days when a second course was administered on day 21. Among 45 evaluable patients, there were 7 complete remissions, 2 partial remissions, 1 incomplete complete remission, and 1 reversion to chronic-phase chronic myelogenous leukemia. Topotecan steady-state plasma concentrations increased with dose. No accumulation of topotecan or ultrafilterable platinum occurred between days 1 and 5 of therapy. Leukemic cell levels of topoisomerase I, checkpoint kinase 1, checkpoint kinase 2, and Mcl-1 correlated with proliferating cell nuclear antigen but not with response. In contrast, low Bcl-2 expression correlated with response (P = 0.014, Mann-Whitney U test). CONCLUSIONS: The maximum tolerated dose was 1.6 mg/m(2)/d topotecan plus 150 mg/m(2)/d carboplatin. The complete remission rate in a heavily pretreated population was 16% (33% at the highest three dose levels). Responses seem to correlate with low pretreatment blast cell Bcl-2 expression.     

四种粘结材料对纤维桩在不同深度根管内的固位力的影响——薄片推出实验

目的:比较4种不同树脂粘结材料在不同深度根管内粘固纤维桩的推出强度。方法:28个单根管离体前牙截冠后行根管充填和桩道预备,随机分为4组,分别用不同的粘结材料(Ⅰ:XP Bond-Dual Cure Calibra resincement;Ⅱ:XP Bond-Dual Cure Fluorocore2;Ⅲ:Excite DSC MultiCore Flow;Ⅳ:Multilink Primer A/B MultilinkAutomix)粘固纤维桩。粘固了纤维桩的牙根切割为1mm厚的试件并将其按照根管的深度分为上部、中部和下部3组,测试其推出强度。结果:Ⅰ组、Ⅱ组上部的推出强度均显著高于下部(P<0.05),Ⅲ组、Ⅳ组的推出强度在不同深度根管间无显著性差异(P>0.05)。结论:材料的类型和根管的深度对纤维桩的固位有影响。     

A new metabolic pathway for N,N-dimethyltryptamine

N,N-Dimethyltryptamine (DMT) undergoes a major structural alteration when added to whole human blood or its red blood cells in vitro. A new high-pressure liquid chromatography (HPLC) peak is present in extracts of these treated tissues. The compound responsible for this peak has been identified by ultraviolet spectrophotometry and by mass spectrometry as dimethylkynuramine (DMK). The enzyme responsible for this appears to be different from tryptophan 2,3-dioxygenase and also from indoleamine 2,3-dioxygenase.     

Parental Traits Associated with Adherence to the Mediterranean Diet in Children and Adolescents in Croatia: A Cross-Sectional Study

The Mediterranean diet (MD) is known to be one of the healthiest dietary patterns. Despite the significance of a healthful diet during the early stage of life, data for young individuals indicate that nutrition problems are common. This cross-sectional study aimed to determine parental factors associated with MD adherence in children and adolescents living in the Mediterranean region in Croatia. In total, 2623 children aged 2 to 18 years and their parents participated in this study. Data were collected during the period from September 2021 to February 2022 by using an anonymous questionnaire. We used KIDMED and MEDAS questionnaires for assessing MD adherence in young individuals and their parents, respectively. To assess the association of children’s MD adherence categories with the parental predictors, we performed multivariate multinomial logistic regression. Results showed that the children of parents with a low MD adherence are much more likely to have poor MD adherence than good (OR = 47.54 (95% C.I 18.24, 123.87), p < 0.001) or average (OR = 5.64 (95% C.I 3.70, 8.6), p < 0.001) MD adherence. Further, children of fathers with higher BMI (OR = 1.035 (95% C.I 1.0, 1.071)) and those who do not live with both parents (OR = 1.703 (95% C.I 0.994, 2.916), p = 0.053) are more likely to have poor MD adherence than good MD adherence. These results indicate that interventions focusing on enhancing the quality of both parents’ diets could effectively improve their children’s eating habits.     

The construction of the Split Sleep Questionnaire on sleep habits during the COVID-19 pandemic in the general population

AimTo construct a single-format questionnaire on sleep habits and mood before and during the COVID-19 pandemic in the general population.MethodsWe constructed the Split Sleep Questionnaire (SSQ) after a literature search of sleep, mood, and lifestyle questionnaires, and after a group of sleep medicine experts proposed and assessed questionnaire items as relevant/irrelevant. The study was performed during 2021 in 326 respondents distributed equally in all age categories. Respondents filled out the SSQ, the Pittsburgh Sleep Quality Index (PSQI), and State Trait Anxiety Inventory (STAI), and kept a seven-day sleep diary.ResultsWorkday and work-free day bedtime during the COVID-19 pandemic assessed with SSQ were comparable to the sleep diary assessment (P = 0.632 and P = 0.203, respectively), as was the workday waketime (P = 0.139). Work-free day waketime was significantly later than assessed in sleep diary (8:19 ± 1:52 vs 7:45 ± 1:20; P < 0.001). No difference in sleep latency was found between the SSQ and PSQI (P = 0.066). Cronbach alpha for Sleep Habits section was 0.819, and 0.89 for Mood section. Test-retest reliability ranged from 0.45 (P = 0.036) for work-free day bedtime during the pandemic to 0.779 (P < 0.001) for sleep latency before the pandemic.ConclusionThe SSQ provides a valid, reliable, and efficient screening tool for the assessment of sleep habits and associated factors in the general population during the COVID-19 pandemic.

The COVID-19 pandemic, along with its multiple adverse effects on various aspects of mental health, has significantly affected sleep. Sleep habits alterations and newly developed sleep disturbances during the COVID-19 pandemic may influence the overall well-being and health (1). Since the beginning of the pandemic, several studies reported a delay in bedtimes and waketimes, and an associated shift in chronotype toward eveningness (2-5).Even though actigraphy and sleep diaries provide a valid and reliable assessment of sleep habits (6,7), to achieve the highest reliability and validity, these methods require an assessment during seven consecutive days including weekends (8). Daily reporting may be perceived by the respondents as an additional burden (6,9), a limitation that may be overcome by the use of single-administration questionnaires (9,10). Since sleep disturbances recognized in the first pandemic outbreak remained stable during new waves of the COVID-19 pandemic (5), single-administration questionnaires may enable screening of large population groups and an extended assessment of sleep disturbances during the pandemic.So far, validated sleep questionnaires have most often aimed at sleep disorders or symptoms associated with sleep disorders (9). Studies commonly report the Pittsburgh sleep Quality Index (PSQI) (11), which provides data on sleep duration, sleep disturbances, and sleep latency during the previous month. However, PSQI reflects mainly sleep quality on workdays (12), while not collecting information on sleep habits on weekends. The Sleep Timing Questionnaire (STQ) has been developed as an alternative to the sleep diary for the healthy adult population, showing good reliability and validity (10). Still, although sleep habits are associated with mood (13), social media use (14-16), learning time in students (17-19), sports or exercise (20), and symptoms of insomnia (21), the STQ does not assess variables such as mood and lifestyle habits.Large studies objectively assessing sleep with wearable devices have recognized sleep timing and sleep duration to be modifiable risk factors for adverse mental health during the current pandemic (22). Young adults are especially at risk for increased mood disorder symptoms, higher levels of perceived stress, and more common alcohol use during the pandemic (23). Even though mood disorders are often reported in pandemic studies on sleep habits, mood itself has been less commonly measured and associated with sleep parameters (24). A review of the literature showed a transactional relationship between mood and emotion (25), indicating that mood is characterized by longer duration than emotion (26). Mood is often assessed with the Brief Mood Introspection Scale (27), the Profile of Mood States (28), or the Visual Analogue Mood Scale (29). A relevant aspect of mood measurement is a hierarchical structure with two broad dimensions in positive and negative affect, and multiple specific states (30). Commonly used mood assessment scales evaluate the basic negative mood of fear/anxiety, sadness/depression, and anger/hostility, as well as at least one positive mood. Therefore, it has been strongly recommended that mood researchers assess a broad range of both positive and negative emotions (30).Linking mood changes and lifestyle habits during the pandemic has been relevant in order to recognize possible predictors of mood changes, especially due to a reported increase in depression (31). Since sleep is often intertwined with mood and lifestyle changes (31), we assumed that a single-format questionnaire comprehensively assessing these variables and sleep may be applicable and timely.The aim of this study was to construct a single-format Split Sleep Questionnaire (SSQ) comprehensively assessing sleep habits, lifestyle habits, and mood changes, as well as to evaluate its reliability and validity in the general population. Sleep habits were validated by using standard instruments such as sleep diary, PSQI, and STAI questionnaires as the measures of construct validity. Additionally, we aimed to assess the psychometric properties of the Mood section and to explore the effects of the COVID-19 pandemic on sleep habits and mood alterations in the general population of Croatia.     

Experience with comprehensive pharmacogenomic multi-gene panel in clinical practice: a retrospective single-center study

AimTo assess the prevalence of actionable pharmacogenetic interventions in patients who underwent pharmacogenetic testing with a multi-gene panel.MethodsWe retrospectively reviewed single-center electronic health records. A total of 319 patients were enrolled who underwent pharmacogenomic testing with the RightMed test panel using TaqMan quantitative real-time PCR method and copy number variation analysis to determine the SNPs in the 27 target genes.ResultsActionable drug-gene pairs were found in 235 (73.7%) patients. Relevant guidelines on genotype-based prescribing were available for 133 (56.7%) patients at the time of testing. Based on the patients’ genotype, 139 (43.6%) patients were using at least one drug with significant pharmacogenetic interactions.ConclusionTwo out of three patients had at least one drug-gene pair in their therapy. Further studies should assess the clinical effectiveness of integrating pharmacogenomic data into patients’ electronic health records.

The field of pharmacogenetics has been booming in the past decades, with research being focused on studying novel genetic variants that impact drug metabolism or pharmacological effect, which ultimately affects the patient’s response to a given dose of medication. Pharmacogenetics examines gene-drug interactions that change pharmacokinetic and/or pharmacodynamic properties of a drug (1). It is impossible to implement any of the principles of personalized medicine without determining the patients'' pharmacogenetic profile before starting a new therapy (2).Several professional organizations, namely, Clinical Pharmacogenetics Implementation Consortium (CPIC) and Dutch Pharmacogenetics Working Group (DPWG), provide comprehensive and understandable guidelines on genotype-based drug prescribing (3,4). Pharmacogenomic prescribing guidelines are growing in number and are available for various drug classes including the cardiovascular drugs, drugs affecting the central nervous system, gastrointestinal drugs, drugs that treat infectious and malignant diseases, immunosuppressives, analgesics, and other (5,6).Several companies specialize in pharmacogenetic panels, making it easily accessible for patients and clinicians of various specialties to obtain the test results in a matter of days or weeks. These commercial tests are developed by industry stakeholders and can be implemented in various settings during the diagnostic or treatment process (7,8). They are comprehensive and include a number of genes that are important for the pharmacologic profile across drug groups, or targeted for a certain category of drugs, ie, psychiatric, analgesics, oncologic drugs, etc. Data on the rate of utilization and clinical utility of such tests are lacking. A recent study found that from 2013 until 2017 only 5712 insured US patients performed pharmacogenetic testing of at least one gene (9). The field of pharmacogenomics is still in its early stages. One of the principal problems is the education of health care providers responsible for ordering and interpreting the test results. In a recent survey, 84.3% of doctors from seven European countries deemed pharmacogenomics relevant for their practice, however 65.7% did not order a pharmacogenomic test in the last year (10). Potential implementation of pharmacogenomics in the clinical practice should be complemented with a clinical decision support tool integrated into the patient’s electronic health record (11,12). In Croatia, pharmacogenomic testing has been available for over a decade, with multiple studies examining population genetics and cost-effectiveness of pharmacogenomic guided therapies (13,14). However, commercial panel-based tests targeting multiple genes known to influence drug response is a new concept that was implemented in 2018 at St. Catherine Hospital in Zagreb (8,15,16).The aim of this retrospective study was to assess the proportion of patients with actionable pharmacogenetic interventions in a single center from 2018 to 2021 who had undergone pharmacogenetic testing of 27 genes by using a commercial gene panel.