A Comparison of Problem‐Based and Didactic Approaches to Learning on an Ambulatory Medicine Clerkship

Teaching in the ambulatory setting is limited by the lack of time for in‐depth discussion of common ambulatory problems. This study was designed to compare the effectiveness of a problem‐based versus didactic approach to teaching common ambulatory problems during a senior ambulatory clerkship. Three outcome measures were examined: (a) student knowledge, measured objectively and by self‐report; (b) student satisfaction; and (c) student self‐directed learning. No significant differences by method were obtained for either student knowledge or student satisfaction. Students in the problem‐based approach demonstrated greater self‐direction in learning as measured by resource utilization and number of hours studied. Conclusions related to learning outcomes, utilization of faculty time, and implications for future student learning are discussed.     

Primary Structure and Antibacterial Activity of Chicken Bone Marrow-Derived β-Defensins

Three biologically active β-defensins were purified by chromatography from chicken bone marrow extract: avian β-defensin 1 (AvBD1), AvBD2, and the newly isolated β-defensin AvBD7. Mass spectrometry analyses showed that bone marrow-derived AvBD1, -2, and -7 peptides were present as mature peptides and revealed posttranslational modifications for AvBD1 and AvBD7 in comparison to their in silico-predicted amino acid sequences. Tandem mass spectrometry analysis using the nanoelectrospray-quadrupole time of flight method showed N-terminal glutaminyl cyclization of mature AvBD7 and C-terminal amidation of mature AvBD1 peptide, while posttranslational modifications were absent in bone marrow-derived mature AvBD2 peptide. Furthermore, mass spectrometry analysis performed on intact cells confirmed the presence of these three peptides in mature heterophils. In addition, the antibacterial activities of the three β-defensins against a large panel of gram-positive and -negative bacteria were assessed. While the three defensins displayed similar antibacterial spectra of activity against gram-positive strains, AvBD1 and AvBD7 exhibited the strongest activity against gram-negative strains in comparison to AvBD2.Defensins belong to the large family of antimicrobial peptides which are important components of innate and adaptive immunity (23). They are 30 to 50 amino acids long and rich in cationic residues, and their tertiary structure is maintained by three disulfide bridges. Depending on their disulfide motifs and the positions of conserved cysteines, defensins are divided into three major groups in vertebrates: α-, β-, and θ-defensins. The largest families comprise α- and β-defensins, which are produced by leukocytes and epithelial cells. The roles of both defensin families are not restricted to antimicrobial effectors at host-pathogen interfaces. In mammals, they have been shown to modulate adaptive immunity by attracting antigen-presenting cells and lymphocytes (45).Interest in defensins as therapeutic drugs is growing because defensins may constitute an alternative to the controversial use of antibiotics. Moreover, defensins may be used as an additive in food preservation. Bird defensins have a double economic interest: besides their interesting antimicrobial properties, the poultry industry may represent an important source of production. The only known bird defensins belong to the β-defensin family (see reference 40 for a review). The three-dimensional structure and broad antimicrobial activity spectrum have been studied only for king penguin avian β-defensin 103b (AvBD103b) (spheniscin-2), which gave new insights into the structure-activity relationship of AvBDs (11, 36). β-Defensins have also been isolated from ostrich heterophils (AvBD1, -2, -4, -7, and -8), the so-called ostricacins, which are highly similar to chicken defensins. The antimicrobial activity of these ostrich peptides is sensitive to cations (35), and their targets seem to be intracellular (34). In chicken, the β-defensin family encompasses 14 genes that have mostly been identified in nucleic acid sequence data (40). The mature peptide of AvBD1 and AvBD2, formerly called gallinacin 1 and gallinacin 2, were the only ones isolated from heterophil granulocytes (7, 8). In these previous studies, the resolution of the mass spectrometry (MS) techniques used allowed for amino acid sequence identification from the average masses of these two peptides but not posttranslational modification characterization. Therefore, in order to further characterize the sequences and the antimicrobial activities of AvBD1 and AvBD2, larger amounts of defensins were required. Bone marrow, in which defensin genes have been shown to be highly expressed (15), should be a relevant source of natural peptides. It is the active site of leukopoiesis and contains the heterophil precursors, which are AvBD1- and AvBD2-producing cells. These cell precursors are present in larger numbers in bone marrow than mature heterophils in blood (25).In the present work, we describe the extraction of AvBD1 and AvBD2 from bone marrow and their fine characterization. With modern proteomic analyses, the primary structure of AvBDs has been refined as well as the N- and C-terminal cleavage sites of mature defensin. Besides AvBD1 and AvBD2, we characterize for the first time AvBD7, whose mature primary sequence was known only as bioinformatic prediction (15, 43). The specific expression of AvBD1, AvBD2, and AvBD7 in mature effector cells has been confirmed using intact-cell matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) MS (ICM-MS). Finally, the antimicrobial activity of the three bone marrow-extracted defensins has been characterized and compared against a large panel of bacterial strains, including zoonotic agents.     

Comparison between serum ferritin and computed tomographic densities of liver,spleen, kidney and pancreas in β-thalassaemia major

Thirty-seven children with β-thalassaemia major, eight children with liver cirrhosis, and 20 matched controls were enrolled in this study. Serum ferritin was determined in each subject by radio-immunoassay and liver enzymes by standard methods. The liver, spleen, kidney and pancreas densities were obtained by computed tomography using a Siemens Somatom 2 Scanner with 8-mm slice thickness. The iron content of liver biopsies from 10 patients was graded by staining. The mean serum ferritin of the thalassaemic patients was significantly higher than that of the control group (p=0.0001). The ferritin of patients with cirrhosis and Wilson's disease was similar to that of the control group. The liver density of the thalassaemic patients was significantly higher than that of the control group (p<0.0001) while that of patients with liver cirrhosis and Wilson's disease was similar to the control group. The liver iron content of patients with liver cirrhosis was within the normal range. The spleen and kidney densities of patients with thalassaemia were higher than that of the control group with p values of 0.02 and 0.056, respectively. The density of the pancreas in patients with thalassaemia was not significantly different from that of the control group, (p=0.52). There was correlation between the liver density and serum ferritin in patients with thalassaemia (r=0.432, p<0.01) while there was no correlation between spleen, pancreas and kidney densities with serum ferritin.     

Effectiveness of Early Intensive Therapy on β-Cell Preservation in Type 1 Diabetes

OBJECTIVE

To assess effectiveness of inpatient hybrid closed-loop control (HCLC) followed by outpatient sensor-augmented pump (SAP) therapy initiated within 7 days of diagnosis of type 1 diabetes on the preservation of β-cell function at 1 year.

RESEARCH DESIGN AND METHODS

Sixty-eight individuals (mean age 13.3 ± 5.7 years; 35% female, 92% Caucasian) were randomized to HCLC followed by SAP therapy (intensive group; N = 48) or to the usual-care group treated with multiple daily injections or insulin pump therapy (N = 20). Primary outcome was C-peptide concentrations during mixed-meal tolerance tests at 12 months.

RESULTS

Intensive-group participants initiated HCLC a median of 6 days after diagnosis for a median duration of 71.3 h, during which median participant mean glucose concentration was 140 mg/dL (interquartile range 134–153 mg/dL). During outpatient SAP, continuous glucose monitor (CGM) use decreased over time, and at 12 months, only 33% of intensive participants averaged sensor use ≥6 days/week. In the usual-care group, insulin pump and CGM use were initiated prior to 12 months by 15 and 5 participants, respectively. Mean HbA_1c levels were similar in both groups throughout the study. At 12 months, the geometric mean (95% CI) of C-peptide area under the curve was 0.43 (0.34–0.52) pmol/mL in the intensive group and 0.52 (0.32–0.75) pmol/mL in the usual-care group (P = 0.49). Thirty-seven (79%) intensive and 16 (80%) usual-care participants had a peak C-peptide concentration ≥0.2 pmol/mL (P = 0.30).

CONCLUSIONS

In new-onset type 1 diabetes, HCLC followed by SAP therapy did not provide benefit in preserving β-cell function compared with current standards of care.Retention of islet cell function in patients with type 1 diabetes has been associated with lower HbA_1c levels and reductions in short- and long-term complications (1,2). Several therapeutic approaches have been tried to preserve residual β-cell function in such patients. One approach, based on animal and human studies, is to optimize glycemic control as soon as possible after diagnosis. In vitro, resting β-cells are less immunogenic and more resistant to autoimmune damage than active β-cells (3). Tight metabolic control at the onset of type 1 diabetes can protect against insulitis in the BB rat (4–6) and insulin therapy in the NOD mouse has immunologic and metabolic effects (7). In humans, β-cell rest induced by closed-loop therapy shortly after the diagnosis of type 1 diabetes was reported to preserve β-cell function as assessed by C-peptide levels 1 year after diagnosis (8). The Diabetes Control and Complications Trial found that assignment to the well-controlled, intensively managed group slowed the rate of decline of stimulated C-peptide levels compared with that in the poorly controlled, conventionally treated group even when intensive metabolic control was initiated between 1 and 5 years after diagnosis (2).With current technology, it may be possible to optimize glycemic control quickly after diagnosis with in-patient closed-loop control followed by home use of sensor-augmented pump (SAP) therapy. To test the hypothesis that use of advanced diabetes technologies within 7 days of onset of type 1 diabetes can preserve endogenous insulin production to a greater extent than current standard care of new-onset type 1 diabetes, we conducted a randomized trial comparing hybrid closed-loop control (HCLC) followed by home use of SAP therapy versus conventional management; the primary outcome was stimulated C-peptide levels 1 year after diagnosis.     

Effects of Leptin Replacement Therapy on Pancreatic β-Cell Function in Patients With Lipodystrophy

OBJECTIVE

Leptin administration is known to directly modulate pancreatic β-cell function in leptin-deficient rodent models. However, human studies examining the effects of leptin administration on β-cell function are lacking. In this study, we examined the effects (16–20 weeks) of leptin replacement on β-cell function in patients with lipodystrophy.

RESEARCH DESIGN AND METHODS

In a prospective, open-label, currently ongoing study, we studied the effects of leptin replacement on β-cell function in 13 patients with congenital or acquired lipodystrophy. Insulin secretory rate (ISR) was calculated by C-peptide deconvolution from plasma glucose and C-peptide levels measured during oral glucose tolerance tests (OGTTs) performed at baseline and after 16–20 weeks of leptin replacement. β-Cell glucose sensitivity and rate sensitivity were assessed by mathematical modeling of OGTT.

RESULTS

There was a significant decrease in triglycerides, free fatty acids, and glycosylated hemoglobin levels (A1C) after leptin therapy. Patients with lipodystrophy have high fasting and glucose-stimulated ISR. However, leptin therapy had no significant effect on fasting ISR, total insulin secretion during OGTT, β-cell glucose sensitivity, rate sensitivity, or insulin clearance.

CONCLUSIONS

In contrast to the suppressive effects of leptin on β-cell function in rodents, 16–20-week treatment with leptin in lipodystrophy patients did not significantly affect insulin secretion or β-cell function in leptin-deficient individuals with lipodystrophy.     

Does Size Really Matter? A Comparison of the Riata Lead Family Based on Size and Its Relation to Performance

Background: Recently, the performance and safety of smaller diameter implantable cardioverter defibrillator (ICD ) leads has been questioned. The purpose of this analysis was to determine the impact of size on lead performance and perforation rates by comparing the performance of 7 French (7F) and 8 French (8F) leads with similar design characteristics implanted by a single operator.
Methods: Patients implanted with a Riata 1580 (8F) or 7000 (7F) series leads (St. Jude Medical, Sylmar, CA, USA) over a 2-year period were evaluated to compare performance and perforation rates.
Results: There were 357 Riata 8F leads and 357 Riata 7F leads implanted in 714 patients. Follow-up ranged from 1 to 24 months. The 8F leads were implanted in the right ventricular apex more often than were 7F leads (129 or 37% vs 72 or 20%, P < 0.0001). Oversensing that did not result in therapy occurred in 2 pts (0.56%) with 8F leads and 1 pt. (0.28%) with a 7F lead (P = 0.56). Oversensing with therapy occurred once in both groups (0.28%, P = NS). One perforation occurred in each group (0.28%, P = NS). Both occurred in leads that were implanted in the right ventricular apex (P = 0.02).
Conclusions: The performance of St. Jude Medical 7F and 8F Riata leads was similar. The incidence of lead-related adverse events was within or below the low end of published acceptable ranges for ICD lead perforation and sensing anomalies. Perforations were less likely to occur in leads that were implanted in nonapical positions.     

A long-term Clinical Observation on Delayed Union and Nonunion of Long Bone Fractures Treated with Decalcified Bone Matrix

Objective To investigate the long-term effect of decalcified bone matrix （DBM） in the treatment of delayed union and nonunion of long bone fractures. Methods From 1986 to 1994, 96 patients with delayed union or nonunion of long bone fractures were treated with DBM. Among them, 38 patients with nonunion were treated with surgical implantation of DBM, 37 with delayed union and 21 with nonunion were treated with percutaneous iniection of DBM. Results All 96 cases were followed up for 4 to 16 years （mean time, 7.5 years）. Of 37 patients with delayed union treated with percutaneous injection, 35 achieved bone union, but 2 with tibial fractures did not. and the union proportion was 94.6%. Of 21 patients with nonunion treated with percutaneous injection, 17 achieved bone union, but 4 （3 with tibial and I with humeral fractures） did not, and the union proportion was 80.1%. The time needed for union was 3 to 8 months （mean, 4.5 months）. Of 38 patients with nonunion treated with implantation of DBM, 36 had bone union, but 2 with fractures in the infcrior 1/3 of the tibia did not, and the union proportion was 94.7%. Conclusion Both percutaneous injection and surgical implantation of DBM can achieve satisfactory therapeutic effects that are even as good as that of autografting. Meanwhile, after dehydration, degreasing, decalcification and irradiation sterilization, DBM is safer and less immunogenic than other bone grafts and can be preserved for a long time so as to be applied both in peacetime and in wartime.     

Visualization of Somatostatin Receptors in Prostate Cancer and its Bone Metastases with Ga-68–DOTATOC PET/CT

Purpose  

To assess DOTATOC-affine somatostatin receptor expression in advanced prostate cancer and its bone metastases with regard to DOTATOC-mediated receptor therapies, using a Ga-68–DOTATOC PET/CT.     

Substrate inhibition of lysosomal hydrolases: α-Galactosidase A and β-glucocerebrosidase

ObjectiveWe have investigated the kinetics of α-galactosidase A and β-glucocerebrosidase deficient in Fabry and Gaucher diseases, respectively.Design and methodsWe have performed spectrofluorymetric measurements of the activity of enzymes using a derivative of 4-methylumbelliferone as a substrate and a human T-cell line as a source of enzymes.ResultsWe have observed the substrate inhibition effect, which is related to temperature.ConclusionsThe diagnostic procedures for Fabry and Gaucher diseases used now in laboratory practice neglect temperature-dependent substrate inhibition, which may significantly reduce the sensitivity of enzyme activity determinations.     

Comparison of myocardial injures between asphyxia and ventricular fibrillation models of cardiac arrests北大核心CSCD

Objective: To compare the difference in cardiac injuries between asphyxia and ventricular fibrillation modes in different periods after cardiac arrest (CA). Methods: The model was established in Cardiopulmonary Resuscitation Lab, Sun Yat-sen University. A total of 35 male SD rats were used to produce the asphyxia or ventricular fibrillation (VF) cardiac arrest models randomly. Both of the two modes were induced 8 minutes cardiac arrest. The myocardial HE stains, mitochondrial respiratory control ratio (RCR), and echocardiography were observed at 4 h, 24 h and 72 h after ROSC (restoration of spontaneous circulation). The results were expressed as (x¯±s), t test was performed to compare between two groups, and one way analysis of variance was used to compare multiple groups. P <0. 05 was considered as significant difference. Results: HE stains showed damages were more serious in the VF mode than in asphyxia mode at 4 h, and both of them had a disorderly-arranged myocardium at 72 h. RCR in VF mode became worse at 4 h, and RCR resumed at 24 h in both modes without significant difference compared with the sham operated rats. The echocardiography showed VF mode had a lower left ventricular ejection fraction (LVEF) than asphyxia mode at 4 h (29.68% vs. 42. 16%, P =0. 03), and there was no difference in LVEF between VF mode and the sham operated rats at 24 h, however no difference in LVEF between the asphyxia and sham operated rats at 72 h. Both of them had a thicker left ventricular anterior wall than the sham operated rats at 72 h (2. 41 mm vs. 1. 72 mm, P = 0. 013; 2. 61 mm vs. 1. 72 mm, P = 0. 007), and there was no significant difference between them. Conclusions: The ventricular fibrillation mode has a more severe injuries in early period, but it recovers sooner than asphyxia one. Both of two groups get compensatory left ventricular hypertrophy in later period of ROSC.     

Reversal of Vanadium-induced Toxicity by Combination Therapy of Tiferron and α-tocopherol in Rat during Pregnancy and their Fetuses

Objective. The aim of this study was to analyze the effect of tiferron (sodium 4, 5-dihydroxybenzene-1, 3-disulfonate) per se and combination with α-tocopherol against vanadium induced developmental toxicity. Vanadium, as vanadyl sulphate pentahydrate, was evaluated for embryotoxic/fetotoxic effect in female albino rats (Sprague Dawley). Methods. The compound was administered by gavage to pregnant animals at a dose of 15 mg/kg/day, p.o. on day 6-15 of pregnancy (organogenesis). Tiferron was given on day 16-18 as chelating agent. Cesarean sections were performed on day 19 of gestation. Results. Maternal toxicity was observed, the level of sugar in the blood decreased, while we observed an increase in serum protein, serum alkaline phosphatase and serum transaminase activity. Level of lipid peroxidation showed enhances value in fetal and maternal liver. Vanadium induced inhibition in glycogen contents. Protein contents were decreased in vital organs where as increased in uterus and placenta. There was increased activity of acid phosphatase with the concomitant decline in alkaline phosphatase, adenosine triphosphatase and succnic dehydrogenase after vanadium intoxication. Toxicant caused severe alteration in histopathological observation of maternal and fetal liver, kidney, uterus and placenta proving its toxic consequences at cellular level. Tiferron along with α-tocopherol dramatically reversed alterations of all variables towards control rather than individual treatment. Conclusion. The combination therapy of tiferron and α-tocopherol played a beneficial role in reducing vanadium induced developmental toxicity.     

Systematic Literature Review of the Impact of Endocrine Monotherapy and in Combination with Targeted Therapy on Quality of Life of Postmenopausal Women with HR+/HER2− Advanced Breast Cancer

Introduction

A major treatment goal for advanced breast cancer (ABC) is to maintain or ideally improve patient quality of life (QoL). Given the changing disease landscape, this systematic literature review (SLR) aims to assess the impact of endocrine therapies (ET), including ET monotherapy (ET mono) and ET combined with targeted therapy (ET + TT), on QoL of women with HR+/HER2? ABC.

Methods

A SLR was conducted to identify randomized controlled trials (RCTs) meeting the following criteria: (1) included ET mono or ET + TT, (2) reported QoL outcomes, (3) focused on women with HR+/HER2? ABC, and (4) published after 2007 (when standardized HER2 testing became available). The databases searched included MEDLINE, EMBASE, Cochrane Library, and key conference proceedings from 2013 to 2016. QoL outcomes for ET mono, ET + TT, and comparisons between the two were summarized from the identified trials.

Results

A total of 11 studies (representing 6 RCTs) were identified. The study populations included first-line (5 studies) and ET-failure settings (6 studies). Across settings, global health status (GHS) maintained or deteriorated slightly on these treatments during the trial period. Time to deterioration (TTD) in QoL measured by GHS was analyzed in 6 studies and 4 RCTs. In the first-line setting, reported median TTD in GHS was similar between ET mono and ET + TT (7.2–13.8 months in ET mono; 11.1 months in ET + TT). In the ET-failure setting, ET + TT showed significantly longer TTD vs. ET mono in GHS (median 5.6–8.4 months in ET mono and 8.3–11.7 months in ET + TT) and some additional domains.

Conclusions

ET + TT users experienced similar QoL in the first-line and ET-failure setting relative to patients on ET mono. Moreover, ET + TT users experienced better QoL outcomes in some domains in the ET-failure setting relative to ET mono users.

Funding

Novartis.

     

Impact of Targeted Therapy on the Quality of End-of-Life Care for Patients With Non–Small-Cell Lung Cancer: A Population-Based Study in Taiwan

Context

Targeted therapies with epidermal growth factor receptor tyrosine kinase inhibitors have been widely used in the treatment of advanced non–small-cell lung cancer (NSCLC). However, little research has focused on the use of targeted therapies at the end of life (EOL).