Impact of minimally invasive surgery on the treatment of esophageal achalasia: a decade of change

BACKGROUND: Twenty years ago an average of 1.5 Heller myotomies were performed per year in our hospital, mostly for patients whose dysphagia did not improve following balloon dilatation or whose esophagus had been perforated during a balloon dilatation. Ten years ago we started using minimally invasive surgery to treat this disease. STUDY DESIGN: This study measures the impact of minimally invasive surgery with regard to the following: the number of patients referred for treatment; the number of patients who came to surgery without previous treatment; and the results of surgical treatment. Between 1991 and 2001, 149 patients had minimally invasive surgery for achalasia: 25 patients (17%) had thoracoscopic Heller myotomy and 124 (84%) had laparoscopic Heller myotomy and Dor fundoplication. Of the 149 patients, 79 patients (53%) had previous treatment (56 patients [71%], balloon dilatation; 7 patients [9%], botulinum toxin injection; 16 patients [20%], both) and 70 patients (43%) had none of these treatments. Mean postoperative followup was 59 +/- 36 months. Patients were divided into two groups: group A, operated on between 1991 and 1995; and group B, operated on between 1996 and 2001. RESULTS: In the past decade, the number of patients referred for surgery has increased substantially--group A, 48; group B, 101; an increasing proportion of patients were referred for surgery without previous treatment--group A, 38%; group B, 51%; and the outcomes of the operation progressively improved--group A, 87%; group B, 95%. CONCLUSIONS: These data show that the high success rate of laparoscopic Heller myotomy for achalasia has brought a shift in practice; surgery has become the preferred treatment of most gastroenterologists and other referring physicians. This has followed documentation that laparoscopic treatment outperforms balloon dilatation and botulinum toxin injection.     

Country-specific estimates and models of HIV and AIDS: methods and limitations

OBJECTIVE: This paper presents the methods used to calculate the end of 1997 country-specific estimates of HIV and AIDS produced by the UNAIDS/WHO Working Group on Global HIV/AIDS and STD Surveillance. The objective of this exercise was to improve estimates on HIV/AIDS by using country-specific models of HIV/AIDS epidemics. The paper describes and discusses the processes and obstacles that were encountered in this multi-partner collaboration including national and international experts. METHODS: The 1997 estimates required two basic steps. First, point prevalence estimates for 1994 and 1997 were carried out and the starting year of the epidemic was determined for each country. The procedures used to calculate the estimates of prevalence differed according to the assumed type of the epidemic and the available data. The second step involved using these estimates of prevalence over time and the starting date of the epidemic to determine the epidemic curve that best described the spread of HIV in each particular country. A simple epidemiological program (EPIMODEL) was used for the calculation of estimates on incidence and mortality from this epidemic curve. RESULTS: Regional models that were used in previous estimation exercises were not able to capture the diversity of HIV epidemics between countries and regions. The result of this first country-specific estimation process yielded higher estimates of HIV infection than previously thought likely, with over 30 million people estimated to be living with HIV/AIDS. The application of survival times that are specific to countries and regions also resulted in higher estimates of mortality, which more accurately describe the impact of the epidemics. At the end of 1997, it was estimated that 11.7 million people worldwide had died as a result of HIV/AIDS since the beginning of the epidemic. CONCLUSION: This exercise is an important step in improving understanding of the spread of HIV in different parts of the world. There are, however, shortcomings in the current systems of monitoring the epidemic. Improvements in HIV surveillance systems are needed in many parts of the world. In addition, further research is needed to understand fully the effects of the fertility reduction as a result of HIV, differing sex ratios in HIV infection and other factors influencing the course and measurement of the epidemic.     

Constitutive receptor systems for drug discovery

This paper discusses the use of constitutively active G-protein-coupled receptor systems for drug discovery. Specifically, the ternary complex model is used to define the two major theoretical advantages of constitutive receptor screening-namely, the ability to detect antagonists as well as agonists directly and the fact that constitutive systems are more sensitive to agonists. In experimental studies, transient transfection of Chinese hamster ovary cyclic AMP response element (CRE) luciferase reporter cells with cDNA for human parathyroid hormone receptor, glucagon receptor, and glucagon-like peptide (GLP-1) receptor showed cDNA concentration-dependent constitutive activity with parathyroid hormone (PTH-1) and glucagon. In contrast, no constitutive activity was observed for GLP-1 receptor, yet responses to GLP-1 indicated that receptor expression had taken place. In another functional system, Xenopus laevi melanophores transfected with cDNA for human calcitonin receptor showed constitutive activity. Nine ligands for the calcitonin receptor either increased or decreased constitutive activity in this assay. The sensitivity of the system to human calcitonin increased with increasing constitutive activity. These data indicate that, for those receptors which naturally produce constitutive activity, screening in this mode could be advantageous over other methods.     

Neural sensitivity to social rejection is associated with inflammatory responses to social stress

Although stress-induced increases in inflammation have been implicated in several major disorders, including cardiovascular disease and depression, the neurocognitive pathways that underlie inflammatory responses to stress remain largely unknown. To examine these processes, we recruited 124 healthy young adult participants to complete a laboratory-based social stressor while markers of inflammatory activity were obtained from oral fluids. A subset of participants (n = 31) later completed an fMRI session in which their neural responses to social rejection were assessed. As predicted, exposure to the laboratory-based social stressor was associated with significant increases in two markers of inflammatory activity, namely a soluble receptor for tumor necrosis factor-α (sTNFαRII) and interleukin-6 (IL-6). In the neuroimaging subsample, greater increases in sTNFαRII (but not IL-6) were associated with greater activity in the dorsal anterior cingulate cortex and anterior insula, brain regions that have previously been associated with processing rejection-related distress and negative affect. These data thus elucidate a neurocognitive pathway that may be involved in potentiated inflammatory responses to acute social stress. As such, they have implications for understanding how social stressors may promote susceptibility to diseases with an inflammatory component.     

Combinational treatment of 5‐fluorouracil and casticin induces apoptosis in mouse leukemia WEHI‐3 cells in vitro

Leukemia is one of the major diseases causing cancer‐related deaths in the young population, and its cure rate is unsatisfying with side effects on patients. Fluorouracil (5‐FU) is currently used as an anticancer drug for leukemia patients. Casticin, a natural polymethoxyflavone, exerts anticancer activity against many human cancer cell lines in vitro, but no other reports show 5‐FU combined with casticin increased the mouse leukemia cell apoptosis in vitro. Herein, the antileukemia activity of 5‐FU combined with casticin in WEHI‐3 mouse leukemia cells was investigated in vitro. Treatment of two‐drug combination had a higher decrease in cell viability and a higher increase in apoptotic cell death, the level of DNA condensation, and the length of comet tail than that of 5‐FU or casticin treatment alone in WEHI‐3 cells. In addition, the two‐drug combination has a greater production rate of reactive oxygen species but a lower level of Ca²⁺ release and mitochondrial membrane potential (ΔΨ_m) than that of 5‐FU alone. Combined drugs also induced higher caspase‐3 and caspase‐8 activities than that of casticin alone and higher caspase‐9 activity than that of 5‐FU or casticin alone at 48 hours treatment. Furthermore, 5‐FU combined with casticin has a higher expression of Cu/Zn superoxide dismutase (SOD [Cu/Zn]) and lower catalase than that of 5‐FU or casticin treatment alone. The combined treatment has higher levels of Bax, Endo G, and cytochrome C of proapoptotic proteins than that of casticin alone and induced lower levels of B‐cell lymphoma 2 (BCL‐2) and BCL‐X of antiapoptotic proteins than that of 5‐FU or casticin only. Furthermore, the combined treatment had a higher expression of cleaved poly (ADP‐ribose) polymerase (PARP) than that of casticin only. Based on these findings, we may suggest that 5‐FU combined with casticin treatment increased apoptotic cell death in WEHI‐3 mouse leukemia cells that may undergo mitochondria and caspases signaling pathways in vitro.     

Tetrandrine inhibits human brain glioblastoma multiforme GBM 8401 cancer cell migration and invasion in vitro

Tetrandrine (TET) has been reported to induce anti‐cancer activity in many human cancer cells and also to inhibit cancer cell migration and invasion. However, there are no reports to show TET inhibits cell migration and invasion in human brain glioblastoma multiforme GBM 8401 cells. In this study, we investigated the anti‐metastasis effects of TET on GBM 8401 cells in vitro. Under sub‐lethal concentrations (from 1, 5 up to 10 μM), TET significantly inhibited cell mobility, migration and invasion of GBM 8401 cells that were assayed by wound healing and Transwell assays. Gelatin zymography assay showed that TET inhibited MMP‐2 activity in GBM 8401 cells. Western blotting results indicated that TET inhibited several key metastasis‐related proteins, such as p‐EGFR_(Tyr1068), SOS‐1, GRB2, Ras, p‐AKT_(Ser473) and p‐AKT_(Thr308), NF‐κB‐p65, Snail, E‐cadherin, N‐cadherin, NF‐κB, MMP‐2 and MMP‐9 that were significant reduction at 24 and 48 hours treatment by TET. TET reduced MAPK signaling associated proteins such as p‐JNK1/2 and p‐c‐Jun in GBM 8401 cells. The electrophoretic mobility shift (EMSA) assay was used to investigate NF‐κB and DNA binding was reduced by TET in a dose‐dependently. Based on these findings, we suggested that TET could be used in anti‐metastasis of human brain glioblastoma multiforme GBM 8401 cells in the future.     

The role of MAPK and Nrf2 pathways in ketanserin-elicited attenuation of cigarette smoke-induced IL-8 production in human bronchial epithelial cells

Cigarette smoking is a major risk factor in chronic obstructive pulmonary disease (COPD) with chronic airway inflammation as a key feature. Blockade of serotonin receptor 2A (5-HTR(2A)) with ketanserin has been found to improve lung function in COPD patients. Furthermore, ketanserin has been shown to possess anti-inflammatory properties in vivo. In this study, we investigated the antioxidative and anti-inflammatory properties of ketanserin and its underlying mechanism of action on cigarette smoke-induced interleukin (IL)-8 release in vitro. Primary normal human bronchial epithelial cells and human bronchial epithelial cell line (BEAS-2B) were treated with or without ketanserin prior to exposure to cigarette smoke medium (CSM). Exposure to CSM caused elevation of both mRNA and release of IL-8 with increased phosphorylation of p38 and extracellular signal-regulated kinases 1 and 2 (ERK1/2). Consistently, CSM-induced IL-8 release was blocked by SB203580, U0126, or MEK1 small interfering RNA (siRNA) but not SP600125. On the other hand, CSM caused a dose-dependent decrease in the ratio of reduced glutathione to oxidized glutathione (rGSH/GSSG) together with an increased translocation of Nrf2 to the nucleus demonstrated by Western blot analysis. Knock down of Nrf2 by siRNA completely blocked CSM-induced IL-8 release. Ketanserin suppressed CSM-induced IL-8 release by inhibiting p38, ERK1/2 MAPK, and Nrf2 signaling pathways and partially inhibited CSM-induced reduction of rGSH/GSSG ratio. Our data demonstrated the novel antioxidative and anti-inflammatory role of ketanserin via the Nrf2 signaling pathway in CSM-exposed human bronchial epithelial cells. This may open up new perspectives in the development of novel therapeutic targets in the treatment of cigarette smoke-related COPD.     

Current Status of Nutrition Training in Graduate Medical Education From a Survey of Residency Program Directors

Introduction: Nutrition leaders surmised graduate medical nutrition education was not well addressed because most medical and surgical specialties have insufficient resources to teach current nutrition practice. A needs assessment survey was constructed to determine resources and commitment for nutrition education from U.S. graduate medical educators to address this problem. Methods: An online survey of 36 questions was sent to 495 Accreditation Council for Graduate Medical Education (ACGME) Program Directors in anesthesia, family medicine, internal medicine, pediatrics, obstetrics/gynecology, and general surgery. Demographics, resources, and open‐ended questions were included. There was a 14% response rate (72 programs), consistent with similar studies on the topic. Results: Most (80%) of the program directors responding were from primary care programs, the rest surgical (17%) or anesthesia (3%). Program directors themselves lacked knowledge of nutrition. While some form of nutrition education was provided at 78% of programs, only 26% had a formal curriculum and physicians served as faculty at only 53%. Sixteen programs had no identifiable expert in nutrition and 10 programs stated that no nutrition training was provided. Training was variable, ranging from an hour of lecture to a month‐long rotation. Seventy‐seven percent of program directors stated that the required educational goals in nutrition were not met. The majority felt an advanced course in clinical nutrition should be required of residents now or in the future. Conclusions: Nutrition education in current graduate medical education is poor. Most programs lack the expertise or time commitment to teach a formal course but recognize the need to meet educational requirements. A broad‐based, diverse universal program is needed for training in nutrition during residency.     

Community-living older people’s interpretation of the Norwegian version of older people’s quality of life (OPQOL) questionnaire

The aim of this study is to investigate how community-living older people interpret the Norwegian version of Older People's Quality of Life (OPQOL) questionnaire. The original OPQOL questionnaire was translated based on guidelines for cross-cultural translation. The Three-Step Test-Interview instrument was adopted to investigate how community-living older people interpreted the questionnaire. Data were collected from 14 participants (72–89 years). The questionnaire was filled in under observation. Semi-structured interviews were then conducted to clarify the observational data and elicit the participants’ experiences and opinions. Lastly, data were analysed using a hermeneutic interpretation approach. Our findings indicate that most of the participants managed to complete the OPQOL questionnaire without problems. The data analysis resulted in four primary themes: relevance & applicability, formulation, consistency & accuracy and subjectivity. The questionnaire covered all aspects related to the participants’ quality of life. However, statements related to religion were found to be irrelevant to their quality of life. Most of the participants thought that religion, philosophy and culture should be separate rather than included in the same statement. The participants missed the option of ‘not applicable’ when the statements were irrelevant to them. The statements are formulated in both positive and negative ways, which was sometimes confusing to them. The participants perceived phases such as “around me” “local,” and “things” as ambiguous, and thus they raised concerns about whether the OPQOL questionnaire could capture consistent data regarding their quality of life. The results of this study pinpoint the issues that community-living older people faced when interpreting and answering the Norwegian version of OPQOL questionnaire. These issues were mostly caused by sociocultural differences. Our work provides an overview of the changes that must be made in the questionnaire in order to address these sociocultural differences while using the OPQOL questionnaire in the Norwegian context.