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Objectives: To compare the ability of SureSmileTM, InsigniaTM and InvisalignTM to achieve predicted intra-arch tooth positions and further compare their objective grading scores for alignment/rotations, marginal ridge relationships and buccolingual inclination.

Two models were used to provide ongoing education about Alzheimer's disease for primary care physicians in a Veterans Health Administration (VHA) network including 8 facilities. The train the trainer model developed by the John A. Hartford Foundation and the American Geriatrics Society was used to prepare physician leaders to conduct Memory Loss Tool Kit sessions for colleagues in their VHA settings. Videoconference techniques were used to present case-based Grand Rounds about best practices around particular patient situations. Methods and evaluation of both programs are discussed. Successful follow through by physician leaders requires ongoing incentives and support. The Videoconference Grand Rounds Program requires skill to initiate and maintain effective technology. Both programs demonstrate successful outcomes. [ABSTRACT FROM AUTHOR]

Abstract Background Several physiological adaptations occur in the respiratory muscles in rodent models of elastase-induced emphysema. Although the contractile properties of the diaphragm are altered in a way that suggests expression of slower isoforms of myosin heavy chain (MHC), it has been difficult to demonstrate a shift in MHCs in an animal model that corresponds to the shift toward slower MHCs seen in human emphysema. Methods We sought to identify MHC and corresponding physiological changes in the diaphragms of rats with elastase-induced emphysema. Nine rats with emphysema and 11 control rats were studied 10 months after instillation with elastase. MHC isoform composition was determined by both reverse transcriptase polymerase chain reaction (RT-PCR) and immunocytochemistry by using specific probes able to identify all known adult isoforms. Physiological adaptation was studied on diaphragm strips stimulated in vitro. Results In addition to confirming that emphysematous diaphragm has a decreased fatigability, we identified a significantly longer time-to-peak-tension (63.9 ± 2.7 ms versus 53.9 ± 2.4 ms). At both the RNA (RT-PCR) and protein (immunocytochemistry) levels, we found a significant decrease in the fastest, MHC isoform (IIb) in emphysema. Conclusion This is the first demonstration of MHC shifts and corresponding physiological changes in the diaphragm in an animal model of emphysema. It is established that rodent emphysema, like human emphysema, does result in a physiologically significant shift toward slower diaphragmatic MHC isoforms. In the rat, this occurs at the faster end of the MHC spectrum than in humans.

Competing Interests: The authors report no conflicts of interest.

Shared decision-making is appropriate for clinical decisions involving multiple reasonable options, which occur frequently in the cardiovascular care of older adults. The process includes the communication of relevant factual information between the patient and the clinician, elicitation of patient preferences, and a mutual agreement on the best course of action to meet the patient's personal goals. For older adults, there are common challenges and considerations with regard to shared decision-making, some of which (eg, cognitive impairment) may be biologically linked to cardiovascular disease. There are tools designed to facilitate the shared decision-making process, known as decision aids, which are broadly effective although have shortcomings when applied to older adults. Novel approaches in clinical research and health systems changes will go some way toward improving shared decision-making for older adults, but the greatest scope for improvement may be within the grass roots areas of communication skills, interdisciplinary teamwork, and simply asking our patients what matters most., (© 2019 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc.)

Purpose: Nongeriatricians must acquire skills and knowledge in geriatric medicine to ensure coordinated care of older adults' complex conditions by interspecialty and interprofessional teams. Chief residents (CRs) are an ideal target for an educational intervention. This study examined whether the Boston Medical Center Chief Resident Immersion Training (CRIT) in the Care of Older Adults was replicable at diverse medical institutions., Method: Between 2008 and 2010, 12 institutions in 11 states received funding, technical support, and a common program model. Each implemented 2.5-day CRITs, consisting of a patient case, geriatrics-related lectures, CR leadership sessions, action project planning, and networking time. Site faculty conducted 21 CRITs for 295 CRs representing 28 specialties. CRs completed knowledge pre- and posttests, and self-report baseline and six-month follow-up surveys. Outcome measures were change in pre- and posttest score, and change from baseline to six months in self-reported surveys., Results: Response rate for CRs was 99% (n = 293) for the pre-post tests and 78% (n = 231) for matchable baseline and follow-up surveys. Participants' knowledge increased from 6.32 to 8.39 (P < .001) averaged from 12 questions. CRs' self-reported ability to apply clinical problem-solving skills to older patients (P < .001), number of geriatrics topics taught (P < .001), frequency of geriatrician consultations (P = .017), confidence in leadership skills (P < .001), and confidence to conduct CR work (P < .001) increased from baseline to follow-up., Conclusions: CRIT is an innovative way to give nongeriatricians knowledge and skills to treat complex older patients.

Background: Many patients who survive an intensive care unit admission develop post-intensive care syndrome and face significant long-term physical, cognitive, and mental health impairments. The intensive care unit diary is a reality-sorting tool that is effective in aiding patients to connect their flashbacks and delusional memories to actual events., Objectives: To describe implementation of an intensive care unit diary in the cardiac intensive care unit and to describe the patient's perspective of the diary., Methods: Consent for participation in the study was given by the patient health care proxy or a family member. The study consisted of 3 phases: writing in the diary about the patient's events in the cardiac intensive care unit, a follow-up visit with the patient within 1 week of cardiac intensive care unit transfer, and a follow-up telephone call 2 months after hospital discharge., Results: Of 26 patients, 13 completed all phases of the study. Four themes were identified from the transcripts of the patients' responses: (1) The diary allowed patients to correlate memories to actual events, (2) it enabled patients to read about their families' experiences during their critical illness, (3) recovery was an emotional process that affected the patient's readiness to read the diary, and (4) patients expressed a desire for more entries by caregivers., Conclusions: The intensive care unit diary can help patients gain clarity of their time in the cardiac intensive care unit. Additional research on the use of the diary and long-term patient follow-up is warranted., (©2018 American Association of Critical-Care Nurses.)

Background: Nurses in the cardiac intensive care unit often attend professional education opportunities. However, it is difficult to share this information among nursing staff. Varying schedules, different shifts, and patient acuity limit the amount of time available for peer-to-peer sharing of educational information. A review of the literature revealed scant research on blogging for peer-to-peer education in general and particularly in nursing., Objectives: To explore nurses' perception of the effectiveness of using a blog as a forum to provide peer-to-peer sharing of relevant professional education., Methods: Using a simple, free blogging website, the unit's nursing practice council developed a private blog for educational information sharing among the nursing staff. An online survey was administered to the unit's staff 15 months after the blog was implemented., Results: Most respondents indicated that they thought the blog is an effective way to share professional education (86%), keeps them abreast of evidence-based practice (81%), and has led to practice change (59%). Nearly 80% of respondents agreed that they are more likely to attend professional conferences, and 62% would consider contributing blog posts., Conclusion: The survey results suggest that blogging may be an effective method of peer-to-peer sharing of education, although more rigorous research is required in this area., (©2017 American Association of Critical-Care Nurses.)

Geriatrics as a field has been fortunate to have the support of several philanthropic organizations to advance geriatrics education and training in the past two decades. Awardees of such grants were presented with unparalleled opportunities to develop new and innovative educational initiatives affecting learners at multiple levels and in multiple disciplines and specialties. The lessons learned from the Donald W. Reynolds Foundation initiatives about effect and sustainability are invaluable to the ongoing strategic development of geriatrics nationally. This article highlights successful educational initiatives developed at four institutions with past and current Donald W. Reynolds Foundation funding. Following an ice hockey playbook, this article identifies 10 strategies and initiatives to "stay in the geriatrics game" by training hospitalists and subspecialty providers. The authors' collective experience suggests that geriatrics educational initiatives can not only influence provider education, but also improve the care of older adults in multiple settings., (© 2014, Copyright the Authors Journal compilation © 2014, The American Geriatrics Society.)

Entrustable professional activities (EPAs) describe the core work that constitutes a discipline's specific expertise and provide the framework for faculty to perform meaningful assessment of geriatric fellows. This article describes the collaborative process of developing the end-of-training American Geriatrics Society (AGS) and Association of Directors of Geriatric Academic Programs (ADGAP) EPAs for Geriatric Medicine (AGS/ADGAP EPAs). The geriatrics EPAs describes a geriatrician's fundamental expertise and how geriatricians differ from general internists and family practitioners who care for older adults., (© 2014, Copyright the Authors Journal compilation © 2014, The American Geriatrics Society.)

Web-based learning methods are being used increasingly to teach core curriculum in medical school clerkships, but few studies have compared the effectiveness of online methods with that of live lectures in teaching the same topics to students. Boston University School of Medicine has implemented an online, case-based, interactive curriculum using videos and text to teach delirium to fourth-year medical students during their required 1-month Geriatrics and Home Medical Care clerkship. A control group of 56 students who received a 1-hour live delirium lecture only was compared with 111 intervention group students who completed the online delirium curriculum only. Evaluation consisted of a short-answer test with two cases given as a pre- and posttest to both groups. The total possible maximum test score was 34 points, and the lowest possible score was -8 points. Mean pre- and posttest scores were 10.5 ± 4.0 and 12.7 ± 4.4, respectively, in the intervention group and 9.9 ± 3.5 and 11.2 ± 4.5, respectively, in the control group. The intervention group had statistically significant improvement between the pre- and posttest scores (2.21-point difference; P < .001), as did the control group (1.36-point difference; P = .03); the difference in test score improvement between the two groups was not statistically significant. An interactive case-based online curriculum in delirium is as effective as a live lecture in teaching delirium, although neither of these educational methods alone produces robust increases in knowledge., (© 2012, Copyright the Authors Journal compilation © 2012, The American Geriatrics Society.)

Intractable and untreatable pain from cancer remains a challenge for both patients and clinicians. The pain may be related to the disease itself or the consequences of treatment, such as surgery, chemotherapy or radiation therapy. Cancer pain is intense and has a major impact on patients' quality of life and survival. A significant number of patients receiving analgesic therapy with opioids report persisting pain of a higher intensity than the pain in those who were not on this class of drugs. The pathophysiology of pain in cancer patients is complex and remains poorly understood. Several research groups have studied and demonstrated that cancer and cancer-related symptoms may have an underlying problem of membrane hyper-excitability due to over-presentation of sodium channels and glutamate build-up or over-stimulation of glutamate/N-methyl-D-aspartate (NMDA)/α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) system in cancer cells and the body. Dimethyl sulfoxide (DMSO) is a naturally derived, inexpensive, non-toxic solvent and pharmaceutical agent that has been demonstrated to have numerous health enhancing and therapeutic benefits. In the present article, we provide the scientific evidence and substantiate possible application of DMSO as a well-tolerated excitatory modulator in the management of cancer pain.

The number of children suffering from atopic eczema has increased over the past 30 years especially in children between the ages of 2 and 5 years. These is a significant group of eczematous children that are resistant to standard therapy. Babies and children with eczema suffer pain, irritation and disfigurement from the dermatitis. In this study, we have followed 14 cases of pediatric patients (ages of 8 months to 64 months) with a history of resistant eczema for a period of at least six months. All of these children received 300 mg to 500 mg standardized Lactobacillus rhamnosus cell lysate daily as an immunobiotic supplement. The results of this open label non-randomized clinical observation showed a substantial improvement in quality of life, skin symptoms and day- and nighttime irritation scores in children with the supplementation of Lactobacillus rhamnosus lysate. There were no intolerance or adverse reactions observed in these children. Lactobacillus rhamnosus cell lysate may thus be used as a safe and effective immunobiotic for the treatment and prevention of childhood eczema and possible other types of atopy (allergic diseases).

The trend in asthma therapy for the last two decades has been based on the suppression of inflammation and bronchodilation via adrenergic agonism or cholinergic antagonism. These strategies help to control asthmatic symptoms but do not lead to a cure. Substantial populations of patients may still have poorly managed symptoms and suffer a decline in quality of life due to the disease. Reversible airflow obstruction and nonspecific airway reactivity are the key features of asthma. Inflammatory changes do not correlate always with symptoms in asthma patients. It is our opinion that the primary defect in asthma is cell membrane excitation-bronchoconstriction and reactivity-rather than inflammation. Our research, clinical experience and the accumulated evidence from medical literature strongly suggest that controlling other excitatory mechanisms such as voltage-gate sodium channel and glutamate receptors in the central nervous system and lung tissue could lead to more effective and safer strategies for asthma prevention and treatment.

As the population ages, it is important that graduating medical students be properly prepared to treat older adults, regardless of their chosen specialty. To this end, the Association of American Medical Colleges (AAMC) and the John A. Hartford Foundation convened a consensus conference to establish core competencies in geriatrics for all graduating medical students. An ambulatory geriatric clerkship for fourth-year medical students that successfully teaches 24 of the 26 AAMC core competencies using an interdisciplinary, team-based approach is reported here. Graduating students (N=158) reported that the clerkship was successful at teaching the core competencies, as evidenced by positive responses on the AAMC Graduation Questionnaire (GQ). More than three-quarters (80-93%) of students agreed or strongly agreed that they learned the seven geriatrics concepts asked about on the GQ, which cover 14 of the 26 core competencies. This successful model for a geriatrics clerkship can be used in many institutions to teach the core competencies and in any constellation of geriatric ambulatory care sites that are already available to the faculty.

Background and Objectives: We addressed a lack of geriatric content in our third-year family medicine clerkship. Adding this content posed a challenge in that students are dispersed to clinical sites across New England. Our goal was to promote student skill in functional assessment of elderly patients., Methods: We used multiple formats: a workshop, a small-group case discussion, an online video, and an online discussion of a new geriatric case. Students were directed to use five assessment tools on actual patients in the office and on a home visit., Results: A total of 155 students participated in the new curriculum. Students completed a required home visit on an older patient and evaluated geriatric patients in an office setting. They performed the Mini-Mental State Exam (MMSE), Activities of Daily Living Scale (ADL), Instrumental Activities of Daily Living Scale (IADL), Geriatric Depression Scale (GDS), and Get-Up-and-Go tests in patients in both settings. There was significant improvement from before to after the clerkship in identification of the appropriate geriatric assessment tool to use (MMSE 86% to 96%; ADL/IADL 32% to 94%; GDS 71% to 94%, and Get-Up-and-Go 4% to 58%). Students evaluated the curriculum positively., Conclusions: We were able to successfully increase the correct selection of and document high rates of use of geriatric functional assessment tools in our third-year family medicine clerkship using a mixture of teaching methods.

Chief residents (CRs) play a crucial role in training residents and students but may have limited geriatrics training or formal preparation for their CR role. A 2-day off-site chief resident immersion training (CRIT) addressed these challenges. Objectives were to foster collaboration between disciplines in the management of complex older patients, increase knowledge of geriatrics principles to incorporate into teaching, enhance leadership skills, and help CRs develop an achievable project for implementation in their CR year. Three cohorts totaling 47 trainees and 18 faculty mentors from 13 medical and surgical disciplines participated over 3 successive years. The curriculum, developed and taught by a multidisciplinary team, featured an interactive surgical case, mini-lectures on geriatrics topics, seminars to enhance teaching and leadership skills, and one-on-one mentoring to develop a project in geriatric care or education. Evaluation included pre- and postprogram tests and self-report surveys and two follow-up surveys or interviews. In 2006 and 2007, scores on a 12-item objective knowledge test increased significantly (P<.001) from before to immediately after CRIT. Self-report knowledge and confidence in teaching geriatrics also increased significantly (P<.05) in all formally covered topics. Mean enhancement of CR skills was 4.3 (1=not at all, 5=very much). Eleven months after CRIT, all but five CRs had implemented at least part of their action projects. CRs reported improved care of older patients, better leadership skills, more and better geriatrics teaching, and more collaboration between disciplines. A 2-day interactive program for CRs can increase institutional capacity regarding geriatrics teaching and care of elderly patients across medical specialties.

Melatonin is a neurohormone naturally found in humans. Melatonin plays a role in maintaining sleep-wake rhythms; supplementation may help to regulate sleep disturbance that occur with jet lag, rotating shift-work and depression. Preliminary study of melatonin has shown potential for use in the treatment of epilepsy, tinnitus, migraine and neurodegenerative diseases. The latest publication in the Journal of Pineal Research by Edward Mills and colleagues has shown a compelling role of melatonin for the treatment of cancer. Melatonin's consistent relationship with cancer has been shown in many studies assessing links between shift work and cancer rates. High levels of melatonin have been linked to slower cancer progression. How melatonin affects cancer remains largely unclear. Although previous studies suggest different possible mechanisms, many of them are far distant from the primary physiological role of melatonin as a neurohormone. Conflicting studies are found on the role of melatonin in neurodegenerative diseases and cancer. In this article, we try to build and substantiate a neurobiological concept for the anticancer effects of melatonin.

Evidence of poor performance in the evaluation and management of common geriatric conditions suggests the need for changing physician behavior in these areas. Traditional lecture-style continuing medical education (CME) has not been shown to be effective. Expert faculty initially trained 60 nonexpert peer educators to conduct small-group, learner-centered CME using tool kits on memory loss, incontinence, and depression. Peer educators presented 109 community-based sessions to 1,309 medical practitioners. Surveys were administered to community participants immediately and 6 months after a session. Evidence of effectiveness included statistically significant increases in self-reported knowledge, attitudes, and office-based practices on the target topics at the time of training and at the 6-month follow-up (P<.001) and two-thirds of respondents reporting continued use of three or more tools at 6 months. Participants reported that the interactive presentation aided their understanding of and ability to use the tool kits more than an off-the-shelf review (mean rating+/-standard deviation 4.1+/-0.71, with 1 = not at all and 5 = significantly). After the formal evaluation period, additional information about the project dynamics and tool kits was obtained through a small interview sample and an on-line survey, respectively. Receiving copies of the tool kits was an important factor in enabling educators to offer sessions. Barriers to offering sessions included finding time, an audience, and space. Findings suggest that modest positive changes in practice in relation to common geriatric problems can be achieved through peer-led, community-based sessions using principles of knowledge translation and evidence-based tool kits with materials for providers and patients.

Cancer, in general, is considered a disease of genetic mutation. Many questions are, however, unanswered. How exactly do mutations occur in the cells? How do gene mutations interface with the cell microenvironment and macroenvironment to create cancer phenotypes? Is mutation the cause of cancer or the consequence of special adaptive responses to aging; hormonal imbalance; physical, chemical and biologic stresses and damage? What makes cancer spread in the body and invade other organs causing death to the patient? In this paper, we hypothesize that the cellular hyperexcitability via stimulation of mineral channels (e.g. sodium voltage-gated channels) and ligand excitatory receptors (e.g. glutamate and other neuron and non-neuronal excitatory receptors) could be a significant causative and pathogenic factor of cancer. Managing hyperexcitatory states of the cells through lifestyle, nutritional changes, phytochemical and pharmaceutical medications theoretically could be a prospective direction in cancer prevention and therapy.

Cancer remains one of the most difficult and elusive disorders to prevent and treat, despite great efforts in research and treatment over the last 30 years. Researchers have tried to understand the pathogenesis of cancer by discovering the single cellular mechanism or pathway derived from a genetic mutation. There are limited efforts made toward discovering a unified concept of cancer. We propose a neuro-bioenergetic concept of cancer pathogenesis based on the central mechanism of cellular hyperexcitability via inducible overexpression of voltage-gated ion channels, ligand-gated channels and neurotransmitters. Exploration of this concept could lead to a better understanding of the cause of cancer as well as developing more effective and specific strategies toward cancer prevention and treatment.

For much of the twentieth century, quality of care was defined specifically in terms of physician characteristics and behaviors. High-quality physicians were well trained, knowledgeable, skillful, and compassionate. More recently, quality of care has been defined in terms of systems of care. High-quality organizations develop and adopt practices to reduce adverse events and optimize outcomes. This essay discusses this transformation from physician-based to organization-based concepts of quality and the consequences for patient care and medical professionalism.

Many community-based internists and family physicians lack familiarity with geriatrics knowledge and best practices, but they face overwhelming fiscal and time barriers to expanding their skills and improving their behavior in the care of older people. Traditional lecture-and-slide-show continuing medical education (CME) programs have been shown to be relatively ineffective in changing this target group's practice. The challenge for geriatrics educators, then, is to devise CME programs that are highly accessible to practicing physicians, that will have an immediate and significant effect on practitioners' behavior, and that are financially viable. Studies of CME have shown that the most effective programs for knowledge translation in these circumstances involve what is known as active-mode learning, which relies on interactive, targeted, and multifaceted techniques. A systematic literature review, supplemented by structured interviews, was performed to inventory active-mode learning techniques for geriatrics knowledge and skills in the United States. Thirteen published articles met the criteria, and leaders of 28 active-mode CME programs were interviewed. This systematic review indicates that there is a substantial experience in geriatrics training for community-based physicians, much of which is unpublished and incompletely evaluated. It appears that the most effective methods to change behaviors involved multiple educational efforts such as written materials or toolkits combined with feedback and strong communication channels between instructors and learners.

Over the last 20 years, the prevalence of asthma has nearly doubled in industrialized countries. A similar increase has been predicted for the next two decades. Asthma is major illness in terms of morbidity and suffering, asthma is the leading cause of hospitalizations in children under 15 years of age. According to many top experts, asthma is correctly characterized as a syndrome rather than disease. This lack of definition for asthma makes the search for a cause, prevention and potential cure elusive. Episodic airway obstruction and reversible bronchial hyperresponsiveness to non-specific irritants are the major symptoms of asthma. Airway inflammation is now widely accepted as the key factor underlying the pathogenesis of asthma. However, many patients show no signs of inflammation, yet they still have severe airflow limitation and asthma symptoms. The primary clinical symptoms of asthma are attacks of shortness of breath, wheezing, and coughing resulting from excessive and inappropriate constriction of the airway smooth muscle. Our research suggests a possible epileptic or hyper-excitatory condition of bronchial system in asthma pathogenesis. The paroxysmal, spasmodic character of asthma attacks may be similar to seizures. We propose a unified pathogenetic mechanism of asthma as a syndrome of inducible or genetically predisposed membrane hyper-excitability (bronchial epilepsy).

As the size of the aged American population increases, so too does the shortage of trained providers in geriatrics. Educational strategies to train physicians at all levels of experience within adult medical and surgical disciplines are needed to complement fellowship training, given the small size of most academic faculties in geriatrics. This article describes a unique faculty development program that creates geriatrically oriented faculty in multiple disciplines. The Boston University Center of Excellence in Geriatrics (COE), funded by the John A. Hartford Foundation, has trained 25 faculty members. Four to six scholars enter the program each year and participate in the COE 1 day per week. Nine months are spent in four content modules-Geriatrics Content, Clinical Teaching, Evidence-based Medicine, and Health Care Systems; 3 months are spent in supervised scholarly activities and clinical settings. A self-report questionnaire and a structured interview were used to evaluate the outcomes of participation in the COE. The results from the first 4 years of the program are reported. The response rate was 83% for the self-report questionnaire and 75% for the structured interview. The results indicate that the COE is effective in improving scholars' assessment and management of older patients. The structured interview revealed that the COE program promotes the integration of geriatrics into clinical teaching at the medical student and resident level. Participants also completed scholarly projects in geriatrics. This program effectively trains faculty scholars to better care for older adults and to teach others to do likewise.

Background: Submucosal saline solution injection may limit the depth of thermal injury to the gut wall by acting as a heat-sink and by increasing the distance between burn and serosa. The aim of this study was to determine the effect of submucosal saline solution injection on depth of colonic thermal injury produced by commonly used endoscopic thermal modalities., Methods: Longitudinal colotomy incisions were made on the antimesenteric colonic border of anesthetized swine. Lesions were made by using a bipolar device (20 W, 2 seconds), heat probe (30 J); monopolar contact with hot biopsy forceps (20 W, 2 seconds), and monopolar noncontact with argon plasma coagulation (45 W, 3 seconds). Ten or more lesions were created with each device. Lesions were made with or without prior submucosal injection of 2 mL of normal saline solution. After 24 hours the lesions were excised for histologic analysis. Injury was assessed in relation to the severity of damage to the deep (longitudinal) muscle layer., Results: The proportions of control lesions (without submucosal saline solution injection) in which deep injury was evident were as follows: argon plasma coagulation, 86%; hot biopsy forceps, 64%; heat probe, 50%; bipolar device, 18%. Submucosal saline solution injection significantly reduced the proportions of lesions with deep injury for argon plasma coagulation (p = 0.009) and heat probe (p = 0.03), but not hot biopsy forceps or bipolar device (argon plasma coagulation, 86% to 21%; heat probe, 50% to 0%; hot biopsy forceps, 64% to 50%; bipolar device, 18% to 9%)., Conclusions: At equivalent energy outputs, the bipolar device results in less deep injury than the monopolar or heat probe. Submucosal saline solution injection reduced injury to the muscularis propria caused by both heat probe and argon plasma coagulation, but not hot biopsy forceps. Despite submucosal saline solution injection, caution should be exercised when using prolonged monopolar cautery.

Background: Argon plasma coagulation has been rapidly accepted for endoscopic obliteration of vascular lesions and superficial tumors. Depth of injury is thought to be limited through preferential discharge of energy to nondesiccated tissue. However, argon plasma coagulation-induced injury has not been well characterized. The aim of this study was to characterize argon plasma coagulation-induced colonic injury by using a porcine model., Methods: Laparotomy was performed in 6 female swine and the colon exteriorized with the subjects under general anesthesia. Lesions were made with an argon plasma coagulation probe held perpendicular and 2 mm from the mucosa. Variables studied were as follows: power (45 W, 60 W, and 75 W) and duration (1, 2, or 3 seconds; n = 11 for each power/duration combination). Injury was graded as either superficial or deep, involving the muscularis propria., Results: Circular muscle layer injury correlated closely with power (p = 0.02), duration (p = 0.001), and total energy delivered (r = 0.977). Longitudinal muscle damage was associated with duration of burn (p = 0.001) and total energy delivered (r = 0.855), but correlated poorly with power (p = 0.40). No perforations occurred. Submucosal injection of saline solution had a protective effect with reductions in circular (90% to 10%, p = 0.002) and longitudinal muscle injury (50% to 0%, p = 0.1)., Conclusions: Injury to the muscularis propria occurs at recommended settings for argon plasma coagulation. Injury correlates with power setting, duration of burn, and total energy delivery. Protective arcing to nondesiccated tissue does not appear to be significant in vivo. Submucosal injection of saline solution protects against deep injury.

Background & Aims: Our previous studies have shown that Cryptosporidium parvum induces biliary epithelial cell apoptosis in vivo and causes apoptosis in bystander uninfected biliary epithelia in vitro. We analyzed C. parvum-induced nuclear factor kappa B (NF-kappaB) activation in human biliary epithelial cells and assessed its relevance to epithelial cell apoptosis., Methods: In vitro models of cryptosporidial infection using a human biliary epithelial cell line were used to assay C. parvum- induced NF-kappaB activation and associated apoptosis., Results: Degradation of I(kappa)B and nuclear translocation of the NF-kappaB family of proteins (p65 and p50) were observed in the biliary epithelial cell cultures directly exposed to the parasite. Activation of NF-kappaB was found only in directly infected cells (but not in bystander uninfected cells). A time-dependent secretion of a known NF-kappaB gene product, interleukin 8, from infected cell cultures was detected. C. parvum-induced biliary epithelial cell apoptosis was limited to bystander uninfected cells. In contrast, inhibition of NF-kappaB activation resulted in apoptosis in directly infected cells and significantly enhanced C. parvum-induced apoptosis in bystander uninfected cells., Conclusions: These observations support the concept that, while C. parvum triggers host cell apoptosis in bystander uninfected biliary epithelial cells, which may limit spread of the infection, it directly activates the NF-kappaB/I(kappa)B system in infected biliary epithelia thus protecting infected cells from death and facilitating parasite survival and propagation.

Background Information: Percutaneous vertebroplasty is a therapeutic, interventional radiologic procedure that involves injection of bone cement into a cervical, thoracic, or lumbar vertebral body lesion for the relief of pain and the strengthening of bone. This procedure only recently has been introduced, and is being used for patients with lytic lesions due to bone metastases, aggressive hemangiomas, or multiple myeloma, and for patients who have medically intractable debilitating pain resulting from osteoporotic vertebral collapse., Findings: Results from two uncontrolled prospective studies and several case series reports, including one with 187 patients, indicate that percutaneous vertebroplasty can produce significant pain relief and increase mobility in 70 percent to 80 percent of patients with osteolytic lesions in the vertebrae from hemangiomas, metastases, or myeloma, or with osteoporotic compression fractures. In these reports, pain relief was apparent within one to two days after injection, and persisted for at least several months up to several years. While experimental studies and preliminary clinical results suggest that percutaneous vertebroplasty can also strengthen the vertebral bodies and increase mobility, it remains to be proven whether this procedure can prevent additional fractures in the injected vertebrae. In addition, the duration of effect is not known; there were no long-term follow-up data on most of these patients, and these data may be difficult to obtain and interpret in patients with an underlying malignant process, because disease progression may confound evaluation of the treatment effect. Complications were relatively rare, although some studies reported a high incidence of clinically insignificant leakage of bone cement into the paravertebral tissues. In a few cases, the leakage of polymer caused compression of spinal nerve roots or neuralgia. Several instances of pulmonary embolism were also reported. Although patient selection criteria have not been definitely established, percutaneous vertebroplasty is considered appropriate treatment for patients with vertebral lesions resulting from osteolytic metastasis and myeloma, hemangioma, and painful osteoporotic compression fractures if the following criteria have been met: o Severe debilitating pain or loss of mobility that cannot be relieved by correct medical therapy. o Other causes of pain, such as herniated intervertebral disk have been ruled out by computed tomography or magnetic resonance imaging. o The affected vertebra has not been extensively destroyed and is at least one third of its original height. o Radiation therapy or concurrent surgical interventions, such as laminectomy, may also be required in patients with compression of the spinal cord due to ingrowth of a tumor., Conclusions: Percutaneous vertebroplasty has only recently been introduced as a treatment for osteolytic lesions and osteoporotic compression fractures of the vertebrae, but early results are promising. Up to 80 percent of patients with pain unresponsive to correct medical treatment experience a significant degree of pain relief, and few serious complications have been reported. However, relatively few patients have undergone this procedure, and there are no data from controlled clinical trials or from studies with long-term follow-up. At the present time this procedure is still in the investigational stages, but may be appropriate for patients with no other reasonable options for medical treatment.

While the clinical features of sclerosing cholangitis secondary to opportunistic infections of the biliary tree in patients with acquired immunodeficiency syndrome (AIDS) are well known, the mechanisms by which microbial pathogens such as Cryptosporidium parvum associated with this syndrome actually cause disease are obscure. We established an in vitro model of biliary cryptosporidiosis employing a human biliary epithelial cell line. Using morphological and biochemical techniques, we examined the interaction of C. parvum with cultured human cholangiocytes. When the apical plasma membrane of polarized, confluent monolayers of human biliary epithelial cells was exposed to C. parvum oocysts that had been excysted in vitro, sporozoites attached to and invaded the cells in a time-, dose-, temperature-, and pH-dependent manner. The infectious process was both plasma membrane domain- and cell-specific, because no attachment or invasion occurred when the basolateral membrane of cholangiocytes was exposed to the parasite, or when a human hepatocyte cell line (HepG2) was used. Time-lapse video microscopy and scanning electron microscopy (SEM) showed that sporozoite attachment was rapid, involved extensive cholangiocyte membrane ruffling, and culminated in parasite penetration into a tight-fitting vacuole formed by invagination of the plasma membrane similar to those found in naturally occurring infection in vivo. Transmission electron microscopy (TEM) showed that C. parvum organisms formed parasitophorus vacuoles and were able to undergo a complete reproductive cycle, forming both asexual and sexual reproductive stages. Unexpectedly, direct cytopathic effects were noted in infected monolayers, with widespread programmed cell death (i.e., apoptosis) of biliary epithelial cells as assessed both morphologically and biochemically beginning within hours after exposure to the organism. The novel finding of specific cytopathic invasion of biliary epithelia by C. parvum may be relevant to the pathogenesis and possible therapy of the secondary sclerosing cholangitis seen in AIDS patients with biliary cryptosporidiosis.

In terminally differentiated ileal villus Na+-absorptive cells, epidermal growth factor (EGF) stimulates NaCl absorption and its component brush border Na+/H+ exchanger, acting via basolateral membrane receptors, and as we confirm here, a brush border tyrosine kinase. In the present study we show that brush border phosphatidylinositol 3-kinase (PI 3-kinase) is involved in EGF stimulation of NaCl absorption and brush border Na+/H+ exchange. In rabbit ileum studied with the Ussing chamber-voltage clamp technique, EGF stimulation of active NaCl absorption is inhibited by the selective PI 3-kinase inhibitor wortmannin. PI 3-kinase, a largely cytosolic enzyme, translocates specifically to the brush border of ileal absorptive cells following EGF treatment. This translocation occurs as early as 1 min after EGF treatment and remains increased at the brush border for at least 15 min. EGF also causes a rapid (1 min) and large (4-5-fold) increase in brush border PI 3-kinase activity. Involvement of PI 3-kinase activity in intestinal Na+ absorption is established further by studies done in the human colon cancer cell line, Caco-2, stably transfected with the intestinal brush border isoform of the Na+/H+ exchanger, NHE3 (Caco-2/NHE3 cells). Brush border Na+/H+ exchange activity was measured using the pH-sensitive fluorescent dye 2'7'-bis(carboxyethyl)5-(6)-carboxyfluorescein. EGF added to the basolateral surface but not apical surface of Caco-2/NHE3 cells increased brush border Na+/H+ exchange activity. The EGF-induced increase in brush border Na+/H+ exchange activity was completely abolished in cells pretreated with wortmannin. EGF treatment caused increased tyrosine phosphorylation of PI 3-kinase in both ileal brush border membranes and Caco-2/NHE3 cells, suggesting that a tyrosine kinase upstream of the PI 3-kinase is involved in the EGF effects on Na+ absorption. In conclusion, the present study provides evidence in two separate intestinal models, the ileum and a human colon cancer cell line, that PI 3-kinase is an intermediate in EGF stimulation of intestinal Na+ absorption.

The effect of hyperosmolarity on cloned Na+/H+ exchanger (NHE) isoforms NHE2 and NHE3 was studied in stably transfected PS120 fibroblasts. Na+/H+ exchanger activity was determined spectrofluorometrically in acidified cells that were exposed to isosmolar (300 mosmol/kg) or hyperosmolar (450 mosmol/kg) media, in which the only difference is the presence or absence of 150 mM mannitol. Hyperosmolar solution reversibly inhibited NHE2 and NHE3 with a delay of approximately 15 s. Hyperosmolarity significantly reduced their maximal reaction velocity compared with isosmolar medium but did not alter their Michaelis-Menten constant for intracellular H+. The Michaelis-Menten constant of the exchangers for extracellular Na+ in hyperosmolar medium was not different from that in isosmolar medium. Pretreatment of PS120/NHE3 cells with the protein kinase C inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine, the tyrosine kinase inhibitor genistein, and the serine/threonine protein phosphatase inhibitor okadaic acid did not affect the hyperosmolar inhibition of NHE3. Hyperosmolar inhibition of Na+/H+ exchanger activity was also observed in PS120 cells transfected with truncated NHE3 cDNAs (E3/585, E3/543, E3509, and E3/475) and NHE2 cDNA (E2/499). We conclude that 1) hyperosmolarity inhibits NHE2 and NHE3, in contrast to the stimulatory effect on the housekeeping isoform NHE1, 2) this inhibition is reversible, and 3) the COOH termini of NHE2 and NHE3 are not necessary for hyperosmolar inhibition of NHE2 and NHE3.

Elevation in intracellular Ca2+ acting via protein kinase C (PKC) is shown to regulate tight junction resistance in T84 cells, a human colon cancer line and a model Cl- secretory epithelial cell. The Ca2+ ionophore A23187, which was used to increase the intracellular Ca2+ concentration, caused a decrease in tight junction resistance in a concentration- and time-dependent manner. Dual Na+/mannitol serosal-to-mucosal flux analysis performed across the T84 monolayers treated with 2 microM A23187 revealed that A23187 increased both fluxes and that in the presence of ionophore there was a linear relationship between the Na+ and mannitol fluxes with a slope of 56.4, indicating that the decrease in transepithelial resistance was due to a decrease in tight junction resistance. Whereas there was no effect of 0.1 microM A23187, 1 or 2 microM produced a 55% decrease in baseline resistance in 1 hr and 10 microM decreased resistance more than 80%. The A23187-induced decrease in tight junction resistance was partially reversible by washing 3 times with a Ringer's-HCO3 solution containing 1% BSA. The A23187 effect on resistance was dependent on intracellular Ca2+; loading the T84 cells with the intracellular Ca2+ chelator BAPTA significantly reduced the decrease in tight junction resistance caused by A23187. This intracellular Ca2+ effect was mediated by protein kinase C and not calmodulin. While the protein kinase C antagonist H-7 totally prevented the action of A23187 on tight junction resistance, the Ca2+/calmodulin inhibitor W13 did not have any effect. Sphingosine, another inhibitor of PKC, partially reduced the A23187-induced decline in tight junction resistance. The PKC agonist PMA mimicked the A23187 effect on resistance, although the effect was delayed up to 1 hr after exposure. In addition, however, PMA also caused an earlier increase in resistance, indicating it had an additional effect in addition to mimicking the effect of elevating Ca2+. The effects of a phospholipase inhibitor (mepacrine) and of inhibitors of arachidonic acid metabolism (indomethacin for the cyclooxygenase pathway, NDGA for the lipoxygenase pathway, and SKF 525A for the epoxygenase pathway) on the A23187 action were also examined. None of these agents altered the A23187-induced decrease in resistance. Monolayers exposed to 2 microM A23187 for 1 hr were stained with fluorescein conjugated phalloidin, revealing that neighboring cells did not part one from another and that A23187 did not have a detectable effect on distribution of F-actin in the perijunctional actomyosin ring. The results indicate that elevation in intracellular Ca2+ decreases tight junction resistance in the T84 monolayer, acting through protein kinase C by a mechanism which does not involve visible changes in the perijunctional actomyosin ring.

Rabbit NHE2 and NHE3 are two epithelial isoform Na+/H+ exchangers (NHE), the messages for which are found predominantly and entirely, respectively, in renal, intestinal, and gastric mucosa. The current studies used Western analysis and immunohistochemistry to identify and characterize the apical vs. basolateral membrane distribution of NHE2 and NHE3 in intestinal epithelial cells. Based on Western analysis, NHE2 and NHE3 both are present in brush-border but not basolateral membranes of small intestine. Both NHE2 and NHE3 are 85-kDa proteins. Consistent with Western analysis, NHE2 and NHE3 are immunolocalired to the brush-border but not basolateral membranes of villus epithelial cells, but not goblet cells, in human jejunum and ileum and in surface epithelial cells in the ascending and descending colon and rectum. In addition, NHE2 and NHE3 are present in small amounts in the crypt cell brush border of human jejunum, ileum, ascending and descending colon, and rectum. In rabbit jejunum, ileum, and ascending colon, NHE2 and NHE3 are present in the brush border of epithelial and not goblet cells, again much more in the villus (small intestine)/ surface cells (colon) than the crypt. NHE2 but not NHE3 is present in the brush border of rabbit descending colon surface cells and in small amounts in crypt cells. NHE2 and NHE3 are both human and rabbit small intestinal and colonic epithelial cell brush-border Na+/H+ exchanger isoforms that colocalize in all intestinal segments except rabbit descending colon, which lacks NHE3.

Study Design: Retrospective review and prospective follow-up of 88 patients who had decompressive laminectomy with or without fusion from 1983 to 1986., Objective: To determine the 7- to 10-year outcome of surgery for degenerative lumbar spinal stenosis., Summary of Background Data: There is limited information on the impact of surgery for lumbar spinal stenosis on symptoms, walking ability, and satisfaction, as well as reoperation., Methods: Patients completed standardized questionnaires in 1993 that included items about reoperations, back pain, leg pain, walking capacity, and satisfaction with surgery. Associations between preoperative demographic and clinical variables and outcomes 7 to 10 years after surgery were evaluated in univariate and multivariate analyses., Results: Average preoperative age was 69 years and eight patients received fusion. Of 88 patients in the original cohort, 20 (23%) were deceased and 20 (23%) had undergone reoperation by 7- to 10-year follow-up. Fifty-five patients answered questionnaires. Average duration of follow-up was 8.1 years. Thirty-three percent of the respondents had severe back pain at follow-up, 53% were unable to walk two blocks, and 75% were satisfied with the results of surgery. The severity of current spine-related symptoms was a stronger correlate of physical functional status at the time of follow-up than age or nonspinal comorbid conditions., Conclusions: Seven to 10 years after decompressive surgery for spinal stenosis, 23% of patients had undergone reoperation and 33% of respondents had severe back pain. Despite a high prevalence of nonspinal problems in this elderly cohort, spinal symptoms were the most important correlate of reduced functional status.

Na+/H+ exchangers are integral plasma membrane proteins that exchange extracellular Na+ for intracellular H+ with a stoichiometry of one for one. They are inhibitable by the diuretic amiloride and have multiple cellular functions, including intracellular pH homeostasis, cell volume control, and electroneutral NaCl absorption in epithelia. The presence of multiple forms of the exchangers was demonstrated by the recent cloning of four mammalian Na+/H+ exchangers, NHE1, NHE2, NHE3, and NHE4. All of these cloned Na+/H+ exchangers have 10-12 putative transmembrane helixes and a long cytoplasmic carboxyl domain. Despite the structural similarity, these Na+/H+ exchanger isoforms differ in their tissue distribution, kinetic characteristics, and response to external stimuli. The present review deals with the recent developments in the molecular identification of the Na+/H+ exchanger gene family, the functional characteristics, and the short-term regulation of Na+/H+ exchange at molecular and cellular levels.

NHE3, a cloned intestinal and renal brush border Na+/H+ exchanger, has previously been shown to be both stimulated and inhibited by different protein kinases/growth factors. For instance, NHE3 is stimulated by serum and fibroblast growth factor (FGF) and inhibited by protein kinase C. In the present study, we used a series of NHE3 C terminus truncation mutants to identify separate regions of the C-terminal cytoplasmic tail responsible for stimulation and inhibition by protein kinases/growth factors. Five NHE3 C terminus truncation mutant stable cell lines were generated by stably transfecting NHE3 deletion cDNAs into PS120 fibroblasts, which lack any endogenous Na+/H+ exchanger. Using fluorometric techniques, the effects of the calcium/calmodulin (CaM) inhibitor W13, calcium/CaM kinase inhibitor KN-62, phorbol myristate acetate, okadaic acid, FGF, and fetal bovine serum on Na+/H+ exchange were studied in these transfected cells. Inhibition of basal activity of full-length NHE3 is mediated by CaM at a site C-terminal to amino acid 756; this CaM effect occurs through both kinase dependent and independent mechanisms. There is another independent inhibitory domain for protein kinase C between amino acids 585 and 689. In addition, there are at least three stimulatory regions in the C-terminal domain of NHE3, corresponding to amino acids 509-543 for okadaic acid, 475-509 for FGF, and a region N-terminal to amino acid 475 for fetal bovine serum. We conclude that separate regions of the C terminus of NHE3 are involved with stimulation or inhibition of Na+/H+ exchange activity, with both stimulatory and inhibitory domains having several discrete subdomains. A conservative model to explain the way these multiple domains in the C terminus of NHE3 regulate Na+/H+ exchange is via an effect on associated regulatory proteins.

A polyclonal antibody (Ab597) was produced in rabbit against a fusion protein of glutathione-S-transferase and the last 87 amino acids of the Na+/H+ exchanger isoform, NHE2. By Western blotting, Ab597 recognized proteins of 75 and 85 kDa in PS120/NHE2 membranes (PS120 cells stably transfected with NHE2), and this antibody did not cross-react with NHE1 and NHE3. When Ab597 was used to immunocytochemically stain PS120/NHE2 cells, permeabilization of the cells was required for staining, confirming the putative membrane topology of NHE2 that the C-terminus is cytoplasmic. NHE1 is N-glycosylated. NHE2 was predicted to be N-glycosylated as it contains one potential N-linked glycosylation site (N350VS), which is conserved among NHE1, NHE3, and NHE4. However, NHE2 was resistant to peptide:N-glycosidase F (PNGase F) and endoglycosidase H (Endo H) digestion, suggesting that NHE2 is not N-glycosylated. In contrast, neuraminidase shifted the mobility of the 85 kDa NHE2 protein in PS120/NHE2 membranes into an 81 kDa band, and O-glycanase further shifted the mobility of the neuraminidase-treated 81 kDa protein to 75 kDa. Incubation of PS120/NHE2 cells with benzyl N-acetyl-alpha-D-galactosaminide (Bz alpha GalNAc), an O-glycosylation inhibitor, decreased the size of the 85 kDa protein to 81 kDa. This treatment had no effect on the initial rate of Na+/H+ exchange of PS120/NHE2 cells. The 75 kDa protein was not affected by the glycosidase treatment of PS120/NHE2 membranes or the Bz alpha GalNAc treatment of PS120/NHE2 cells.(ABSTRACT TRUNCATED AT 250 WORDS)

The kinetics and second messenger regulation of three cloned mammalian intestinal Na+/H+ exchangers were studied using fluorometric techniques. These exchangers, NHE1, NHE2, and NHE3, were stably expressed in PS120 fibroblasts, which lack an endogenous Na+/H+ exchanger. H+ kinetic data indicated cooperativity by internal protons, with Hill coefficients of approximately 2 for all three isoforms. In contrast, Na+ kinetic data fit Michaelis-Menten kinetics, with Km (Na+) 15-18 mM and a Hill coefficient of approximately 1. The exchangers were all activated by growth factors and thrombin; in NHE1 these agonists increased the apparent affinity for intracellular H+, but did not change Vmax, while for NHE2 and NHE3 the effect was on Vmax alone. Phorbol ester stimulated NHE1 and NHE2, but inhibited NHE3 with a decrease in Vmax. ATP-depletion decreased Vmax and the apparent affinity for H+ for all three isoforms, and reduced the Hill coefficient to approximately 1, suggesting that a basal level of phosphorylation was required for the cooperativity. The differences in kinetics and second messenger regulation suggest that the NHE isoforms may serve different cellular functions. The up- and down-regulation of NHE3 by kinases indicates that this isoform may be involved in a specialized function such as Na+ absorption.

We previously cloned an isoform Na+/H+ exchanger (NHE3), which was expressed only in intestine, kidney, and stomach. We show here the functional characteristics of NHE3 as a Na+/H+ exchanger by stably transfecting NHE3 cDNA into PS120 cells, a fibroblast cell line that lacks endogenous Na+/H+ exchangers. NHE3 was 39- and 160-fold more resistant to inhibition by amiloride and ethylisopropyl amiloride, respectively, than NHE1, the housekeeping Na+/H+ exchanger isoform. Although both exchangers were stimulated by serum, NHE3 was inhibited by phorbol 12-myristate 13-acetate (PMA), which stimulated NHE1. Mechanistically, serum and PMA stimulated NHE1 by an increase in the apparent affinity of the exchanger for intracellular H+. In contrast, serum stimulated and PMA inhibited NHE3 by a Vmax change. When NHE3 was stably expressed in Caco-2 cells, an intestinal epithelial cell line, NHE3 was functionally expressed in the apical membrane. Thus, NHE3 is a good candidate to be an epithelial brush border Na+/H+ exchanger. Furthermore, Na+/H+ exchangers can be rapidly regulated by mechanisms that change either the Vmax or the affinity for intracellular H+, depending on the Na+/H+ exchanger subtype.

A family of Na+/H+ exchanger isoforms (called NHE1, NHE2, and NHE3) which exhibits a wide range of amiloride sensitivity has recently been cloned and characterized. A part of the domain, which determines amiloride sensitivity in the epithelial Na+/H+ exchanger isoform, NHE2, was identified by site-directed mutagenesis and functional studies using cDNAs stably expressed in a fibroblast cell line. It has previously been reported that AR300, an amiloride resistant mutant of the ubiquitous Na+/H+ exchanger isoform, NHE1, is 30-fold more resistant to methylpropyl amiloride (MPA) compared to NHE1 and contains a single amino acid substitution of L167F in the fourth putative transmembrane helix, which corresponds to L143 in NHE2. Therefore, in the present study point mutational substitutions were introduced into the equivalent of this fourth transmembrane helix of rabbit NHE2 (including Y144F; L143F; L143F and Y144F) to mimic the corresponding amino acids in NHE1, NHE3 (another epithelial isoform) and AR300, respectively. NHE2/L143F (mimicking NHE3) increased the IC50 for amiloride by 5-fold and for ethylisopropyl amiloride (EIPA) by 20-fold. Similarly, NHE2/L143F and Y144F (mimicking AR300) increased the resistance to both amiloride and EIPA by 10-fold. On the other hand, NHE2/Y144F (mimicking NHE1) did not affect the sensitivity to amiloride or EIPA, and this mutant, like wild type NHE2, is partially resistant to EIPA. Thus, amino acid 143 of NHE2 is critical for, but is not the only amino acid responsible for, amiloride and EIPA inhibition of Na+/H+ exchange. That none of the mutations studied altered the Na+ affinity of these Na+/H+ exchangers further suggests that amiloride binding and Na+ transport sites are not identical.