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The etiology of breast cancer. Characteristic alteration in hydroxyl radical-induced DNA base lesions during oncogenesis with potential for evaluating incidence risk.

BACKGROUND: Substantial hydroxyl radical (.OH)-induced base lesions, recently found in the DNA of invasive ductal carcinoma of the female breast, are likely to be intimately related to oncogenesis. However, virtually no information was available regarding relationships between the different base lesions in the normal and cancerous breast. Such information is essential in understanding initial stages in the development of breast cancer and the potential of the base lesions as early predictors of cancer risk. METHODS: The .OH-induced DNA base lesions in normal reduction mammoplasty tissue (RMT) were compared with those from invasive ductal carcinoma (IDC) and nearby microscopically normal tissue (MNT). Comparisons were then undertaken on relationships between the base lesion profiles in the normal and cancerous breast using 22 statistical models. RESULTS: DNA from the RMT was characterized by a high ratio of ring-opening products (e.g., 4,6-diamino-5-formamidopyrimidine) to hydroxy-adducts of adenine and guanine. A dramatic shift in this relationship in favor of carcinogenic hydroxy-adducts (e.g., 8-hydroxyguanine) was found in the cancerous breast. Statistical models with a high sensitivity (91%) and specificity (97%) provided a consistent means of classifying tissues (e.g., 96% correct). CONCLUSIONS: The dramatic shift in the DNA base lesion relationships in oncogenesis is attributed to alterations in the redox potential of the breast favoring oxidative conditions and cancer formation. These findings suggest that base lesion profiles are potential sentinels for cancer risk assessment. Further, intervention in controlling the tissue redox potential may provide benefit in delaying or preventing early oncogenic changes and the ultimate manifestation of cancer.

Breast↗

Abnormal serotonergic development in a mouse model for the Smith-Lemli-Opitz syndrome: implications for autism.

The Smith-Lemli-Opitz syndrome (SLOS) is a malformation/mental retardation syndrome resulting from an inborn error in 3beta-hydroxysteroid Delta7-reductase (DHCR7), the terminal enzyme required for cholesterol biosynthesis. Using a targeting strategy designed to virtually eliminate Dhcr7 activity, we have created a SLOS mouse model that exhibits commissural deficiencies, hippocampal abnormalities, and hypermorphic development of serotonin (5-HT) neurons. The latter is of particular interest with respect to current evidence that serotonin plays a significant role in autism spectrum disorders and the recent clinical observation that 50% of SLOS patients present with autistic behavior. Immunohistochemical analyses have revealed a 306% increase in the area of 5-HT immunoreactivity (5-HT IR) in the hindbrains of mutant (Dhcr7-/-) mice as compared to age-matched wild type animals. Amount of 5-HT IR was measured as total area of IR per histological section. Additionally, a regional increase as high as 15-fold was observed for the most lateral sagittal hindbrain sections. In Dhcr7-/- mice, an expansion of 5-HT IR into the ventricular zone and floor plate region was observed. In addition, the rostral and caudal raphe groups exhibited a radial expansion in Dhcr7-/- mice, with 5-HT IR cells present in locations not seen in wild type mice. This increase in 5-HT IR appears to represent an increase in total number of 5-HT neurons and fibers. These observations may help explain the behavioral phenotype seen in SLOS, and provide clues for future therapeutic interventions that utilize pharmacological modulation of the serotonergic system.

Animals↗

Expert approaches to communicating violence risk.

There has been virtually no empirical study of the way in which evaluating clinicians communicate their conclusions about the risk of violence toward others. Risk communication has become particularly important in recent years, serving as the link between empirical data from recent studies and the understanding and use of such data by evaluators and decision makers. The present study considered how psychologists and psychiatrists, identified as experts in violence risk assessment, responded to eight vignettes that systematically measured preferences for risk communication. The vignettes involved the presentation of the following factors in a 2 x 2 x 2 within-subjects design, counterbalanced for order: (1) risk model (prediction vs. management), (2) risk level (high vs. low risk of the individual being assessed), and (3) risk factors (the predominance of static vs. dynamic risk factors). A total of 71 individuals (41 psychologists, 2 sociologists, and 28 psychiatrists) responded to a survey mailed to 100 individuals, for a response rate of 71%. Participants were asked to rate the value of six forms of risk communication for each of the eight vignettes. There were few significant differences between the ratings assigned by psychologists and those assigned by psychiatrists. The most highly valued form of risk communication involved identifying risk factors applicable to the individual and specifying interventions to reduce risk. A repeated-measures multivariate analysis of variance yielded a main effect for risk level and an interaction between risk level and risk factors. The implications of these findings for research and practice are discussed.

Expert Testimony↗

Biopsychological and cognitive differences in children with premature vs. on-time adrenarche.

BACKGROUND: Puberty consists of 2 components: gonadarche and adrenarche. Both components have distinct endocrine changes. Adrenarche has virtually been ignored with respect to examining hormone-behavior relations. OBJECTIVES: To provide descriptive biological and behavioral information on children with premature adrenarche (PA) and to examine differences in biological, psychological, and cognitive variables of children with PA and a healthy comparison group of children with on-time adrenarche. DESIGN: Descriptive pilot study. SETTING: A consecutive sample of patients was recruited from pediatric endocrine clinics; comparison children were recruited from the community. PARTICIPANTS: Children aged 6 to 9 years. Mean (+/-SD) age of children with PA (n = 9) was 7.8 (+/-1.3) years; of children with on-time adrenarche (n = 20), 8.0 (+/-1.2) years. METHODS AND MEASURES: Serum and saliva samples were collected for measurement of hormone concentrations. Questionnaires, tests, and interviews were completed by children and parents. RESULTS: Compared with the on-time group, the PA group had significantly higher concentrations of adrenal androgens, estradiol, thyrotropin, and cortisol. By parent report on the Diagnostic Interview Schedule for Children, 4 children (44%) met diagnostic criteria for psychological disorders (primarily anxiety disorders). The PA group also had more self-reported depression and parent-reported behavior problems and lower scores on various intelligence tests. CONCLUSIONS: Although PA is considered a normal variation of pubertal development that warrants no medical intervention, PA presents with significant psychosocial problems. Children with PA may need psychological evaluation and follow-up. Future studies should confirm these findings with a larger sample and examine the long-term ramifications of this early presenting abnormality.

Adrenal Hyperplasia, Congenital↗

The urological fate of young adults with myelomeningocele: a three decade follow-up study.

OBJECTIVE: Virtually all patients with myelomeningocele suffer from neurogenic disorder of the bladder. Problems with incontinence are common and there is also a risk of deterioration of renal function. The aim of the present study was to determine the long-term urological fate of this patient group. PATIENTS AND METHODS: Twelve young adults with myelomeningocele were interviewed and their records reviewed. RESULTS: The patients started clean intermittent catheterization (CIC) at the age of 10-21 years. Three patients underwent urological surgery prior to the start of CIC. This was also the case for 3 patients after having started CIC. Only 1 patient is completely continent. In the rest, the degree of incontinence varies. With few exceptions, the glomerular filtration rate was well preserved. Six of the incontinent patients had, on at least one occasion, denied incontinence to his doctor. CONCLUSION: It seems that the prognosis is good as far as renal function is concerned. However, continence is a prerequisite for good social adjustment. An obstacle for a rational treatment of incontinence, in the adolescent patient group, is the patient's strong tendency to underreport the actual incontinence situation. Thus, every effort must be made in order to obtain a correct history. In patients with validated incontinence, an aggressive treatment policy, including surgical intervention, is justified.

Adolescent↗

Unsubscribe, pleeezz!!!: management and training of media competence in computer-mediated communication.

Computer-mediated communication (CMC) has created a new communication divide. Mostly, this division is due to technical and access problems. Overlooked is yet another divide in terms of user communication competence. This contribution focuses on media competence based on theories about communication competence and theories about CMC. Two field studies are presented: an analysis of a virtual seminar chat communication (22 participants, 3 weeks' duration) and an analysis of unsubscribe-failures within 2 years of a German mailing list (average of 1,000 subscriptions). Data from both studies reveal that help-seeking CMC users with low media-specific competence experience setbacks in terms of interpersonal relations and information gathering. There is a spiral of neutral to negative reactions and an increase in stress and aggression-related language in the reaction of the addressed peers. From the perspective of external raters, we found a contraintuitive result: The style, content, and wording of the message of the respondent is considered as an indicator for a less competent and socially attractive person behind the follow-up message than those of the initial message. On the one hand, media experts are needed and appreciated as technical problem-solvers; on the other hand, they might be perceived as socially narrow-minded freaks who are less interested in the task itself than in CMC-based task completion. This leads to the question of how sensibility for the social context, task orientation, and media competence can be combined (and trained for) in one person. Two competence trainings for text-based synchronous and asynchronous communication are introduced as interventions.

Communications Media↗

Stress hormones during the wake-up test in scoliosis surgery.

STUDY OBJECTIVE: To compare hemodynamic and endocrine stress responses of two anesthetic regimes during intraoperative wake-up tests in scoliosis surgery. DESIGN: Randomized, controlled clinical study. SETTING: University hospital. PATIENTS: 40 ASA physical status I and II teenage patients scheduled for scoliosis surgery. INTERVENTION: Patients were randomly divided into two groups: the propofol group (Group P) and the sevoflurane group (Group S). In Group P, anesthesia was induced with propofol and remifentanil and was maintained with infusions. Sevoflurane and remifentanil were used in Group S. After surgical instrumentation, patients were awakened, and the wake-up times were recorded. To determine the stress responses, blood samples were taken before induction, 10 minutes after surgical incision, before the wake-up test, during the wake-up test, and 10 minutes after the wake-up test. Cortisol, epinephrine, and norepinephrine concentrations, and hemodynamics all were recorded at the same time. MEASUREMENTS AND MAIN RESULTS: The times from discontinuation of anesthetics to eye opening and movement were similar in both groups. Epinephrine and norepinephrine concentrations during the wake-up test were significantly higher than pretest results in both groups (p < 0.001). There were no statistically significant differences between groups in heart rate or blood pressure. CONCLUSIONS: Propofol-remifentanil anesthesia is equivalent to sevoflurane-remifentanil anesthesia for a wake-up test. Both the propofol- and sevoflurane-based anesthetic regimens abolish hemodynamic and endocrine stress responses to incision for scoliosis surgery in teenagers. Intraoperative wake-up testing is associated with substantial catecholamine stress despite virtually unchanged mean arterial pressure and heart rate.

Adolescent↗

Tobacco use in the Dominican Republic: understanding the culture first.

OBJECTIVE: To conduct formative research on the landscape of tobacco use to guide survey and subsequent intervention development in the Dominican Republic (DR). DESIGN: Rapid Assessment Procedures, systematic qualitative methods (participant-observations, in-depth interviewing, focus groups) using bilingual mixed age and gendered teams from the United States and DR. SUBJECTS: Over 160 adults (men and women), ages 18 to 90 years, current, former and never smokers, community members and leaders from six underserved, economically disadvantaged DR communities. MAIN OUTCOME MEASURES: Key domains: tobacco use patterns and attitudes; factors affecting smoking initiation, continuation, quitting; perceived risks/benefits/effects of smoking; and awareness/effects of advertising/regulations. RESULTS: Perceptions of prevalence varied widely. While "everybody" smokes, smokers or ex-smokers were sometimes difficult to find. Knowledge of health risks was limited to the newly mandated statement "Fumar es prejudicial para la salud" [Smoking is harmful to your health]. Smokers started due to parents, peers, learned lifestyle, fashion or as something to do. Smoking served as an escape, relaxation or diversion. Quit attempts relied on personal will, primarily for religious or medical reasons. Social smoking (custom or habit) (< 10 cigarettes per day) was viewed as a lifestyle choice rather than a vice or addiction. Out of respect, smokers selected where they smoked and around whom. Health care providers typically were reactive relative to tobacco cessation, focusing on individuals with smoking related conditions. Tobacco advertising was virtually ubiquitous. Anti-tobacco messages were effectively absent. Cultures of smoking and not smoking coexisted absent a culture of quitting. CONCLUSIONS: Systematic qualitative methods provided pertinent information about tobacco attitudes and use to guide subsequent project steps. Integrating qualitative then quantitative research can be replicated in similar countries that lack empirical data on the cultural dimensions of tobacco use.

Adolescent↗

Outcome of stroke in patients undergoing hemodialysis.

BACKGROUND: While elevated levels of serum creatinine have been shown to be a risk factor for diminished survival after stroke, it is unknown how renal replacement therapy may affect the outcome. METHODS: Strokes occurring in 26 consecutive patients undergoing hemodialysis at our institution were reviewed and clinical and laboratory variables and outcome were compared with those of patients who had a stroke but had normal renal function. RESULTS: Twenty-four strokes in the patients undergoing hemodialysis were ischemic while only 2 were hemorrhagic. Virtually all the patients had hypertension, half had diabetes mellitus, and most had some prior evidence of cardiovascular disease at the time of their stroke. Fifty percent of the patients undergoing hemodialysis had a good outcome (defined as being discharged home) while the remainder had a poor outcome (defined as dying or being discharged to a nursing facility). The combined presence of hypertension and coronary artery disease had a sensitivity of 91.2% for identifying patients with a poor outcome, while male sex, the presence of coronary artery disease, and the combined presence of hypertension, coronary artery disease, and/or congestive heart failure had sensitivities greater than 80% but low specificity. The outcome of patients undergoing hemodialysis was comparable with that of a control group of patients who had a stroke but had normal renal function, although the length of hospital stay was greater (mean [+/-SEM] 29.8+/-6.4 days vs 12.7+/-1.1 days, respectively; P<.01). CONCLUSIONS: Hospitalized patients undergoing hemodialysis in whom stroke occurs appear to have as good an outcome as that of patients with normal renal function, although they are hospitalized longer. In addition, certain clinical variables seem to be associated with a worse outcome. Aggressive measures to prevent and treat stroke seem as warranted for patients undergoing hemodialysis as for patients with normal renal function, although interventions to reduce the length of hospital stay are needed.

Adult↗

The pediatrician and disaster preparedness.

Recent natural disasters and events of terrorism and war have heightened society's recognition of the need for emergency preparedness. In addition to the unique pediatric issues involved in general emergency preparedness, several additional issues related to terrorism preparedness must be considered, including the unique vulnerabilities of children to various agents as well as the limited availability of age- and weight-appropriate antidotes and treatments. Although children may respond more rapidly to therapeutic intervention, they are at the same time more susceptible to various agents and conditions and more likely to deteriorate if not monitored carefully. The challenge of dealing with the threat of terrorism, natural disasters, and public health emergencies in the United States is daunting not only for disaster planners but also for our medical system and health professionals of all types, including pediatricians. As part of the network of health responders, pediatricians need to be able to answer concerns of patients and families, recognize signs of possible exposure to a weapon of terror, understand first-line response to such attacks, and sufficiently participate in disaster planning to ensure that the unique needs of children are addressed satisfactorily in the overall process. Pediatricians play a central role in disaster and terrorism preparedness with families, children, and their communities. This applies not only to the general pediatrician but also to the pediatric medical subspecialist and pediatric surgical specialist. Families view pediatricians as their expert resource, and most of them expect the pediatrician to be knowledgeable in areas of concern. Providing expert guidance entails educating families in anticipation of events and responding to questions during and after actual events. It is essential that pediatricians educate themselves regarding these issues of emergency preparedness. For pediatricians, some information is currently available on virtually all of these issues in recently produced printed materials, at special conferences, in broadcasts of various types, and on the Internet. However, selecting appropriate, accurate sources of information and determining how much information is sufficient remain difficult challenges. Similarly, guidance is needed with respect to developing relevant curricula for medical students and postdoctoral clinical trainees.

Child↗

Randomized, double-blinded, placebo-controlled study of effect of wheat bran fiber and calcium on fecal bile acids in patients with resected adenomatous colon polyps.

BACKGROUND: Ongoing epidemiologic and nutritional studies suggest that colorectal carcinogenesis is consistent with complex interactions between genetic susceptibility and environmental and dietary factors. Among the dietary components found to reduce colon cancer risk are high intakes of dietary fiber and calcium. PURPOSE: We designed and conducted a randomized, double-blinded, placebo-controlled trial involving supplementation of the customary dietary intake with fiber and calcium and measurements of fecal bile acids to examine the potential mechanisms by which added dietary interventions might reduce colorectal cancer risk. METHODS: In a randomized, double-blinded, phase II study, we used a factorial design to measure the effects of dietary wheat bran fiber (2.0 or 13.5 g/day) in the form of cereal and supplemental calcium carbonate (250 or 1500 mg/day elemental calcium) taken as a tablet on fecal bile acid concentrations and excretion rates. Measurements were made at base-line randomization (i.e., after a 3-month placebo run-in period using 2.0 g wheat bran fiber plus 250 mg calcium carbonate) and after 3 and 9 months on treatment in a randomly selected 52-patient subsample of the 95 fully assessable study participants who had a history of colon adenoma resection. Concentrations of fecal bile acids, total, primary (i.e., chenodeoxycholic and cholic), and secondary (i.e., deoxycholic, lithocholic, and ursodeoxycholic), were measured in 72-hour stool samples by gas-liquid chromatography. All P values resulted from two-sided tests. RESULTS: All geometric mean fecal bile acid concentrations and excretion rates were lower at 9 months than at 0 months or 3 months on treatment in the high-dose fiber, high-dose calcium, and high-dose fiber/high-dose calcium treatment groups. The high-dose fiber effect at 9 months of supplementation was statistically significant with respect to virtually all geometric mean fecal bile acid concentrations and excretion rates. For example at 9 months versus 0 months, high-dose fiber supplementation caused a reduction in fecal concentrations of total bile acids (52% reduction; P = .001) and deoxycholic acid (48% reduction; P = .003). High-dose calcium supplementation also had a significant, but lower, effect at 9 months versus 0 months on the geometric mean total bile acid (35% reduction; P = .044) and deoxycholic fecal bile acid (36% reduction; P = .052) concentrations. CONCLUSIONS: High-dose wheat bran fiber and calcium carbonate supplements given for 9 months are associated with statistically significant reductions in both total and secondary fecal bile acid concentrations and excretion rates in patients with resected colon adenomas. This study supports the hypothesis that one of the important ways in which a high intake of wheat bran fiber and calcium may reduce the risk of colorectal neoplasia and cancer is by reduction of the concentrations of fecal bile acids. IMPLICATION: Phase III studies of these agents in the prevention of adenoma recurrence are necessary to confirm this hypothesis and have now been initiated at multiple institutions.

Adenomatous Polyposis Coli↗

Reinforcement of esophageal anastomoses with an extracellular matrix scaffold in a canine model.

BACKGROUND: The gastric pull-up procedure, a standard intervention after radical esophagectomy, is associated with high morbidity and mortality due to leaks and stricture. A previous preclinical study showed that an extracellular matrix (ECM) scaffold with autologous muscle tissue could be used to repair a complete circumferential defect in the cervical esophagus. The aim of the present study was to determine if healing of end-to-end anastomoses of the esophagus could be improved by reinforcement with an ECM scaffold. METHODS: Twelve female mongrel dogs underwent a complete transection of either the cervical esophagus (n = 6) or the gastroesophageal junction (n = 6). A portion of the endomucosa at the anastomotic site was resected and replaced with an ECM scaffold in contact with the subjacent muscle and the muscle was anastomosed. The measured end points included macroscopic and microscopic evaluation and quantification of the esophageal diameter at the anastomotic site. RESULTS: No anastomotic leaks or systemic complications were observed in the ECM-treated animals. Morphologic findings in both groups showed complete mucosal covering of the surgery site. The remodeled esophageal tissue showed angiogenesis and complete epithelialization. Intact, organized layers of muscle tissue were present between the native muscularis externa and the submucosal layer and effectively bridged the transected ends. CONCLUSIONS: The ECM scaffold altered the default mechanism of esophageal repair. Scar tissue formation with associated stricture was virtually eliminated, and the esophageal healing response was characterized by the replacement with structurally normal tissue layers. These findings suggest that the high morbidity rate associated with esophagectomy procedures may be reduced by this ECM augmentation procedure at the anastomotic site.

Anastomosis, Surgical↗

Starting mental health services in Cambodia.

Cambodia has undergone massive psychosocial trauma in the last few decades, but has had virtually no western-style mental health services. For the first time in Cambodia a number of mental health clinics in rural areas have been started. This experience is used to discuss the risks and opportunities in introducing these services in the present war-torn situation. Basic statistics from the clinics are presented in the context of the historical and traditional setting, and the effort to maintain a culturally informed approach is described. The contrasting results in the clinics are analyzed in relation to factors intrinsic to the health care system and those related to the local population in order to highlight the issues involved in establishing future mental health services, both locally in other provinces and in situations similar to Cambodia. The efficacy of introducing low-cost, basic mental health care is shown, and related to the need to find solutions for prevailing problems on the psychosocial level. They can be introduced with modest means, and can be complementary to local health beliefs and traditional healing. In introducing mental health services, an approach is needed which adapts to the absorption potential of the health system as well as to the patients' need to find meaningful help. Existing resources, from the traditional healing sector to rudimentary village structures, cannot be neglected in the rehabilitation of the community, or in interventions to help the individual patient.

Adolescent↗

Atherosclerotic renovascular disease and progressive renal failure.

PURPOSE: To evaluate information on the prevalence and rate of progression of atherosclerotic renovascular disease and the effect of angiotensin-converting enzyme inhibition on this process, with the goal of developing a rational approach to the diagnosis and management of this disorder. DATA SOURCES: Relevant articles were identified from the authors' files and from MEDLINE searches. Additional references were obtained from the bibliographies of identified articles. STUDY SELECTION: Virtually no controlled prospective studies have been reported. The articles presented are primarily retrospective analyses and include those that provide sufficient information about the incidence or progression of renovascular disease and about the outcome and mortality rate associated with various treatments, to allow evaluation. DATA EXTRACTION: For the outcomes of interest, data from individual reports are presented in tabular form, the results summed, and averages obtained. RESULTS: Atherosclerotic renovascular disease, in many cases involving both renal arteries, is a common finding in patients older than 50 years, particularly those with diffuse atherosclerotic vascular disease. Hypertension is not a particularly sensitive indicator of this disease (almost one half are not hypertensive). The disease progresses and may account for 5% to 15% of all patients developing end-stage renal disease each year. Angiotensin-converting enzyme inhibition may damage ischemic renal tissue, but this is counterbalanced by beneficial effects of this therapy. Once end-stage renal disease is present, mortality rates are high despite dialysis support (> 50% over 3 years). Both surgery and angioplasty can preserve or improve renal function and may delay or prevent the need for dialysis therapy. These invasive procedures may have lower rates of morbidity and mortality than the so-called "conservative" approach of dialysis therapy when renal failure develops. CONCLUSIONS: Given available information, diagnosis and intervention should be considered seriously in patients at high risk for renovascular disease who have clearly progressing renal insufficiency. Prospective trials are needed, however, to determine the costs and benefits of each approach to treatment in all patients with renovascular disease and renal insufficiency.

Arteriosclerosis↗

Therapeutic efficacy of the Epley canalith repositioning maneuver.

OBJECTIVES/HYPOTHESES: The hypotheses of the current study are as follows: 1) That if the Epley canalith repositioning maneuver is an effective treatment for benign positional vertigo (BPV), relief from the vertigo should occur virtually immediately after the performance of the maneuver; 2) that the Epley canalith repositioning maneuver does provide almost immediate relief in BPV and should be the established treatment of choice for this disorder in both primary and tertiary care settings; and 3) that residual symptoms of lightheadedness and imbalance do persist after the resolution of the vertigo. The distinction of these symptoms from the vertigo is required for the accurate evaluation of the efficacy of positional maneuvers. STUDY DESIGN: Prospective cohort study in a tertiary care balance center. METHODS: Eighty-six patients (95 cases) with a history and physical examination consistent with active BPV were entered in the study. Patients were treated with a modified Epley canalith repositioning maneuver. A modified 360 degrees roll was used to treat those patients with horizontal canal BPV. Patients were provided with a preprinted diary in which they were to circle the answer most relevant to their symptoms for 14 days after the maneuver. Patients were then re-evaluated in the office at 2 weeks after the maneuver. RESULTS: The mean duration of the BPV before treatment was 9 weeks. Seventy-four percent of cases that were treated with one or two canalith repositioning maneuvers had a resolution of vertigo as a direct result of the maneuver. A resolution attributable to the first intervention was obtained in 70% of cases within 48 hours of the maneuver. An additional 14% of cases that were treated had a resolution of vertigo; however, it is not possible to say that these patients definitely benefited from the canalith repositioning maneuver. Only 4% of cases (three patients) manifested BPV that persisted after four treatments. Residual symptoms of lightheadedness or imbalance, or both, were frequent (47% of cases) but rarely required formal intervention with vestibular rehabilitation physical therapy. CONCLUSIONS: The Epley canalith repositioning maneuver results in a resolution of vertigo in the majority of patients (70% of cases) immediately after one treatment. It is safe and requires no special equipment or investigations. It should be established as the treatment of choice for BPV in both primary and tertiary care settings.

Aged↗

Drug dependence as a disorder of neural plasticity: focus on dopamine and glutamate.

Drug addiction, as a disease, has grown to reach the level of a social illness. Psychostimulants, opiates, alcohol, nicotine and cannabis abuse affects millions worldwide and virtually all classes of modern society. In spite of the enormous proportions of its spread, intimate neurobiological mechanisms leading to distintictive features of this pathological status, such as craving for the abused substance and loss of control over intake, remain largely obscure and pharmacotherapies sadly unsatisfactory. In the last decade, preclinical and clinical research in this field has made great progress to improve our understanding of the brain mechanisms which form the basis of this illness. The review of recent literature, which represents the focus of the present paper, leads to the emerging consensus that an alteration of physiological mechanisms of neural plasticity within the brain dopamine and glutamate systems may underlie some of the behavioral abnormalities occurring during the dependence cycle. In particular, a reduction of dopamine neuronal activity and glutamate neurotransmission at the level of the ventrotegmental area, after withdrawal from chronic administration of drugs of abuse, may work in concert with alterations in other forebrain areas, such as the nucleus accumbens and the amygdaloid complex. In addition, following prolonged periods of abstinence, even after somatic withdrawal signs have vanished, responsiveness of these systems to drugs of abuse remains abnormal. This suggests that these two neurotransmitters may play a substantial role in the long-lasting, enduring changes typical of the addictive process and may represent ideal targets for pharmacological intervention aimed at normalizing forms of neural plasticity impaired after chronic drug intake.

Animals↗

Interleukin-6 response to laparoscopic and open colectomy.

PURPOSE: It has been postulated that cortisol and interleukin-6 play a significant role in the modulation of the early inflammatory response following surgical intervention. There are no available data on the normal responses of these mediators following major laparoscopic procedures. The purpose of this study was to assess changes in cortisol (by fluorescence polarization immunoassay), interleukin-6 (by enzyme-linked immunoassay), and interleukin-1 (by enzyme-linked immunoassay) after elective laparoscopic colon resections. METHODS: All patients undergoing colon resection between February 1, 1992 and April 30, 1992 were eligible for study. Selection of laparoscopic (N = 12) vs. open (N = 41) resection was determined by the attending surgeon. All patients received a standard general anesthetic with endotracheal intubation. Cortisol, interleukin-6, and interleukin-1 were measured at preinduction, 1 hour, 2 hours, 3 hours, 4 hours, and 5 hours after the induction. Interleukin-6 and interleukin-1 were additionally measured at 12 hours, 24 hours, and 72 hours after induction. Comparisons were made between the laparoscopic patients (N = 12) and age, sex, and operation-matched open patients (N = 12). RESULTS: Cortisol levels rose in the early postoperative period in both open and laparoscopic groups with no significant differences occurring between the cohorts at any of the measured time intervals. The interleukin-6 levels of the laparoscopic cohort (N = 12) were significantly lower than those of the open cohort (N = 12) between 3 and 24 hours postinduction (P < 0.05). Interleukin-1 levels remained undetectable in virtually all patients irrespective of operative technique or postoperative interval. There was no correlation between peak interleukin-6 levels and operative times (laparoscopic, r = 0.31; open, r = 0.36) or blood loss (laparoscopic, r = 0.10; open, r = 0.20). CONCLUSION: The results indicate that laparoscopic colon resections do not appear to alter cortisol or interleukin-1 responses when compared with open colon resection. There is, however, a significant blunting of the interleukin-6 response associated with the use of laparoscopic techniques for colectomy compared with standard laparotomy.

Blood Loss, Surgical↗

Differential expression of inducible nitric oxide synthase messenger RNA along the longitudinal and crypt-villus axes of the intestine in endotoxemic rats.

OBJECTIVES: To characterize the mechanisms leading to excessive production of nitric oxide within the gut as a consequence of endotoxemia. We sought to: a) determine the time course of inducible nitric oxide synthase (iNOS) messenger RNA (mRNA) expression in the intestine after challenging rats with lipopolysaccharide (LPS); and b) investigate whether there is differential expression of iNOS in enterocytes along the longitudinal or crypt-villus axes of the intestine in rats after LPS administration. DESIGN: Prospective, randomized, unblinded study. SETTING: Research laboratories at a large university-affiliated medical center. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: At T = 0 hr, rats were injected with O111:B4 Escherichia coli LPS (5 mg/kg) or a similar volume of the saline vehicle. At various time points thereafter, samples of duodenum, jejunum, ileum, colon, and liver were harvested for subsequent extraction of RNA. In some cases, populations of enterocytes enriched in either crypt or villus cells were harvested from the ileum. In some studies, rats were injected with cycloheximide (25 mg i.p.) 15 mins before being challenged with LPS or dexamethasone (2 mg i.p.) 30 mins before being injected with LPS. MEASUREMENTS AND MAIN RESULTS: iNOS mRNA was undetectable in ileal tissue from rats under basal conditions, but was evident by T = 1 hr and was maximal at T = 2 hrs after injection of LPS. Thereafter, ileal iNOS mRNA concentrations decreased and were undetectable again at T = 24 hrs. At T = 2 hrs after LPS injection, there was marked expression of iNOS mRNA in the ileum, whereas much lower concentrations of iNOS mRNA were detected in the jejunum and colon, and no iNOS mRNA was detected in the duodenum. At T = 3 hrs after LPS injection, expression of iNOS mRNA was up-regulated in both villus and crypt cells, although LPS-induced iNOS mRNA was more prominent in the former than the latter cell type. Pretreatment of rats with dexamethasone virtually abrogated the expression of iNOS mRNA in ileal samples obtained 3 hrs after the injection of LPS. Prior treatment of rats with the protein synthesis inhibitor, cycloheximide, also blunted LPS-induced iNOS mRNA expression. CONCLUSIONS: LPS-induced iNOS expression is differentially regulated along both the longitudinal and crypt villus axes of the intestinal mucosa, being most prominent in the villus cells of the ileum. LPS-induced iNOS expression is blunted by pretreating rats with dexamethasone or cycloheximide. The latter finding suggests that LPS-induced expression of iNOS mRNA in the gut requires new protein synthesis. Differential regulation of nitric oxide production along the longitudinal and crypt-villus axes of the gut may be a determinant of the pattern of sepsis-induced intestinal damage.

Animals↗