Induction of CYP1A in the beagle dog by an inhibitor of kinase insert domain-containing receptor: differential effects in vitro and in vivo on mRNA and functional activity.

Compound I [3-[5-(4-methanesulfonyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-quinolin-2-one] is a potent inhibitor of human kinase insert domain-containing receptor (KDR kinase), which is under investigation for the treatment of cancer. Bile duct-cannulated male beagle dogs were administered 6 mg/kg compound I q.d. for 14 days. There was an approximately 2.5-fold decrease in the mean plasma area under the curve of I on days 7 and 14 (approximately 11.3 microM . h), relative to day 1 (28.2 microM . h). In the dog, compound I was eliminated by metabolism, with a major pathway being aromatic hydroxylation and subsequent sulfation to form the metabolite M3. Metabolic profiling suggested that the pathway leading to the formation of the sulfated conjugate M3 was induced upon multiple dosing of I. Studies conducted in vitro suggested that CYP1A1/2 was responsible for the formation of the hydroxylated metabolite, which is sulfated to yield M3. Additional studies confirmed induction of CYP1A protein and activity in the livers of dogs treated with I. However, studies in a dog hepatocyte model of induction showed a surprising decrease both in CYP1A mRNA and enzymatic activity in the presence of I, emphasizing the need to consider the results from a variety of in vitro and in vivo studies in deriving an understanding of the metabolic fate of a drug candidate. It is concluded that the autoinduction observed after multiple treatments with compound I occurs since compound I is both an inducer and a substrate for dog CYP1A.     

Urinary pharmacokinetics of betalains following consumption of red beet juice in healthy humans.

The aim of the present pilot study was to characterise the renal elimination of betalains after consumption of red beet juice (RBJ). Six healthy, non-smoking female volunteers were given a single oral dose of either 500 mL of a commercial RBJ containing 362.7 mg of betalains and 500 mL of tap water, respectively, in a sequential manner. Urine was collected in intervals up to 24 h post-dose. Renal excretion of betalains was determined spectrophotometrically and quantified as betanin-equivalents. In addition, the identity of individual compounds was confirmed by HPLC coupled with diode-array detection and positive ion electrospray mass spectrometry, respectively. The amount (mean+/-S.D.) of intact betalains (betanin and isobetanin) recovered in urine was 1001+/-273 microg corresponding to 0.28+/-0.08% of the administered dose. Maximum excretion rates were observed after a median tmax,R of 3.0 h (range 2.5-8.0 h) amounting to 91.7+/-30.1 microg/h. The terminal elimination rate constant (lambdaz) and the corresponding half-life were 0.097+/-0.021 h(-1) and 7.43+/-1.47 h, respectively. Using the lambdaz estimates obtained the expected total betalain amount excreted in urine was 1228+/-291 microg. Based on the results obtained it is assumed that either the bioavailability of the betalains is low or that renal clearance is a minor route of systemic elimination for these compounds. The urinary excretion rates of unmetabolised betalains were fast and appeared to be monoexponential suggesting a one-compartment model. In order to get a more complete picture of the pharmacokinetics and health-promoting properties of red beet betalains, quantitative data on betalain bioavailability should include measurements of unchanged compounds and their corresponding metabolites in plasma, urine and bile.     

Violence in the Schools: Clinical Issues and Case Analysis for High-Risk Children

School violence in rural communities has gained considerable attention nationally. Examined are theoretical considerations involving escape theory, the risk and protective factors for school violence, case analyses of recent case studies, and discussion of recent school violence involving fatal injuries to others. Also discussed are diagnostic issues in understanding children who are at-risk for school violence and ways school violence maybe managed in the schools. Suggestions and recommendations including recommendations provided by the National School Safety Center for school personnel are offered, as are steps to be taken in creating a safe school environment. This information may be helpful to child psychiatry and clinical personnel who provide services to school aged children.     

Aseptic meningitis after posterior fossa surgery treated by pseudomeningocele closure

Aseptic meningitis is a recognised complication after posterior fossa surgery. It is often self limiting but occasionally runs a protracted course requiring repeated CSF examination to exclude infection, and treatment with systemic steroids. A patient is described with aseptic meningitis after posterior fossa surgery who underwent posterior fossa re-exploration nearly 3 years after the initial operation. This disclosed a pseudomeningocele, which was closed. The patient remains symptom free almost 2 years after closure. In this case of chronic aseptic meningitis after posterior fossa surgery, closure of the pseudomeningocele found at exploratory surgery led to resolution of the symptoms.     

Surgical complications and their management in a series of 300 consecutive pediatric cochlear implantations.

OBJECTIVE: To report the short- and long-term complications encountered in a large number of consecutive children undergoing implantation in a single center. The current study also describes the management and sequelae of each complication. STUDY DESIGN: Prospective study assessing the surgical findings and complications of deaf children undergoing implantation. SETTING: Pediatric tertiary referral center for cochlear implantation. PATIENTS: The present study includes 300 consecutive children undergoing implantation, with a mean age at implantation of 5.1 years, ranging from 1.3 to 16.9 years. Of these children, 196 (65%) had congenital deafness of unknown cause. The commonest known cause was meningitis (73 of 300 [24%]) followed by congenital cytomegalovirus infection (17 of 300 [6%]). Children have been followed up regularly after implantation, typically at yearly intervals after the first year. The mean duration of follow-up at the time of the study was 4 years (range, 0.1-14 yr). RESULTS: There were no major perioperative (within 1 d after surgery) or major early postoperative (within 1 wk after surgery) complications. In the same periods, there were 19 and 15 minor complications, respectively. These complications (e.g., eardrum perforation, hematoma, flap swelling, wound infection, temporary facial weakness) settled with conservative treatment or minor intervention. With regard to the late surgical complications (>1 wk after surgery), there were 7 major (e.g., severe flap infection requiring explantation, cholesteatoma, persistent eardrum perforation) and 14 minor complications (e.g., mild flap infection, flap swelling, hematoma). A number of complications were encountered even 14 years after the original operation, and some of them needed repeated interventions, highlighting the importance of long-term follow-up. However, most of the complications occurred very close to the surgical procedure (<1 yr). CONCLUSION: An overall rate of 2.3% for major surgical complications and an overall rate of 16% for minor surgical complications suggest that cochlear implantation is a relatively safe surgical operation in experienced centers. Most surgical complications are minor and can be managed with conservative treatment or minor surgical intervention. However, meticulous attention to surgical detail, especially handling soft tissues and leaving the posterior canal wall intact, and long-term follow-up are of paramount importance in minimizing the incidence of surgical complications.     

Development of a diabetes care management curriculum in a family practice residency program.

Improving the quality of care for patients with chronic illness has become a high priority. Implementing training programs in disease management (DM) so the next generation of physicians can manage chronic illness more effectively is challenging. Residency training programs have no specific mandate to implement DM training. Additional barriers at the training facility include: 1) lack of a population-based perspective for service delivery; 2) weak support for self-management of illness; 3) incomplete implementation due to physician resistance or inertia; and 4) few incentives to change practices and behaviors. In order to overcome these barriers, training programs must take the initiative to implement DM training that addresses each of these issues. We report the implementation of a chronic illness management curriculum based on the Improving Chronic Illness Care (ICIC) Model. Features of this process included both patient care and learner objectives. These were: development of a multidisciplinary diabetes DM team; development of a patient registry; development of diabetes teaching clinics in the family practice center (nutrition, general management classes, and one-on-one teaching); development of a group visit model; and training the residents in the elements of the ICIC Model, ie, the community, the health system, self-management support, delivery system design, decision support, and clinical information systems. Barriers to implementing these curricular changes were: the development of a patient registry; buy-in from faculty, residents, clinic leadership, staff, and patients for the chronic care model; the ability to bill for services and maintain clinical productivity; and support from the health system key stakeholders for sustainability. Unique features of each training site will dictate differences in emphasis and structure; however, the core principles of the ICIC Model in enhancing self-management may be generalized to all sites.     

Who will need long-term care? Creation and validation of an instrument that identifies older people at risk.

The aim of this study was to create and measure the predictive validity of a screening instrument that identifies older people who are at risk for developing a need for long-term care within a year. This was an observational study, with participants allocated to either a derivation cohort or a validation cohort, in the United States. A nationally representative sample of older community-dwelling Medicare beneficiaries (n = 6,538) participated in the Medicare Current Beneficiary Survey. Questions addressed sociodemographic, functional, health-related, and utilization characteristics in 1991 and 1992, linked to records of Medicare payments for health services during 1991-1992. In the derivation cohort, 14 self-reported characteristics were significant predictors of developing a need for long-term care within 1 year. In the validation cohort, these 14 characteristics identified a high-risk subgroup (18%) that, during the following year, developed a need for long-term care at six times the rate of the low-risk majority. This brief survey instrument identifies a high-risk minority of older people that will, during the following year, develop a need for long-term care at six times the rate of the low-risk majority. This instrument may be useful for targeting at-risk subgroups of older populations to receive interventions designed to preserve functional independence and avert the need for long-term care.     

Development of a Regionalized,Comprehensive Care Network for Pediatric Sickle Cell Disease to Improve Access to Care in a Rural State

Sickle cell disease (SCD), an inherited group of blood disorders, is a major public health problem worldwide. Patients experience severe anemia, increased risk of life-threatening infections, painful crisis, and chronic organ damage. Access to comprehensive care for SCD is known to improve outcomes; however, it is only reported from large urban centers serving one metropolitan area. Alabama, US, is a largely rural state with a significant number of children born each year with SCD. Prior to the development of our regional clinic network, the Children and Youth Sickle Network (CYSN^SM), 50% of patients identified by newborn screening were not enrolled in comprehensive sickle cell care. The majority of non-enrolled patients lived in southern Alabama. Rural areas in this region are particularly plagued by poverty and poor access to healthcare. Life expectancy is equivalent to residents of Sri Lanka. This area has 15.7 doctors/10 000 residents compared with the statewide ratio of 41.9 doctors/10 000 residents.To improve access to care, a regional clinic network, the CYSN^SM, was established in 1995. This paper reviews the impact of the CYSN^SM on pediatrie SCD in Alabama over the first 5 years of implementation.Since its inception in 1995, the CYSN^SM has provided care for 923 patients compared with 450 prior to the development of the clinic network. Currently, 90% of all cases identified by newborn screening are enrolled compared with 50% pre-CYSN^SM. Prior to the network, the average age of patients at their first clinic visit was 21 months. In the post-CYSN^SM period, the average age at first clinic visit decreased substantially to 5.3 months. Prior to the CYSN^SM, patients traveled on average 90 miles to a comprehensive clinic. Post-CYSN^SM, this distance has been cut in half to an average of 45 miles. A total of 70% of patients now live within 30 miles of a clinic. Most importantly, the infection death rate has decreased from 5.71 deaths/100 patient years to 1.94 deaths/100 patient years.The development, implementation, and evaluation of the CYSN^SM show that comprehensive care delivery in a rural setting is feasible and improves outcomes in pediatric SCD.