Transdiscal instrumentation in single-level lumbosacral fusion for high-grade isthmic pediatric spondylolisthesis: Technical note and review of the literature.

Pediatric spondylolisthesis is a common cause of back pain in children, typically managed conservatively with bracing and non-steroidal anti-inflammatory drugs. When posterolateral fusion is performed for refractory pain, pseudarthrosis and implant failure may occur, necessitating reoperation. To improve patient outcomes, there is a need for alternative surgical techniques to effectively manage high-grade isthmic slips. Here, the authors report the case of a child with Meyerding grade III anterolisthesis of L5 on S1 who was treated with a single-level, instrumented fusion using bilateral S1-L5 transdiscal screws, supported with L5-S1 posterolateral instrumentation and arthrodesis. Postoperatively, there was improvement in the patient's symptoms with good clinical and radiographic outcomes. The patient continues to be symptom free with radiographic evidence of hardware stability and bony fusion across the segment. The authors detail a novel surgical technique in children as well as a review of lumbosacral transdiscal screw fixation. Further evidence is required to definitively establish the safety, outcomes, and biomechanical strength of this technique.

The frequency of early-activated hapten-specific B cell subsets predicts the efficacy of vaccines for nicotine dependence.

Therapeutic vaccines for nicotine addiction show pre-clinical efficacy. Yet, clinical evaluation of the first-generation nicotine vaccines did not meet expectations because only a subset of immunized subjects achieved effective serum antibody levels. Recent studies suggest that vaccine design affects B cell activation, and that the frequency of the hapten-specific B cell subsets contributes to vaccine efficacy against drugs of abuse. To extend this hypothesis to nicotine immunogens, we synthesized a novel hapten containing a carboxymethylureido group at the 2-position of the nicotine structure (2CMUNic) and compared its efficacy to the previously characterized 6CMUNic hapten. Haptens were conjugated to the keyhole limpet hemocyanin (KLH) carrier protein, and evaluated for efficacy against nicotine in mice using the clinically approved alum adjuvant. Using a novel fluorescent antigen-based magnetic enrichment strategy paired with multicolor flow cytometry analysis, polyclonal hapten-specific B cell subsets were measured in mice immunized with either 6CMUNic-KLH or 2CMUNic-KLH. The 6CMUNic-KLH showed significantly greater efficacy than 2CMUNic-KLH on nicotine distribution to serum and to the brain. The 6CMUNic-KLH elicited higher anti-nicotine serum antibody titers, and greater expansion of hapten-specific B cells than 2CMUNic-KLH. Within the splenic polyclonal B cell population, a higher number of hapten-specific IgM(high) and germinal centre B cells predicted greater vaccine efficacy against nicotine distribution. These early pre-clinical findings suggest that hapten structure affects activation of B cells, and that variations in the frequency of early-activated hapten-specific B cell subsets underlie individual differences in vaccine efficacy.

Hapten-specific naïve B cells are biomarkers of vaccine efficacy against drugs of abuse.

Vaccination against drugs of abuse shows efficacy in animal models, yet few subjects achieve effective serum antibody titers in clinical studies. A barrier to translation is the lack of pre-vaccination screening assays that predict the most effective conjugate vaccines or subjects amenable to vaccination. To address this obstacle, we developed a fluorescent antigen-based enrichment method paired with flow cytometry to characterize hapten-specific B cells. Using this approach, we studied naïve and activated B cells specific for structurally-related model haptens based on derivatization of the morphinan structure at the C6 position on oxycodone or at the C8 position on hydrocodone, and showing different pre-clinical efficacy against the prescription opioid oxycodone. Prior to vaccination, naïve B cells exhibited relatively higher affinity for the more effective C6-derivatized oxycodone-based hapten (6OXY) and the 6OXY-specific naïve B cell population contained a higher number of B cells with greater affinity for free oxycodone. Higher affinity of naïve B cells for hapten or oxycodone reflected greater efficacy of vaccination in blocking oxycodone distribution to brain in mice. Shortly after immunization, activated hapten-specific B cells were detected prior to oxycodone-specific serum antibodies and provided earlier evidence of vaccine failure or success. Analysis of hapten-specific naïve and activated B cells may aid rational vaccine design and provide screening tools to predict vaccine clinical efficacy against drugs of abuse or other small molecules.

Co-administration of morphine and oxycodone vaccines reduces the distribution of 6-monoacetylmorphine and oxycodone to brain in rats.

Opioid conjugate vaccines have shown promise in animal models as a potential treatment for opioid addiction. Individual vaccines are quite specific and each targets only a limited number of structurally similar opioids. Since opioid users can switch or transition between opioids, we studied a bivalent immunization strategy of combining 2 vaccines that could target several of the most commonly abused opioids; heroin, oxycodone and their active metabolites. Morphine (M) and oxycodone (OXY) haptens were conjugated to keyhole limpet hemocyanin (KLH) through tetraglycine (Gly)(4) linkers at the C6 position. Immunization of rats with M-KLH alone produced high titers of antibodies directed against heroin, 6-monoacetylmorphine (6-MAM) and morphine. Immunization with OXY-KLH produced high titers of antibodies against oxycodone and oxymorphone. Immunization with the bivalent vaccine produced consistently high antibody titers against both immunogens. Bivalent vaccine antibody titers against the individual immunogens were higher than with the monovalent vaccines alone owing, at least in part, to cross-reactivity of the antibodies. Administration of a single concurrent intravenous dose of 6-MAM and oxycodone to rats immunized with the bivalent vaccine increased 6-MAM, morphine and oxycodone retention in serum and reduced the distribution of 6-MAM and oxycodone to brain. Vaccine efficacy correlated with serum antibody titers for both monovalent vaccines, alone or in combination. Efficacy of the individual vaccines was not compromised by their combined use. Consistent with the enhanced titers in the bivalent group, a trend toward enhanced pharmacokinetic efficacy with the bivalent vaccine was observed. These data support the possibility of co-administering two or more opioid vaccines concurrently to target multiple abusable opioids without compromising the immunogenicity or efficacy of the individual components.

An oxycodone conjugate vaccine elicits drug-specific antibodies that reduce oxycodone distribution to brain and hot-plate analgesia.

Opioid conjugate vaccines have shown promise in attenuating the behavioral effects of heroin or morphine in animals. The goal of this study was to extend this approach to oxycodone (OXY), a commonly abused prescription opioid. Haptens were generated by adding tetraglycine (Gly)(4) or hemisuccinate (HS) linkers at the 6-position of OXY. Immunization of rats with OXY(Gly)(4) conjugated to the carrier proteins bovine serum albumin (BSA) or keyhole limpet hemocyanin (KLH) produced high-titer antibodies to OXY and its metabolite oxymorphone with substantially lower affinities for other structurally related opioid agonists and antagonists. There was no measurable binding of antibody by the (Gly)(4) linker alone or off-target opioids methadone and buprenorphine. OXY(HS) conjugates were less immunogenic despite achieving protein haptenation ratios comparable to OXY(Gly)(4)-BSA. In rats given a single intravenous dose of OXY, immunization with OXY(Gly)(4)-KLH increased OXY protein binding and retention in serum while decreasing its unbound (free) concentration in plasma and distribution to brain. Vaccine efficacy correlated with serum antibody titers, and it was greatest in rats given the lowest OXY dose (0.05 mg/kg) but was significant even after a larger OXY dose (0.5 mg/kg), equivalent to the high end of the therapeutic range in humans. These effects of OXY(Gly)(4)-KLH on drug disposition were comparable to those of nicotine or cocaine vaccines that are in clinical trials as addiction treatments. Immunization with OXY(Gly)(4)-KLH also reduced OXY analgesia in a thermal nociception test. These data support further study of vaccination with the OXY(Gly)(4)-KLH immunogen as a potential treatment option for OXY abuse or addiction.

Cognitive reserve in aging.

Cognitive reserve explains why those with higher IQ, education, occupational attainment, or participation in leisure activities evidence less severe clinical or cognitive changes in the presence of age-related or Alzheimer's disease pathology. Specifically, the cognitive reserve hypothesis is that individual differences in how tasks are processed provide reserve against brain pathology. Cognitive reserve may allow for more flexible strategy usage, an ability thought to be captured by executive functions tasks. Additionally, cognitive reserve allows individuals greater neural efficiency, greater neural capacity, and the ability for compensation via the recruitment of additional brain regions. Taking cognitive reserve into account may allow for earlier detection and better characterization of age-related cognitive changes and Alzheimer's disease. Importantly, cognitive reserve is not fixed but continues to evolve across the lifespan. Thus, even late-stage interventions hold promise to boost cognitive reserve and thus reduce the prevalence of Alzheimer's disease and other age-related problems.

Neurobehavioral abnormalities in the dysbindin-1 mutant, sandy, on a C57BL/6J genetic background.

Sandy mice have a deletion mutation in the gene encoding dysbindin-1, Dtnbp1, with consequent reduction of the protein in heterozygotes and its loss in homozygotes. The sandy mouse thus serves as an animal model of dysbindin-1 function. As this protein is concentrated in synaptic tissue and affects transmitter release, it may affect neuronal processes that mediate behavior. To investigate the neurobehavioral effects of the Dtnbp1 mutation, we studied littermate sandy and wild-type controls on a C57BL/6J genetic background. The three animal groups were indistinguishable in their external physical characteristics, sensorimotor skills and indices of anxiety-like behaviors. In the open field, however, homozygous animals were hyperactive and appeared to show less habituation to the initially novel environment. In the Morris water maze, homozygous animals displayed clear deficits in spatial learning and memory with marginal deficits in visual association learning. Apart from the last mentioned deficits, these abnormalities are consistent with hippocampal dysfunction and in some cases with elevated dopaminergic transmission via D2 dopamine receptors. As similar deficits in spatial learning and memory have been found in schizophrenia, where decreased dysbindin-1 has been found in the hippocampus, the sandy mouse may also model certain aspects of cognition and behavior relevant to schizophrenia.

Transformation of Rickettsia prowazekii to erythromycin resistance encoded by the Escherichia coli ereB gene.

Rickettsia prowazekii, the etiologic agent of epidemic typhus, is an obligate, intracytoplasmic, parasitic bacterium. Recently, the transformation of this bacterium via electroporation has been reported. However, in these studies identification of transformants was dependent upon either selection of an R. prowazekii rpoB chromosomal mutation imparting rifampin resistance or expression of the green fluorescent protein and flow cytometric analysis. In this paper we describe the expression in R. prowazekii of the Escherichia coli ereB gene. This gene codes for an erythromycin esterase that cleaves erythromycin. To the best of our knowledge, this is the first report of the expression of a nonrickettsial, antibiotic-selectable gene in R. prowazekii. The availability of a positive selection for rickettsial transformants is an important step in the characterization of genetic analysis systems in the rickettsiae.

Pneumothorax in sports: issues in recognition and follow-up care.

Spontaneous and traumatic pneumothoraces are rare conditions found occasionally in athletes. Although generally not life-threatening, these conditions can be fatal if not appropriately diagnosed and managed. Expedient diagnosis depends on a thorough understanding of possible presenting signs and symptoms such as chest pain, dyspnea, and diminished breath sounds. A chest radiograph may be required for definitive diagnosis. Management depends on the size, stability, and type of pneumothorax and may include serial monitoring, tube thoracostomy, pleurodesis, or apical resection. Return-to-play guidelines after pneumothorax have not been previously published. We present recomendations based on a review of published case reports, our clinical experience, and communication with North American sports medicine providers.

Smokeless tobacco, reaction time, and strength in athletes.

PURPOSE: This study investigated the effects of smokeless tobacco on reaction time and strength in a group of Division III athletes. METHODS: Athletes were tested for simple and choice reaction time, maximum voluntary force, and maximum rate of force generation of the knee extensors on a KinCom dynamometer at 250 degrees.s-1. Smokeless tobacco-using athletes (N = 20) were tested while both using and after abstaining from smokeless tobacco. Another group of athletes (N = 20) who did not use smokeless tobacco served as a control group. RESULTS: Simple and complex reaction times were not affected by smokeless tobacco use or abstention. In the simple reaction time test, maximum voluntary knee extensor force was higher in the smokeless tobacco-using group while abstaining (P < 0.05). Maximum rate of force generation in the simple reaction time test was not statistically different between the conditions. In the choice reaction test, both strength parameters (maximum force and maximum rate of force generation) were higher in the user group while abstaining (P < 0.05) compared with the using condition. The strength parameter measurements in the control group were not statistically different from the tobacco-using group, while either using or abstaining. CONCLUSIONS: We conclude that smokeless tobacco use has no effect on reaction time but may detrimentally influence maximum voluntary force and maximum rate of force generation.

Transformation of Rickettsia prowazekii to rifampin resistance.

Rickettsia prowazekii, the causative agent of epidemic typhus, is an obligate intracellular parasitic bacterium that grows directly within the cytoplasm of the eucaryotic host cell. The absence of techniques for genetic manipulation hampers the study of this organism's unique biology and pathogenic mechanisms. To establish the feasibility of genetic manipulation in this organism, we identified a specific mutation in the rickettsial rpoB gene that confers resistance to rifampin and used it to demonstrate allelic exchange in R. prowazekii. Comparison of the rpoB sequences from the rifampin-sensitive (Rifs) Madrid E strain and a rifampin-resistant (Rifr) mutant identified a single point mutation that results in an arginine-to-lysine change at position 546 of the R. prowazekii RNA polymerase beta subunit. A plasmid containing this mutation and two additional silent mutations created in codons flanking the Lys-546 codon was introduced into the Rifs Madrid E strain of R. prowazekii by electroporation, and in the presence of rifampin, resistant rickettsiae were selected. Transformation, via homologous recombination, was demonstrated by DNA sequencing of PCR products containing the three mutations in the Rifr region of rickettsial rpoB. This is the first successful demonstration of genetic transformation of Rickettsia prowazekii and represents the initial step in the establishment of a genetic system in this obligate intracellular pathogen.

The development of a risk-adjusted capitation payment system: the Maryland Medicaid model.

This article describes the risk-adjusted payment methodology employed by the Maryland Medicaid program to pay managed care organizations. It also presents an empirical simulation analysis using claims data from 230,000 Maryland Medicaid recipients. This simulation suggests that the new payment model will help adjust for adverse or favorable selection. The article is intended for a wide audience, including state and national policy makers concerned with the design of managed care Medicaid programs and actuaries, analysts, and researchers involved in the design and implementation of risk-adjusted capitation payment systems.

Common soccer injuries. Diagnosis, treatment and rehabilitation.

Soccer is a game with worldwide appeal. Increasing numbers of participants are members of all age groups and skill levels. The game presents to the sports medicine practitioner a wide variety of musculoskeletal and medical problems. Soccer injuries increase in frequency as the age of participant increases, with a low incidence of injury in preadolescent players. Musculoskeletal injuries most commonly affect the lower extremities and include contusions, acute and chronic musculotendinous strains, and ligamentous injuries to the knee and ankle. Most injuries are minor and respond to analgesics, therapy modalities and exercise therapy. Groin pain is a common problem and particularly prevalent among soccer players owing to the game's specific stresses. Other less common but important injuries include facial trauma, mild brain injury (concussion) and heat-related injury. Team physicians, athletic trainers and physical therapists need to possess a basic understanding of the most common injuries and problems in order to maximise safe participation for their athletes.

Taking health status into account when setting capitation rates: a comparison of risk-adjustment methods.

OBJECTIVE: To compare performance of different health status measures for risk-adjusting capitation rates. DESIGN: Cross-sectional study. Health status measures derived from 1 year were used to predict resources for that year and the next. SETTING: Group-network health maintenance organization in Minnesota. PARTICIPANTS: Sample of 18- to 64-year-old (n=3825) and elderly (aged > or = 65 years; n=1955) members enrolled in a network-model health maintenance organization in Minnesota. MAIN OUTCOME MEASURES: Total expenditures in the year concurrent with the health status survey (July 1991 through June 1992) and total expenditures in the year following the survey (July 1992 through June 1993). RESULTS: Capitation adjustment based on demographic measures performed least well. Both self-reported health status measures and diagnoses predicted future expenditures twice as well as demographics. When predicting costs for groups of patients rather than individuals, the demographic model worked well for average groups but tended to overpredict healthier groups and underpredict sicker groups. Ambulatory Care Groups based on diagnoses performed better than self-reported health status both in the retrospective models and across healthier and sicker groups. CONCLUSIONS: Without risk adjustment, capitation rates are likely to overpay or underpay physicians for certain patient groups. It is possible to improve prediction using health status measures for risk adjustment. When selection bias is suspected and administrative data are available, we recommend a risk-adjustment method based on diagnostic information. If diagnostic data are not available, we recommend a system based on simple self-reported measures, such as chronic conditions, rather than complex functional status measures.

Role of plasminogen activator inhibitor in the reciprocal regulation of bovine aortic endothelial and smooth muscle cell migration by TGF-beta 1.

Vascular endothelial and smooth muscle cells exhibit reciprocal migratory responses after transforming growth factor (TGF)-beta 1 treatment. Endothelial cells exhibit a decreased migratory rate and smooth muscle cells exhibit an increased migratory rate. Previous studies have demonstrated increases in extracellular matrix and integrin synthesis and expression in response to TGF-beta 1. In this report, we illustrate the roles of plasminogen activator inhibitor in modulating the migratory rates in these two cell types. Endothelial cells appear to require a proteolytic phenotype for rapid migration, whereas vascular smooth muscle cells appear to require an anti-proteolytic phenotype. Modulation of proteinase/anti-proteinase activity ratios was accomplished via TGF-beta 1 induction, addition of exogenous plasminogen activator inhibitor, addition of anti-catalytic antibodies directed against urokinase plasminogen activator, overexpression of plasminogen activator inhibitor utilizing stable transfectants, and the use of vitronectin as a substratum. The reciprocal migratory behaviors exhibited by these two vascular cell types in response to TGF-beta 1 is discussed in the context that these two vascular cell types utilize distinct adhesive and signaling pathways in their interactions with extracellular matrix components and responsiveness to proteolytic activity.

Profiling primary care physician resource use: examining the application of case mix adjustment.

Growing emphasis on managed care has led to increased interest in physician practice profiling. Standardized techniques for conducting profiling are not yet well established. One particularly challenging methodologic issue, case mix adjustment, is explored here using actual cost profiles derived from primary care physicians at two independent practice association (IPA)-model health maintenance organizations (HMOs). Specifically, this article examines how the ambulatory care group case mix methodology can be applied to profiling and illustrates that it provides more depth of information with which to assess performance than does standard demographic adjustment alone. This analysis suggests both the potential and methodologic limitations of profiling at the individual physician level.

Shoulder pain in a football player.

A 19-yr-old college football player presents with a 1.5-yr history of right shoulder pain and associated easy fatigability of the right arm. The history is significant for an automobile accident 3 yr prior to presentation in which the right shoulder struck the dashboard of the car. An extensive workup proved unremarkable. Treatment included multiple trials of anti-inflammatory medication and extensive physical therapy without benefit. The patient underwent a first rib resection for thoracic outlet syndrome with significant relief of symptoms. Thoracic outlet syndrome (TOS) may mimic other more common causes of shoulder and arm symptoms. Diagnosis may be difficult as tests are often nonconfirmatory. Conservative treatment usually is adequate. In resistant cases, surgery may be indicated.

Realizing the potential of practice pattern profiling.

In January 1992, the Physician Payment Review Commission held a conference to learn about the appropriateness of present uses of profiling of practice patterns, and to identify what will be required to realize the full potential of this technique in the future. The conference addressed the data needs of profiling, the development of valid and relevant profiles, the impact of profiles on medical practice, and controversies surrounding public access to profiling information and the uses to which profiling has been put. This paper, based in part on that conference, reviews the basic concepts that underlie profiling and describes the roles that profiling can play in quality improvement, assessment of provider performance, and utilization review. It uses case studies to illustrate the types of problems that have arisen in actual usage and discusses what will be required to resolve them. The final section describes the roles that profiling can play in achieving the goals of health care reform, and concludes with what is needed in data and infrastructure development to improve the quality and usefulness of profiling.