Discontinuity of psychiatric care for patients with schizophrenia, relation to previous psychiatric care and practice variation between providers: a retrospective longitudinal cohort study.

BACKGROUND: Patients with schizophrenia need continuous integrated healthcare, but many discontinue their treatment, often experiencing adverse outcomes. The first objective of this study is to assess whether patient characteristics or treatment history are associated with discontinuity of psychiatric elective care. The second objective is to assess whether practice variation between providers of psychiatric care contributes to discontinuity of elective care. METHODS: A large registry-based retrospective cohort of 9194 schizophrenia patients, who were included if they received elective psychiatric care in December 2014-January 2015. Logistic regression models were used to identify predictive factors of discontinuity of care. The dependent variable was the binary variable discontinuity of care in 2016. Potential independent predictive variables were: age, sex, urbanization, and treatment history in 2013-2014. Practice variation between providers was assessed, adjusting for the case mix of patients regarding their demographic and care utilization characteristics. RESULTS: 12.9% of the patients showed discontinuity of elective psychiatric care in the follow-up year 2016. The risk of discontinuity of care in 2016 was higher in younger patients (between age 18 and 26), patients with a history of receiving less elective psychiatric care, more acute psychiatric care, more quarters with elective psychiatric care without antipsychotic medication, or receiving no elective treatment at all. No evidence for practice variation between providers was found. CONCLUSIONS: Our findings show that the pattern of previous care consumption is an important prognostic factor of future discontinuity of elective care. We propose that previous care consumption can be used to design strategies to improve treatment retention and focus resources on those most at risk of dropping out.

The Impact of Antipsychotic Formulations on Time to Medication Discontinuation in Patients with Schizophrenia: A Dutch Registry-Based Retrospective Cohort Study.

BACKGROUND: Many patients with schizophrenia discontinue antipsychotic medication, frequently with adverse outcomes. Although different antipsychotic formulations are associated with different times to discontinuation, not much is known about discontinuation rates with oral-weekly formulations. Such a formulation of penfluridol is available in both the Netherlands and several other countries. OBJECTIVES: We aimed to investigate the impact of antipsychotic formulations on time to discontinuation, especially the oral-weekly formulation. METHODS: In a large, registry-based, retrospective cohort study from 1 January 2013 to 31 December 2016, we determined the time to medication discontinuation during the follow-up period with antipsychotic formulations, including oral-daily, oral-weekly, depot, or a combination of these. Patients with schizophrenia aged between 18 and 69 years were included and stratified according to the duration of recent antipsychotic use (taking the same formulation for ≤ 60 days or > 60 days before follow-up: short-term or long-term recent antipsychotic use). Medication discontinuation was defined as discontinuation of current antipsychotic formulation. RESULTS: Overall, 8257 patients were included for analyses, with 80% of patients discontinuing antipsychotic medication. Time to discontinuation was longer in those with long-term recent antipsychotic use before the follow-up period and longest for oral-daily formulations. Patterns for discontinuation of oral-weekly and depot formulations were similar, regardless of the duration of recent antipsychotic use before follow-up. More prior discontinuations were associated with shorter time to discontinuation. CONCLUSIONS: Time to discontinuation differed considerably between formulations. The duration of recent antipsychotic use was a strong predictor of time to discontinuation. While oral-daily formulations had the longest time to discontinuation in the long-term recent antipsychotic use group, discontinuation trends were similar for oral-weekly and depot formulations. An oral-weekly formulation, whose administration route is noninvasive, might therefore be considered an alternative to depot formulations.

Characterization of displacement forces and image artifacts in the presence of passive medical implants in low-field (<100 mT) permanent magnet-based MRI systems, and comparisons with clinical MRI systems.

PURPOSE: To investigate the displacement forces and image artifacts associated with passive medical implants for recently-developed low-field (<100 mT) MRI systems, and to compare these with values from higher field strengths used for clinical diagnosis. METHODS: Setups were constructed to measure displacement forces in a permanent magnet-based Halbach array used for in vivo MRI at 50 mT, and results compared with measurements at 7 T. Image artifacts were assessed using turbo (fast) spin echo imaging sequences for four different passive medical implants: a septal occluder, iliac stent, pedicle screw and (ferromagnetic) endoscopic clip. Comparisons were made with artifacts produced at 1.5, 3 and 7 T. Finally, specific absorption rate (SAR) simulations were performed to determine under what operating conditions the limits might be approached at low-field. RESULTS: Displacement forces at 50 mT on all but the ferromagnetic implant were between 1 and 10 mN. Image artifacts at 50 mT were much less than at clinical field strengths for all passive devices, and with the exception of the ferromagnetic clip. SAR simulations show that very long echo train (>128) turbo spin echo sequences can be run with short inter-pulse times (5-10 ms) within SAR limits. CONCLUSIONS: This work presents the first evaluation of the effects of passive implants at field strengths less than 100 mT in terms of displacement forces, image artifacts and SAR. The results support previous claims that such systems can be used safely and usefully in challenging enviroments such as the intensive care unit.

Rising co-payments coincide with unwanted effects on continuity of healthcare for patients with schizophrenia in the Netherlands.

BACKGROUND: Co-payments, used to control rising costs of healthcare, may lead to disruption of appropriate outpatient care and to increases in acute crisis treatment or hospital admission in patients with schizophrenia. An abrupt rise in co-payments in 2012 in the Netherlands offered a natural experiment to study the effects of co-payments on continuity of healthcare in schizophrenia. METHODS: Retrospective longitudinal registry-based cohort study. Outcome measures were (i) continuity of elective (planned) psychiatric care (outpatient care and/or antipsychotic medication); (ii) acute psychiatric care (crisis treatment and hospital admission); and (iii) somatic care per quarter of the years 2009-2014. RESULTS: 10 911 patients with schizophrenia were included. During the six-year follow-up period the level of elective psychiatric outpatient care (-20%); and acute psychiatric care (-37%) decreased. Treatment restricted to antipsychotic medication (without concurrent outpatient psychiatric care) increased (67%). The use of somatic care also increased (24%). Use of acute psychiatric care was highest in quarters when only antipsychotic medication was received. The majority (59%) of patients received continuous elective psychiatric care in 2009-2014. Patients receiving continuous care needed only half the acute psychiatric care needed by patients not in continuous care. On top of these trends time series analysis (ARIMA) showed that the abrupt rise in co-payments from 2012 onwards coincided with significant increases in stand-alone treatment with antipsychotic medication and acute psychiatric care. CONCLUSIONS: The use of psychiatric care decreased substantially among a cohort of patients with schizophrenia. The high rise in co-payments from 2012 onwards coincided with significant increases in stand-alone treatment with antipsychotic medication and acute psychiatric care.

How does an integrated primary care approach for patients in deprived neighbourhoods impact utilization patterns? An explorative study.

BACKGROUND: To explore changes in utilization patterns for general practice (GP) and hospital care of people living in deprived neighbourhoods when primary care providers work in a more coherent and coordinated manner by applying an integrated approach. METHODS: We compared expected (based on consumption patterns of a health insurers' total population) and actual utilization patterns in a deprived Dutch intervention district in the city of Utrecht (Overvecht) with control districts 1 (Noordwest) and 2 (Kanaleneiland) over the period 2006-2011, when an integrated care approach was increasingly provided in the intervention district. Standardized insurance claims data were used to indicate use of GP care and hospital care. RESULTS: Our findings revealed that the utilization of total GP care increased more in the intervention district than in the control districts. And that the intervention district showed a more pronounced decreasing trend in total hospital use as compared to what was expected, in particular from 2008 onwards. In addition, we observed a change in type of GP care use in the intervention district in particular: the number of regular consultations, long consultations, GP home visits and evening, night and weekend consultations were increasingly higher than expected. The intervention district also showed the largest decrease between actual and expected use of ambulatory care, clinical care and 1-day hospitalizations. CONCLUSIONS: Utilization patterns for general practice and hospital care of people living in deprived districts may change when primary care professionals work in a more coherent and coordinated manner by applying a more 'comprehensive' integrated care approach. Results support the expectation that a comprehensive integrated care approach might eventually contribute to the future sustainability of healthcare systems.

Spinal emergencies.

True spinal emergencies are rare and represent a potential loss of function if not treated properly. This review describes the most frequently encountered spinal emergencies. Early diagnosis is the key to preventing significant morbidity in the form of permanent disability. The recognition of red flags, followed by a thorough neurologic exam and appropriate imaging, should prompt a thorough examination with a heightened sense of urgency regarding the workup for serious forms of pathology. Spinal emergencies threaten loss of function if not treated properly. Providers must be aware of the presenting symptoms and be able to accurately interpret imaging results in order to promptly diagnose and treat these conditions.

A health insurance company-initiated practice support intervention for optimizing acid-suppressing drug prescriptions in primary care.

BACKGROUND: A health insurance-initiated programme to improve cost-effectiveness of acid-suppressing drugs (ASDs). AIM: To evaluate the effect of two different interventions of general practitioner support in reducing drug prescription. MATERIALS AND METHODS: A sequential cluster randomized controlled trial with 90 participating general practitioners in a telephone support (TS) group or practice visit (PV) group. TS group received support in phase-1 (first 6 months), but served as control group in phase-2 (6-12 months period). PV group received no intervention in phase-1, serving as the control group for the TS group, but received support in phase-2. Prescription data were extracted from Agis Health Insurance Database. Outcomes were the proportion of responders to drug reduction and the number of defined daily dose (DDD). Differences in users and DDD were analysed using multilevel regression analysis. RESULTS: At baseline, 3424 patients used ASD chronically (211 DDDs, on average). The difference between TS and control groups among responders was 3.2% [95% confidence interval (CI): 0.8; 5.6] and relative risk was 1.26 (95% CI: 1.06; 1.51). The difference between PV and control groups was not relevant (0.4%, 95% CI: -1.99; 2.79 and relative risk: 1.01, 95% CI: 0.82; 1.20). The difference in DDD per patient was -3.0 (95% CI: -8.9; 2.9) and -5.82 (95% CI: -12.4; 0.73), respectively. CONCLUSION: This health insurance company-initiated intervention had a moderate effect on ASD prescription. In contrast to TS, PVs did not seem to reduce ASD prescription rates.

A health insurance company-initiated multifaceted intervention for optimizing acid-suppressing drug prescriptions in primary care: a randomized controlled trial.

OBJECTIVE: To evaluate the effectiveness of a health insurance company-initiated intervention strategy aimed at optimizing acid-suppressing drug (ASD) prescriptions in primary care. METHODS: In a cluster randomized controlled trial design, 112 primary care physician (PCP) peer review groups (993 PCPs) in the central region of the Netherlands were randomized. The PCPs in the intervention group received an ASD prescription optimization protocol, a list of their patients taking ASDs frequently on a long-term basis, and financial compensation for additional consultations with these patients. The PCPs in the control group did not receive any of these interventions. Prescription data on 23 433 patients were extracted from the database of the regional health insurance company. The main outcome measures were the proportion of patients who reduced ASD consumption by more than 50% and changes in annual volume and costs of ASD prescriptions. Differences in ASD reduction and in volume were analyzed applying multilevel regression analyses. RESULTS: At baseline, 2.4% of the patients (n = 967 506) of the participating practices used ASDs frequently on a long-term basis (>180 daily defined doses [DDDs] annually). During the 6-month intervention, 14.1% of the patients in the intervention group reduced ASD consumption compared with 13.7% in the control group (adjusted relative risk, 1.04; 95% confidence interval [CI], 0.97-1.11). Changes in intervention and control group in mean volume of ASD prescription per patient were similar (beta = 0.33 for DDD; 95% CI -3.00 to 3.60). CONCLUSIONS: A health insurance company-initiated multifaceted intervention, including practical tools and financial incentives, did not alter ASD prescription practice in primary care. More tailored interventions, including patient-targeted initiatives, are required to optimize ASD prescription.

Effect of slice thickness on liver lesion detection and characterisation by multidetector CT.

The purpose of our study was to compare the effectiveness of 3.2 mm, 5 mm and 7.5 mm slice thicknesses in the detection and characterisation of liver lesions found on CT in patients with known or suspected malignant disease. 110 patients underwent portal phase imaging using four-slice MDCT. Two blinded observers independently read hard copy images at each slice thickness. The size and location of each lesion detected was recorded by each observer on a diagram of liver segmental anatomy. Each lesion was characterised as benign, malignant or indeterminate in nature. A diagnostic confidence score was allocated for each lesion on a scale of 1-4. The pathology or behaviour of lesions was assessed using surgery with intra-operative ultrasound (IOUS) and histology, or interval imaging with MRI, CT, or sonography. 294 lesions were detected, 64 (22%) of which were malignant. Both observers detected significantly more lesions on the 3.2 mm versus 7.5 mm slice thickness (p < 0.0001). Both observers detected more malignant lesions on 3.2 mm and 5 mm slice thicknesses versus 7.5 mm. As slice thickness decreased there was a significant increase in the sensitivity of malignant lesion detection for observer 1 (p < 0.001) and borderline significance for observer 2 (p = 0.07). As slice thickness decreased the proportion of lesions characterised as indeterminate by both observers fell. With thinner slices, both detection and characterisation of liver lesions were improved. A slice thickness no greater than 5 mm should be used to maximise both detection and correct characterisation of liver lesions.

Gender-related differences in recovery of locomotor function after spinal cord injury in mice.

STUDY DESIGN: In order to study the role of gender in recovery, we induced a thoracic compression spinal cord injury (SCI) separately in 2-month-old male and female C57Bl/6 mice. OBJECTIVES: We intended to assess effects of gender on recovery of hindlimb motor function and to correlate these with histomorphologic profiles of injured spinal cord tissue. METHODS: Locomotor function was evaluated by three means: a modified locomotor scoring system for rodents, beam walking and computerized activity meter. Histology was analyzed by comparison of hematoxylin and eosin-stained perfused specimens. RESULTS: Locomotor scores were 2.2+/-0.9 on day 1 in male mice, while, in contrast, they were significantly higher, 7.3+/-1.7, in females (P<0.02). On day 14 Basso, Beattie and Bresnahan scores were 9.5+/-2.2 in male mice and 16.0+/-2.2 in females (P<0.03). Terminal histology showed that the spinal cord architecture was relatively better preserved in female mice and that the extent of necrosis and infiltration of inflammatory cells was less compared to males. SETTING: Neurobiology Research Laboratory of University of Kansas Medical School in US Department of Veterans Affairs Medical Center, Kansas City, Missouri. CONCLUSION: We found that the severity of the initial injury as well as the ultimate recovery of motor function after SCI is significantly influenced by gender, being remarkably better in females. The mechanism(s) of neuroprotection in females, although not yet elucidated, may be associated with the effects of estrogen on pathophysiological processes (blood flow, leukocyte migration inhibition, antioxidant properties, and inhibition of apoptosis). SPONSORSHIP: Medical Research, US Department of Veterans Affairs, the Christopher Reeve Paralysis Foundation and NIH.

Neuroprotective signal transduction in model motor neurons exposed to thrombin: G-protein modulation effects on neurite outgrowth, Ca(2+) mobilization, and apoptosis.

Thrombin, the ultimate protease in the blood coagulation cascade, mediates its known cellular effects by unique proteolytic activation of G-protein-coupled protease-activated receptors (PARs), such as PAR1, PAR3, and PAR4, and a "tethered ligand" mechanism. PAR1 is variably expressed in subpopulations of neurons and largely determines thrombin's effects on morphology, calcium mobilization, and caspase-mediated apoptosis. In spinal cord motoneurons, PAR1 expression correlates with transient thrombin-mediated [Ca(2+)](i) flux, receptor cleavage, and elevation of rest [Ca(2+)](i) activating intracellular proteases. At nanomolar concentrations, thrombin retracts neurites via PAR1 activation of the monomeric, 21 kDa Ras G-protein RhoA, which is also involved in neuroprotection at lower thrombin concentrations. Such results suggest potential downstream targets for thrombin's injurious effects. Consequently, we employed several G-protein-specific modulators prior to thrombin exposure in an attempt to uncouple both heterotrimeric and monomeric G-proteins from motoneuronal PAR1. Cholera toxin, stimulating Gs, and lovastatin, which blocks isoprenylation of Rho, reduced thrombin-induced calcium mobilization. In contrast, pertussis toxin and mastoparan, inhibiting or stimulating G(o)/G(i), were found to exacerbate thrombin action. Effects on neuronal rounding and apoptosis were also detected, suggesting therapeutic utility may result from interference with downstream components of thrombin signaling pathways in human motor neuron disorders, and possibly other neurodegenerative diseases. Published 2001 John Wiley & Sons, Inc.

Rapid upregulation of caspase-3 in rat spinal cord after injury: mRNA, protein, and cellular localization correlates with apoptotic cell death.

Although the precise mechanisms explaining loss of, and failure to regain, function after spinal cord injury are unknown, there is increasing interest in the role of "secondary cell death." One prevalent theme in cell loss in other regions of the CNS involves apoptosis executed by the intracellular caspase proteases. A recent study demonstrated that spinal cord injury rapidly increased the activation of caspase-3. Our previous studies demonstrated peak apoptosis in three of four cellular compartments 3 days after controlled contusion in the rat. We have extended these analyses to include enzyme and substrate studies of caspase subfamilies both in rostral and in caudal adjacent segments compared to the lesion site. Although presumed activation of programmed proenzyme is considered the mechanism for enhanced caspases, our novel analyses were designed to detect upregulation of gene expression. We surveyed traumatically injured spinal cord for caspase family messages with a modified differential mRNA display approach and found that the caspase-3 (CASP3) message was present and upregulated severalfold after injury. Our results clearly demonstrate that cell death in the spinal cord occurs after posttranslational activation of caspases that follow, at least for caspase-3, initial upregulation of CASP3 mRNA levels.

Metastatic testicular cancer presenting as spinal cord compression: report of two cases.

BACKGROUND: Testicular cancers are heterogenous neoplasms often found in young adults. They tend to metastasize to the chest, retroperitoneum, or neck, but rarely to the long bones or skeleton. However, they can cause neurologic compromise and should be considered in young male patients who present with symptoms of a spine lesion and no known primary cancer. METHODS: Two patients presented with back pain and a rapid progression of lower extremity weakness. Both underwent radiographic workup and emergency surgery. Metastatic workup revealed testicular cancer and widespread metastases. RESULTS: Both patients improved neurologically after surgery, but neither regained the ability to ambulate independently. They both underwent chemotherapy. One patient is alive at 1 year follow-up; the other died 9 months after surgery of widespread metastases. CONCLUSIONS: Vertebral metastases from testicular tumors, although rare, should be considered in young men presenting with spinal cord compression. Work-up should include magnetic resonance imaging (MRI) of the spine and computed tomography (CT) of the chest, abdomen, and pelvis. Urgent intervention may be required, as these two cases show that loss of neurologic function can be rapid and permanent.

Selective developmental regulation of gene expression for insulin-like growth factor-binding proteins in mouse spinal cord.

STUDY DESIGN: Prospective, randomized experimental study in mice. STUDY OBJECTIVE: To determine whether insulin-like growth factor binding proteins (IGFBPs) are present in mouse spinal cord and, if so, what role they play in its development. SUMMARY OF BACKGROUND DATA: Insulin-like growth factors are well recognized hormonal effectors of growth hormone and are expressed in the mammalian spinal cord. The IGFBPs are a group of six genetically distinct proteins that bind IGFs and modulate their bioactivity. They appear in the brain during development, localize to the neuromuscular junction, and promote motor neuron survival. The benefit of IGF-I in amyotrophic lateral sclerosis ALS and its potential use in preventing motor neuron apoptosis in spinal cord injury dictates that studies of the presence and response of IGFBPs in that tissue be performed. METHODS: The IGFBPs in mouse spinal cord were analyzed by Western ligand blot, Western immunoblot, and reverse transcription-polymerase chain reaction at various time points from embryonic day 14 to postnatal day 30. RESULTS: Three IGFBPs with molecular masses of 24, 28, and 32 kDa were found, the latter two being the most prominent. The data indicate that these are IGFBP-4, -5, and -2. CONCLUSION: Both IGFBP-2 and BP-5 are developmentally regulated in mouse spinal cord, with higher levels of those at early embryonic stages indicating their potential role in development of the mouse spinal cord.

Upregulation of neurotoxic serine proteases, prothrombin, and protease-activated receptor 1 early after spinal cord injury.

Apoptosis, well-established in development and now also in degenerative disease, occurs with regularity in several cell compartments early after controlled contusion spinal cord injury (SCI). Cell death in astrocytic, microglial, and neuronal populations peaks at 3 days, while oligodendroglial apoptosis is found 10-14 days later. In this regard, the executioners of apoptosis, the caspase proteases, are also activated within 3 days of SCI. On the other hand, serine proteases, which have been shown to initiate apoptosis and activate caspases in culture models, have not been extensively studied in regards to nervous system trauma. As part of an ongoing effort to examine the spectrum of genes that are up- and downregulated in the injured rat spinal cord, we synthesized serine protease family specific primers to take advantage of conserved residues in the charge relay system and the codon preferences of these mammalian genes. These primers were then employed in a modified, family-specific differential mRNA display technique. One specific serine protease gene we found that was upregulated after injury was prothrombin. Qualitative and quantitative RT-PCR techniques indicated that this increase occurred early, already evident at 8 h after injury, and reached a maximum level fourfold above baseline at 24 h. Peak expression for prothrombin mRNA occurred prior to peak levels of apoptosis in astrocytic, microglial and neuronal compartments at 72 h. Of additional interest, gene database mining revealed that prothrombin shared approximately 48% similarity with myelencephalon-specific protease (MSP), a neurotoxic serine protease previously found to be increased two- to threefold at 3 days after excitotoxic SCI. Since thrombin induces apoptosis in murine and chick motor and rat hippocampal neurons by activating a member of the novel protease-activated receptor (PAR) gene family known as PAR-1, we also analyzed PAR-1 by similar techniques and found that it, too, was upregulated after SCI with the same kinetics as prothrombin. We confirmed these results with gene array analyses that revealed more than one trypsin subfamily serine protease was activated by SCI. They imply the possibility of using specific, tissue-directed serine protease inhibition at translational or transcriptional levels, and offer a potential paradigm shift in drug discovery for SCI to limit the extent of apoptosis, and consequent functional loss, in the human spinal cord.

Insulin-like growth factor binding proteins in cerebrospinal fluid during human development and aging.

We analyzed samples of insulin-like growth factor binding proteins (IGFBPs) in human cerebrospinal fluid (CSF) in neurologically normal patients from one day after birth to age 76 years. CSF samples were separated on SDS-PAGE and then transferred to nitrocellulose membranes where IGFBPs were detected by Western ligand blot using [(125)I]-IGF-II, confirming other reports where we found the presence of IGFBP-2, 3, 4, 5. The 34 kDa IGFBP-2 was present in all samples, and progressively decreased with age. A broad 28- to 30-kDa IGFBP band, having the appearance of IGFBP-5, was triphasic: faint during infancy, barely detectable at 6 months, but intense in adult and aged individuals. The 24-kDa IGFBP-4 band was only seen in neonatal CSF samples, while the IGFBP-3 doublet gradually increased during aging. Thus, these present results show that IGFBP-2, 3, 4 and 5 in CSF are developmentally regulated, suggesting roles for these molecules in the development of the nervous system.

Strategies for managing upper tract calculi in young children.

PURPOSE: Pediatric urolithiasis is relatively uncommon and there is little information on the application of modern surgical procedures in young children. We present a single center experience with the surgical management of upper tract calculi in this age group. MATERIALS AND METHODS: We reviewed presentation, co-morbidity, treatment, outcome and complications in all prepubertal patients who required surgical treatment for ureteral or renal calculi during a 4-year period. The series consists of 24 girls and 17 boys 17 months to 14 years old (mean age 7.5 years). A total of 26 children were anatomically normal, and 4 had myelomeningocele, 4 had ureteropelvic junction obstruction (in a pelvic kidney in 1), 2 had cloacal anomalies, 2 had vesicoureteral reflux, and 1 each had nonrefluxing megaureter, orthotopic ureterocele and a functioning renal transplant. RESULTS: Extracorporeal shock wave lithotripsy was performed in 24 patients. Stents or nephrostomy tubes were only used in the 4 patients who presented with pyonephrosis. Of the 41 cases 17 were rendered stone-free, 3 had a decreased stone burden and 4 were failures. Ureteroscopic extraction of distal ureteral calculi was successful in 11 of 12 children, of whom the youngest was 2.5 years old. No child had postoperative infection or evidence of ureteral obstruction. Stent placement facilitated stone passage or dissolution in 2 patients, a renal calculus was percutaneously extracted in 2 and 7 required open surgery, mostly for correcting simultaneous anatomical abnormalities or after minimally invasive surgery failed. Some metabolic abnormality was detected in 80% of the children tested. CONCLUSIONS: The surgical management of upper urinary tract calculi in young children parallels that in adults. Minimally invasive surgical methods may be safely used even in young infants. Most children do not need elective stenting before lithotripsy. Open procedures are still required in 17% of cases. The majority of children have definable metabolic abnormalities.

Efficacy of variable-angle screws in transpedicular fixation.

The purpose of this study was to evaluate the usefulness and efficacy of variable-angle screws in transpedicular fixation. Sixteen patients (10 men and six women, age range 44-73 years) underwent a posterior transpedicular fixation procedure in which variable-angle screws were placed at two or more levels. Four patients experienced spinal instability secondary to trauma, 10 patients suffered from degenerative spondylosis requiring fusion, and two patients were treated for spinal metastatic disease. All patients underwent posterior transverse process fusion in which autologous bone was used. In total, 37 vertebral levels were fixed with variable-angle screws placed at 22 levels. Postoperatively all patients were fitted with an external orthosis that was worn for 12 weeks. Serial postoperative plain x-ray films were obtained in all cases. Follow-up periods ranged from 11 to 24 months. Based on clinical and radiographic data, solid fusion was achieved in 14 of 16 patients. There were two early disconnections of the rod/screw connectors, which were related to errors in technique. With the exception of these disconnections, there were no cases of construct failure. There were no wound infections, and no patient experienced a decline in neurological function as compared with preoperative levels. Both instrumentation systems were easy to use, and the flexibility in trajectory allowed for quicker screw placement and decreased operating room time. Variable-angle pedicle screws are a safe, useful adjunct to transpedicular fixation, particularly in multisegment fixation and in spines with abnormal alignment.

Thrombin is an extracellular signal that activates intracellular death protease pathways inducing apoptosis in model motor neurons.

Apoptosis, often also termed "programmed cell death", occurs in normal development in the brain and spinal cord. Important to concepts of disease and potential intervention is the exciting finding that apoptosis is also found after neurotrauma and in a number of neurodegenerative diseases. Although the precise mechanism of neuronal cell loss remains unknown, much emphasis has been placed recently on the activation of cell death protease cascades within the cell. How these cascades may be activated, especially from extracellular influences, is currently poorly understood. Thrombin, the multifunctional coagulation protease, is an early phase modulator at sites of tissue injury and has been shown to induce cell death in neurons by an apoptotic mechanism by activating its receptor, PAR-1. Using a model motor neuronal cell line, NSC19, which we have shown undergoes apoptosis after treatment with classic apoptosis inducers such as the topoisomerase inhibitors camptothecin and etoposide, we unambiguously found that nanomolar thrombin induced characteristic signs of apoptosis. Strikingly, endonucleolysis was accompanied by an increase in caspase-3-like activity in cellular extracts, which correlated with both detection of caspase-induced signature cleavage of the cortical cytoskeleton component nonerythroid spectrin (alpha-fodrin) and identification of increased accessibility of a caspase cleavage domain, using an antibody (Ab127) made against a synthetic peptide KGDEVD. Demonstrating that thrombin activation of death proteases was linked to cell death, we were able to inhibit thrombin-induced apoptosis by using a caspase family inhibitor, benzyloxycarbonyl-Asp-(oMe)-fluoromethyl ketone (Boc-D-FMK). These novel results demonstrate that thrombin serves as an extracellular "death signal" to activate intracellular protease pathways. These pathways lead to apoptotic cell death and can be modulated by inhibiting caspase activity downstream to PAR-1.

Apoptosis in cellular compartments of rat spinal cord after severe contusion injury.

Following a controlled, severe contusion lesion to the lower thoracic spinal cord in adult rats, we found that apoptosis occurred in cells located in both gray and white matter. This suggested that both nonneuronal cells, including astrocytes, oligodendroglia and microglia, as well as neurons, might participate in programmed cell death (PCD) following spinal cord injury (SCI). Determination of which cell populations participate, and the kinetics and extent of their involvement might reveal new paradigms for approaches to therapy. Consequently, we assessed the functional deficit, comparing a comprehensive locomotor rating scale (LRS) with the inclined plane test at various times after injury. Using standard histology, along with cell-specific markers, we assessed PCD in different spinal cord segments using several parameters of apoptosis. Our results indicate that hind limb motor function was lost at day 1, and then only gradually and ineffectively (about 10-15%) recovered over the next month. Evidence for increased cell number was present for astrocytes and microglia beginning at day 1 after injury. Over the postinjury time period, apoptotic cells appeared (from day 1 to 14), and peaked (in terms of apoptotic index) on day 3. About one-third were microglia, whereas neurons, both large and small, also underwent apoptosis, again peaking at day 3. However, neurons continued to die and were not replaced by proliferation, so that at day 7, three times as many neurons (as a percentage) underwent PCD compared with the glial compartment. Oligodendrocytes also underwent apoptosis, with a biphasic curve, both at days 3 and 14 following injury. Thus, in addition to immediate, passive necrosis, delayed and apoptotic PCD also occurred in all cell populations in severely injured spinal cord.