Medicaid Expansion Is Associated With Increases in Medicaid-Funded Total Joint Arthroplasty.

BACKGROUND: Existing literature presents competing views concerning the impact of Medicaid expansion on total joint arthroplasty (TJA) utilizations. While some reports demonstrate that expansion does not increase Medicaid acceptance by surgeons, others show increases in Medicaid-funded TJA via limited analyses. We conducted a nationwide, multi-insurance, econometric study to determine if Medicaid-funded and all-funding-source total hip arthroplasty (THA) or total knee arthroplasty (TKA) utilizations increased following expansion. METHODS: This study examined 999,015 THA and 2,099,975 TKA from 2010 to 2017 using a commercially available national payer database. Difference-in-differences analyses, econometric regression methods used to assess the impact of policy change, were used to examine the impact of Medicaid expansion on TJA utilizations, and event analyses were used to confirm the parallel trends assumption, which helps to ensure that the estimated effect is not a result of existing differences in trends between treatment and nontreatment groups. RESULTS: Event analyses confirmed parallel trends in the pre-expansion period. Difference-in-differences analyses found a persistent increase in Medicaid-funded THA (40.4%, P = .001, confidence interval [CI]: 12.7, 62.1%), but not THA from all funding sources (4.6%, P = .128, CI: -1.3, 10.8%). Medicaid-funded TKA (35.8%, P < .001, CI: 17.4, 68.0%) increased, but not TKA from all funding sources (3.4%, P = .321, CI: -3.1, 10.1%). CONCLUSION: While the number of Medicaid-funded TJAs increased, expansion had no significant effect when examining all funding sources. This suggests that Medicaid expansion primarily affected source of TJA funding, not overall volume. Further research is needed to examine state-specific predictors of response to Medicaid expansion.

Somatostatin Receptor-PET/CT/MRI of Head and Neck Neuroendocrine Tumors.

BACKGROUND AND PURPOSE: Due to its high sensitivity, somatostatin receptor-PET may detect smaller lesions and more extensive disease than contrast-enhanced MR imaging, while the superior spatial resolution of MR imaging enables lesions to be accurately localized. We compared results of somatostatin receptor-PET/MRI with those of MR imaging alone and assessed the added value of vertex-to-thigh imaging for head and neck neuroendocrine tumors. MATERIALS AND METHODS: Somatostatin receptor-PET/CT was acquired as limited brain or head and neck imaging, with optional vertex-to-thigh imaging, following administration of 64CU/68GA DOTATATE. Somatostatin receptor-PET was fused with separately acquired contrast-enhanced MR imaging. DOTATATE activity was classified as comparable, more extensive, and/or showing additional lesions compared with MR imaging. Vertex-to-thigh findings were classified as positive or negative for metastatic disease or incidental. RESULTS: Thirty patients (with 13 meningiomas, 11 paragangliomas, 1 metastatic papillary thyroid carcinoma, 1 middle ear neuroendocrine adenoma, 1 external auditory canal mass, 1 pituitary carcinoma, 1 olfactory neuroblastoma, 1 orbital mass) were imaged. Five had no evidence of somatostatin receptor-positive lesions and were excluded. In 11/25, somatostatin receptor-PET/MRI and MR imaging were comparable. In 7/25, somatostatin receptor-PET/MRI showed more extensive disease, while in 9/25, somatostatin receptor-PET/MRI identified additional lesions. On vertex-to-thigh imaging, 1 of 17 patients was positive for metastatic disease, 8 of 17 were negative, and 8 of 17 demonstrated incidental findings. CONCLUSIONS: Somatostatin receptor-PET detected additional lesions and more extensive disease than contrast-enhanced MR imaging alone, while vertex-to-thigh imaging showed a low incidence of metastatic disease. Somatostatin receptor-PET/MRI enabled superior anatomic delineation of tumor burden, while any discrepancies were readily addressed. Somatostatin receptor-PET/MRI has the potential to play an important role in presurgical and radiation therapy planning of head and neck neuroendocrine tumors.

Underweight Patients are at Increased Risk for Complications following Total Hip Arthroplasty.

BACKGROUND: Given the prevalence of obesity in the United States, much of the adult reconstruction literature focuses on the effects of obesity and morbid obesity. However, there is little published data on the effect of being underweight on postoperative outcomes. This study aimed to examine the risk of low body mass index (BMI) on complications after total hip arthroplasty (THA). METHODS: A large national database was queried between 2010 and 2020 to identify patients who had THAs. Using International Classification of Disease codes, patients were grouped into the following BMI categories: morbid obesity (BMI>40), obesity (BMI 30 to 40), normal BMI (BMI 20 to 30), and underweight (BMI<20). There were 58,151 patients identified, including 2,484 (4.27%) underweight patients, 34,710 (59.69%) obese patients, and 20,957 (36.04%) morbidly obese patients. Control groups were created for each study group, matching for age, sex, and a comorbidity index. Complications that occurred within 1 year postoperatively were isolated. Subanalyses were performed to compare complications between underweight and obese patients. Statistical analyses were performed using Pearson Chi-squares. RESULTS: Compared to their matched control group, underweight patients showed increased odds of THA revision (Odds Ratio (OR) = 1.32, P = .04), sepsis (OR = 1.51, P = .01), and periprosthetic fractures (OR = 1.63, P = .01). When directly comparing underweight and obese patients (BMI 30 and above), underweight patients had higher odds of aseptic loosening (OR = 1.62, P = .03), sepsis (OR = 1.34, P = .03), dislocation (OR = 1.84, P < .001), and periprosthetic fracture (OR = 1.46, P = .01). CONCLUSION: Morbidly obese patients experience the highest odds of complications, although underweight patients also had elevated odds for several complications. Underweight patients are an under-recognized and understudied high risk arthroplasty cohort and further research is needed.

Malnutrition, Body Mass Index, and Associated Risk of Complications After Posterior Lumbar Spine Fusion: A 3:1 Matched Cohort Analysis.

OBJECTIVE: The effect of malnutrition on outcomes after posterior lumbar fusion (PLF) remains understudied. This study analyzes the effect of malnutrition across a comprehensive range of body mass index (BMI) on complications after PLF. METHODS: The Pearldiver Mariner database was queried between 2010 and 2020 using International Classification of Diseases (Ninth and Tenth Revisions) codes for malnutrition and Current Procedural Terminology codes for PLF. Patients were identified with preoperative BMI diagnosis codes and partitioned into one of the following BMI cohorts: underweight (BMI <20), normal (BMI 19-30), obese (BMI 30-40), and morbidly obese (BMI >40). An additional all-BMI cohort was created using patients with any BMI code. All cohorts were matched 1:3 to control patients within the same BMI group without malnutrition based on age, gender, and Charlson comorbidity index. Complication rates were calculated using the Pearson χ2 method with statistical significance set to P < 0.05. RESULTS: The number of patients in each cohort were 1106 (all-BMI), 227 (underweight), 808 (normal), 667 (obese), and 449 (morbidly obese). Statistical analysis showed that the all-BMI cohort had greater odds of complications related to instrumentation (odds ratio [OR]: 2.28; P < 0.001), need for revision fusion (OR: 2.04; P < 0.001), pulmonary complications (OR: 1.45; P < 0.001), sepsis (OR: 2.89; P < 0.001), surgical site complications (OR: 1.87; P < 0.001), and urinary complications (OR: 1.41; P < 0.001). No difference was noted between the BMI-specific cohorts for complication risk. CONCLUSION: Our analysis indicates that malnutrition may independently increase PLF complication risk. Surgeons may consider preoperative optimization for malnutrition patients to reduce complication risk.

Contributions of Parietal Cortex to the Working Memory of an Obstacle Acquired Visually or Tactilely in the Locomoting Cat.

A working memory of obstacles is essential for navigating complex, cluttered terrain. In quadrupeds, it has been proposed that parietal cortical areas related to movement planning and working memory may be important for guiding the hindlegs over an obstacle previously cleared by the forelegs. To test this hypothesis, parietal areas 5 and 7 were reversibly deactivated in walking cats. The working memory of an obstacle was assessed in both a visually dependent and tactilely dependent paradigm. Reversible bilateral deactivation of area 5, but not area 7, altered hindleg stepping in a manner indicating that the animals did not recall the obstacle over which their forelegs had stepped. Similar deficits were observed when area 5 deactivation was restricted to the delay during which obstacle memory must be maintained. Furthermore, partial memory recovery observed when area 5 function was deactivated and restored within this maintenance period suggests that the deactivation may suppress, but not eliminate, the working memory of an obstacle. As area 5 deactivations incurred similar memory deficits in both visual and tactile obstacle working memory paradigms, parietal area 5 is critical for maintaining the working memory of an obstacle acquired via vision or touch that is used to modify stepping for avoidance.

Memory-Guided Stumbling Correction in the Hindlimb of Quadrupeds Relies on Parietal Area 5.

In complex environments, tripping over an unexpected obstacle evokes the stumbling corrective reaction, eliciting rapid limb hyperflexion to lift the leg over the obstruction. While stumbling correction has been characterized within a single limb in the cat, this response must extend to both forelegs and hindlegs for successful avoidance in naturalistic settings. Furthermore, the ability to remember an obstacle over which the forelegs have tripped is necessary for hindleg clearance if locomotion is delayed. Therefore, memory-guided stumbling correction was studied in walking cats after the forelegs tripped over an unexpected obstacle. Tactile input to only one foreleg was often sufficient in modulating stepping of all four legs when locomotion was continuous, or when hindleg clearance was delayed. When obstacle height was varied, animals appropriately scaled step height to obstacle height. As tactile input without foreleg clearance was insufficient in reliably modulating stepping, efference, or proprioceptive information about modulated foreleg stepping may be important for producing a robust, long-lasting memory. Finally, cooling-induced deactivation of parietal area 5 altered hindleg stepping in a manner indicating that animals no longer recalled the obstacle over which they had tripped. Altogether, these results demonstrate the integral role area 5 plays in memory-guided stumbling correction.

Leg mechanics contribute to establishing swing phase trajectories during memory-guided stepping movements in walking cats: a computational analysis.

When quadrupeds stop walking after stepping over a barrier with their forelegs, the memory of barrier height and location is retained for many minutes. This memory is subsequently used to guide hind leg movements over the barrier when walking is resumed. The upslope of the initial trajectory of hind leg paw movements is strongly dependent on the initial location of the paw relative to the barrier. In this study, we have attempted to determine whether mechanical factors contribute significantly in establishing the slope of the paw trajectories by creating a four-link biomechanical model of a cat hind leg and driving this model with a variety of joint-torque profiles, including average torques for a range of initial paw positions relative to the barrier. Torque profiles for individual steps were determined by an inverse dynamic analysis of leg movements in three normal cats. Our study demonstrates that limb mechanics can contribute to establishing the dependency of trajectory slope on the initial position of the paw relative to the barrier. However, an additional contribution of neuronal motor commands was indicated by the fact that the simulated slopes of paw trajectories were significantly less than the observed slopes. A neuronal contribution to the modification of paw trajectories was also revealed by our observations that both the magnitudes of knee flexor muscle EMG bursts and the initial knee flexion torques depended on initial paw position. Previous studies have shown that a shift in paw position prior to stepping over a barrier changes the paw trajectory to be appropriate for the new paw position. Our data indicate that both mechanical and neuronal factors contribute to this updating process, and that any shift in leg position during the delay period modifies the working memory of barrier location.

Frontotemporal dementia in elderly individuals.

OBJECTIVE: To determine whether cases of frontotemporal lobar degeneration (FTLD) do exist in elderly individuals and have clinical and neuropathological features distinct from those with presenile onset. DESIGN: Retrospective matched cohort study. SETTING: Regional Neuroscience Centre, North East England. PATIENTS: We compared clinicopathological features of 11 cases of FTLD in elderly individuals with 19 cases of presenile-onset FTLD. RESULTS: Retrospective case note analysis showed that most elderly patients with FTLD had behavioral features consistent with orbitofrontal and basofrontal involvement, similar to presenile-onset FTLD, though symptomatic memory loss was present in 91% (10 of 11) of elderly patients with FTLD compared with only 36% (7 of 19) of patients with presenile-onset FTLD. Neuropathologically, the group of elderly patients with FTLD comprised 7 with FTLD­TDP-43, 1 with ubiquitin-positive FTLD, 2 with FTLD-tau/Pick disease, and 1 with FTLD-tau/neurofibrillary tangle­predominant dementia with TDP-43, a composition similar to presenile-onset FTLD. However, hippocampal sclerosis was more common in elderly patients with FTLD than patients with presenile-onset FTLD (82% vs 37%) and more severe in elderly patients with FTLD (P < .05). By contrast, severe atrophy of the frontal and temporal lobes was less common in elderly patients with FTLD (frontal: 45%; temporal: 27%) than patients with presenile-onset FTLD (frontal: 63%; temporal: 78%). Elderly patients with FTLD represented 3.2% of all elderly patients with dementia autopsied at Newcastle General Hospital. CONCLUSIONS: Frontotemporal lobar degeneration in elderly patients does exist as a separate entity from presenile-onset FTLD. Its main features include (1) clinically frequent memory loss and behavioral change predominating over language and semantic dysfunction and (2) neuropathologically prominent hippocampal sclerosis but less pronounced cortical lobar atrophy. Clinically, FTLD in elderly patients is underrecognized and should be considered in the elderly subjects presenting with an "atypical Alzheimer disease" phenotype.

Diagnostic strategy used to establish etiologies of encephalitis in a prospective cohort of patients in England.

The laboratory diagnostic strategy used to determine the etiology of encephalitis in 203 patients is reported. An etiological diagnosis was made by first-line laboratory testing for 111 (55%) patients. Subsequent testing, based on individual case reviews, resulted in 17 (8%) further diagnoses, of which 12 (71%) were immune-mediated and 5 (29%) were due to infection. Seventy-five cases were of unknown etiology. Sixteen (8%) of 203 samples were found to be associated with either N-methyl-d-aspartate receptor or voltage-gated potassium channel complex antibodies. The most common viral causes identified were herpes simplex virus (HSV) (19%) and varicella-zoster virus (5%), while the most important bacterial cause was Mycobacterium tuberculosis (5%). The diagnostic value of testing cerebrospinal fluid (CSF) for antibody was assessed using 139 samples from 99 patients, and antibody was detected in 46 samples from 37 patients. Samples collected at 14 to 28 days were more likely to be positive than samples taken 0 to 6 days postadmission. Three PCR-negative HSV cases were diagnosed by the presence of virus-specific antibody in the central nervous system (CNS). It was not possible to make an etiological diagnosis for one-third of the cases; these were therefore considered to be due to unknown causes. Delayed sampling did not contribute to these cases. Twenty percent of the patients with infections with an unknown etiology showed evidence of localized immune activation within the CNS, but no novel viral DNA or RNA sequences were found. We conclude that a good standard of clinical investigation and thorough first-line laboratory testing allows the diagnosis of most cases of infectious encephalitis; testing for CSF antibodies allows further cases to be diagnosed. It is important that testing for immune-mediated causes also be included in a diagnostic algorithm.

Long-lasting working memories of obstacles established by foreleg stepping in walking cats require area 5 of the posterior parietal cortex.

Walking animals rely on working memory to avoid obstacles. One example is the stepping of the hindlegs of quadrupeds over an obstacle. In this case, the obstacle is not visible at the time of hindleg stepping, because of its position between the fore and hindlegs, and working memory must be used to avoid it. We have previously shown that this memory is very precise and surprisingly long-lasting and that it depends on the stepping of the forelegs over the obstacle for its initiation. In this study, we test the hypothesis that area 5 in the posterior parietal cortex of cats is necessary for the maintenance of this long-lasting working memory. We report that small bilateral lesions to area 5 do not affect the amplitude of normal stepping of the hindlegs over obstacles, but they profoundly reduce the long-lasting working memory of obstacles. We propose that inputs to area 5 associated with foreleg stepping initiate long-lasting activity that maintains the memory of obstacle height in another brain region to guide the hindlegs over obstacles.

CSF protein biomarkers for proximal axonal damage improve prognostic accuracy in the acute phase of Guillain-Barré syndrome.

Early predictors of prognosis in Guillain-Barré syndrome (GBS) are needed to identify patients who are likely to make a poor recovery and to guide therapeutic decision-making in the acute phase. Here we investigate whether axonal protein biomarkers released into the cerebrospinal fluid (CSF) following proximal axonal damage improve the early prognostic accuracy in GBS. A prospective multicenter study including 132 patients (38 GBS, 38 neurological controls, 42 headaches, 14 chronic inflammatory demyelinating neuropathy). CSF levels of axonal [neurofilament (NfH) and tau] and glial (S100B and glial fibrillary acidic protein) protein biomarkers were measured on admission. Nerve conduction studies were performed at the time of lumbar puncture and patients were classified according to neurophysiological criteria. Outcome was assessed on the Hughes functional score (F-score). Poor outcome was defined as the inability to walk independently (F-score > or = 3). High NfH levels (>0.73 ng/ml) predicted poor outcome (P = 0.01) with an odds ratio of 7.3 and correlated with the outcome F-score (R = 0.51, P < 0.01), as did hTau levels (R = 0.47, P < 0.01). Patients with poor outcome had significantly higher CSF NfH (median 1.78 ng/ml) when compared to those with good outcome (0.03 ng/ml) or all of the control groups (neurological controls 0.18 ng/ml, headaches 0.06 ng/ml, chronic inflammatory demyelinating neuropathy 0.05 ng/ml). Except for age (P < 0.05) and need for ventilatory support (P < 0.05), none of the other features reliably predicted outcome. Improved prognostic accuracy in the acute phase of GBS seems possible using CSF NfH levels.

The longitudinal profile of CSF markers during external lumbar drainage.

BACKGROUND: External lumbar drainage (ELD) is known as a good predictor of favourable outcome in shunting patients suffering from idiopathic normal pressure hydrocephalus (iNPH). METHODS: Eleven patients suffering from iNPH had a lumbar drain (LD) inserted for 72 h and participated in a research study to quantify any improvement in their clinical symptoms. The lumbar cerebrospinal fluid (CSF) levels of lactate, 8-isoprostane, vascular endothelial growth factor (VEGF), glial fibrillar acidic protein (GFAP), neurofilament (heavy chain) protein (NF (h)), Abeta(1-42) (beta-amyloid) and total tau were assayed samples from all three time points. RESULTS: The concentrations of lactate, VEGF, GFAP and tau increased significantly during the 72 h of drainage. There were also increases in 8-isoprostane and Abeta(1-42) (non significant). The concentration of NF (h) was reduced significantly following 72 h of drainage. There was a significant positive correlation between Abeta(1-42) and total tau in the first sample. GFAP was negatively correlated in a significant fashion with both Abeta(1-42) and total tau. NF (h) was negatively correlated with VEGF. CONCLUSION: Evidence is provided that ELD is producing measurable changes in the CSF composition of patients with iNPH. The present paper discusses how such changes may be implicated in the pathophysiology of the condition.

Improving the recovery of S100B protein in cerebral microdialysis: implications for multimodal monitoring in neurocritical care.

INTRODUCTION: Cerebral microdialysis is an established research tool that is used by an increasing number of neurocritical care units as a component of bedside multimodality monitoring. Body fluid biomarkers are an emerging tool for the assessment of brain injury. The correct interpretation of body fluid biomarker levels depends on the degree of recovery, i.e. relative recovery and the accuracy of the analytical technique. METHODS: In vitro recovery experiments were performed on 100mL volumes of cerebrospinal fluid and solutions of S100B, glucose, lactate and pyruvate comparing relative recoveries using commercially available 20 kDa (CMA70) and 100 kDa (CMA71) microdialysis catheters. We also compared the CMA 600 microdialysis analyzer with a YSI 2003 STAT Plus analyzer for glucose and lactate to determine its reliability. RESULTS: Significantly, we demonstrate the improved recovery of the protein S100B using a larger molecular weight (MW) cut-off catheter (20 kDa range: 0.1-9%; 100 kDa range: 1.7-18.3%) while maintaining comparable performance for the conventional markers glucose, lactate and pyruvate. Additionally we found that the CMA 600 analyzer may be prone to overestimation of lactate readings at higher concentration with implications for clinical decision-making. CONCLUSION: Our data demonstrates that the 100 kDa MW cut-off catheter allows for the improved recovery of macromolecules in cerebral microdialysis research while maintaining the value of existing MD data for routine clinical use.

Spinal 5-HT7 receptors are critical for alternating activity during locomotion: in vitro neonatal and in vivo adult studies using 5-HT7 receptor knockout mice.

5-HT7 receptors have been implicated in the control of locomotion. Here we use 5-HT7 receptor knockout mice to rigorously test whether 5-HT acts at the 5-HT7 receptor to control locomotor-like activity in the neonatal mouse spinal cord in vitro and voluntary locomotion in adult mice. We found that 5-HT applied onto in vitro spinal cords of 5-HT7+/+ mice produced locomotor-like activity that was disrupted and subsequently blocked by the 5-HT7 receptor antagonist SB-269970. In spinal cords isolated from 5-HT7-/- mice, 5-HT produced either uncoordinated rhythmic activity or resulted in synchronous discharges of the ventral roots. SB-269970 had no effect on 5-HT-induced rhythmic activity in the 5-HT7-/- mice. In adult in vivo experiments, SB-269970 applied directly to the spinal cord consistently disrupted locomotion and produced prolonged-extension of the hindlimbs in 5-HT7+/+ but not 5-HT7-/- mice. Disrupted EMG activity produced by SB-269970 in vivo was similar to the uncoordinated rhythmic activity produced by the drug in vitro. Moreover, 5-HT7-/- mice displayed greater maximal extension at the hip and ankle joints than 5-HT7+/+ animals during voluntary locomotion. These results suggest that spinal 5-HT7 receptors are required for the production and coordination of 5-HT-induced locomotor-like activity in the neonatal mouse and are important for the coordination of voluntary locomotion in adult mice. We conclude that spinal 5-HT7 receptors are critical for alternating activity during locomotion.

Object avoidance during locomotion.

Many animals rely on vision for navigating through complex environments and for avoiding specific obstacles during locomotion. Navigation and obstacle avoidance are tasks that depend on gathering information about the environment by vision and using this information at later times to guide limb and body movements. Here we review studies demonstrating the use of short-term visual memory during walking in humans and cats. Our own investigations have demonstrated that cats have the ability to retain a memory of an obstacle they have stepped over with the forelegs for many minutes and to use this memory to guide stepping of the hindlegs to avoid the remembered obstacle. A brain region that may be critically involved in the retention of memories of the location of obstacles is the posterior parietal cortex. Recordings from neurons in area 5 in the posterior parietal cortex in freely walking cats have revealed the existence of neurons whose activity is strongly correlated with the location of an obstacle relative to the body. How these neurons might be used to regulate motor commands remains to be established. We believe that studies on obstacle avoidance in walking cats have the potential to significantly advance our understanding of visuo-motor transformations. Current knowledge about the brain regions and pathways underlying visuo-motor transformations during walking are reviewed.

New technique for drug application to the spinal cord of walking mice.

With the increasing availability of mutant mice that allow the conditional silencing of specific classes of interneurons in the spinal cord by drug application, a method for easily delivering drugs locally on spinal cord segments in adult animals has the potential for providing insights into the functioning of neuronal networks controlling walking. Here we describe a simple technique for this purpose. The drug is applied in high concentrations in a bath created with Vaseline walls around one to three segments of the spinal cord exposed under general anesthetic (isoflurane) combined with a strong, long-lasting analgesic (buprenorphine). After 20min of drug application the Vaseline and the drug is removed and skin closed. We first document that the surgery and analgesic have no obvious influences on the kinematics of hind leg movements after recovery from the anesthetic, and that the analgesic enhanced locomotor activity. We then describe the influence of applying a glycine-receptor antagonist onto the lumbar segments of the spinal cord to demonstrate that the method is effective in modifying the functioning of neuronal systems in the spinal cord. Combining this method with kinematic and electromyographic recording techniques allows the detailed investigation of the effects of drugs on the walking behavior in adult mice.

Descending command systems for the initiation of locomotion in mammals.

Neurons in the brainstem implicated in the initiation of locomotion include glutamatergic, noradrenergic (NA), dopaminergic (DA), and serotonergic (5-HT) neurons giving rise to descending tracts. Glutamate antagonists block mesencephalic locomotor region-induced and spontaneous locomotion, and glutamatergic agonists induce locomotion in spinal animals. NA and 5-HT inputs to the spinal cord originate in the brainstem, while the descending dopaminergic pathway originates in the hypothalamus. Agonists acting at NA, DA or 5-HT receptors facilitate or induce locomotion in spinal animals. 5-HT neurons located in the parapyramidal region (PPR) produce locomotion when stimulated in the isolated neonatal rat brainstem-spinal cord preparation, and they constitute the first anatomically discrete group of spinally-projecting neurons demonstrated to be involved in the initiation of locomotion in mammals. Neurons in the PPR are activated during treadmill locomotion in adult rats. Locomotion evoked from the PPR is mediated by 5-HT(7) and 5-HT(2A) receptors, and 5-HT(7) antagonists block locomotion in cat, rat and mouse preparations, but have little effect in mice lacking 5-HT(7) receptors. 5-HT induced activity in 5-HT(7) knockout mice is rhythmic, but coordination among flexor and extensor motor nuclei and left and right sides of the spinal cord is disrupted. In the adult wild-type mouse, 5-HT(7) receptor antagonists impair locomotion, producing patterns of activity resembling those induced by 5-HT in 5-HT(7) knockout mice. 5-HT(7) receptor antagonists have a reduced effect on locomotion in adult 5-HT(7) receptor knockout mice. We conclude that the PPR is the source of a descending 5-HT command pathway that activates the CPG via 5-HT(7) and 5-HT(2A) receptors. Further experiments are necessary to define the putative glutamatergic, DA, and NA command pathways.

Cerebrospinal Fluid Studies in Kenyan Children with Severe Falciparum Malaria.

The pathogenesis of the neurological complications of Plasmodium falciparum malaria is unclear. We measured proteins and amino acids in paired plasma and cerebrospinal fluid (CSF) samples in children with severe falciparum malaria, to assess the integrity of the blood brain barrier (BBB), and look for evidence of intrathecal synthesis of immunoglobulins, excitotoxins and brain damage. METHODS: Proteins of different molecular sizes and immunoglobulins were measured in paired CSF and plasma samples in children with falciparum malaria and either impaired consciousness, prostrate, or seizures. RESULTS: The ratio of CSF to plasma albumin (Q(alb)) exceeded the reference values in 42 (51%) children. The CSF concentrations of the excitotoxic amino acid aspartate and many non-polar amino acids, except alanine, were above the reference value, despite normal plasma concentrations. IgM concentrations were elevated in 21 (46%) and the IgM index was raised in 22 (52%). Identical IgG oligoclonal bands were found in 9 (35%), but only one patient had an increase in the CSF IgG without a concomitant increase in plasma indicating intrathecal synthesis of IgG. CONCLUSIONS: This study indicates that the BBB is mildly impaired in some children with severe falciparum malaria, and this impairment is not confined to cerebral malaria, but also occurs in children with prostrate malaria and to a lesser extent the children with malaria and seizures. There is evidence of intrathecal synthesis of immunoglobulins in children with malaria, but this requires further investigation. This finding, together with raised level of excitotoxic amino acid aspartate could contribute to the pathogenesis of neurological complications in malaria.