Isolated Patellofemoral Joint Arthroplasty: Can Preoperative Bone Scans Predict Survivorship?

BACKGROUND: Isolated patellofemoral joint arthritis has been identified in 10% of the population presenting with symptomatic knee osteoarthritis. Patient selection is important in order to improve survivorship following PF arthroplasty. The purpose of this study is to compare the use of a preoperative bone scan vs a magnetic resonance imaging (MRI) to identify the patient with isolated PF arthritis. METHODS: This is a retrospective review of 32 patients undergoing isolated PF arthroplasty for PF arthritis using the same implant design. Sixteen consecutive patients received a preoperative bone scan to confirm isolated PF arthritis. These patients were matched by age and gender to patients where an MRI was used to determine isolated PF arthritis. The bone scan cohort contained 13 females and three males with an average age of 48 years and average follow-up of 52 months. There was no significant difference in age, body mass index, follow-up, or preoperative range of motion between the groups. The MRI and bone scan results were reported by a radiologist specializing in orthopedic radiology. RESULTS: Survivorship was 100% in the PF arthroplasty group selected using a preoperative bone scan. Revision surgery with conversion to TKA was required in 5 of 16 patients (31%) when an MRI was used to identify isolated PF arthritis. Revision in all patients in the MRI group was due to progression of knee arthritis in the tibial-femoral joint. There were no cases of implant-related failures. CONCLUSION: Patellofemoral arthroplasty using a modern design implant demonstrated 100% survivorship when a preoperative bone scan was used for patient selection to confirm isolated PF arthritis. In the group where only an MRI was used, there was a 31% failure due to progression of the disease. Based on this study, we would recommend the use of a bone scan as a tool in the selection criteria for patients undergoing PF arthroplasty.

Resolvin D2 Enhances Postischemic Revascularization While Resolving Inflammation.

BACKGROUND: Resolvins are lipid mediators generated by leukocytes during the resolution phase of inflammation. They have been shown to regulate the transition from inflammation to tissue repair; however, it is unknown whether resolvins play a role in tissue revascularization following ischemia. METHODS: We used a murine model of hind limb ischemia (HLI), coupled with laser Doppler perfusion imaging, microcomputed tomography, and targeted mass spectrometry, to assess the role of resolvins in revascularization and inflammation resolution. RESULTS: In mice undergoing HLI, we identified resolvin D2 (RvD2) in bone marrow and skeletal muscle by mass spectrometry (n=4-7 per group). We also identified RvD2 in skeletal muscle biopsies from humans with peripheral artery disease. Monocytes were recruited to skeletal muscle during HLI and isolated monocytes produced RvD2 in a lipoxygenase-dependent manner. Exogenous RvD2 enhanced perfusion recovery in HLI and microcomputed tomography of limb vasculature revealed greater volume, with evidence of tortuous arterioles indicative of arteriogenesis (n=6-8 per group). Unlike other treatment strategies for therapeutic revascularization that exacerbate inflammation, RvD2 did not increase vascular permeability, but reduced neutrophil accumulation and the plasma levels of tumor necrosis factor-α and granulocyte macrophage colony-stimulating factor. In mice treated with RvD2, histopathologic analysis of skeletal muscle of ischemic limbs showed more regenerating myocytes with centrally located nuclei. RvD2 enhanced endothelial cell migration in a Rac-dependent manner, via its receptor, GPR18, and Gpr18-deficient mice had an endogenous defect in perfusion recovery following HLI. Importantly, RvD2 rescued defective revascularization in diabetic mice. CONCLUSIONS: RvD2 stimulates arteriogenic revascularization during HLI, suggesting that resolvins may be a novel class of mediators that both resolve inflammation and promote arteriogenesis.

Glycine is a transmitter in the human and chimpanzee cochlear nuclei.

Introduction: Auditory information is relayed from the cochlea via the eighth cranial nerve to the dorsal and ventral cochlear nuclei (DCN, VCN). The organization, neurochemistry and circuitry of the cochlear nuclei (CN) have been studied in many species. It is well-established that glycine is an inhibitory transmitter in the CN of rodents and cats, with glycinergic cells in the DCN and VCN. There are, however, major differences in the laminar and cellular organization of the DCN between humans (and other primates) and rodents and cats. We therefore asked whether there might also be differences in glycinergic neurotransmission in the CN. Methods: We studied brainstem sections from humans, chimpanzees, and cats. We used antibodies to glycine receptors (GLYR) to identify neurons receiving glycinergic input, and antibodies to the neuronal glycine transporter (GLYT2) to immunolabel glycinergic axons and terminals. We also examined archival sections immunostained for calretinin (CR) and nonphosphorylated neurofilament protein (NPNFP) to try to locate the octopus cell area (OCA), a region in the VCN that rodents has minimal glycinergic input. Results: In humans and chimpanzees we found widespread immunolabel for glycine receptors in DCN and in the posterior (PVCN) and anterior (AVCN) divisions of the VCN. We found a parallel distribution of GLYT2-immunolabeled fibers and puncta. The data also suggest that, as in rodents, a region containing octopus cells in cats, humans and chimpanzees has little glycinergic input. Discussion: Our results show that glycine is a major transmitter in the human and chimpanzee CN, despite the species differences in DCN organization. The sources of the glycinergic input to the CN in humans and chimpanzees are not known.

Results of a Highly Porous Metal-Backed Cementless Patella Implant: A Minimum 5-Year Follow-Up.

Initial design cementless metal-backed patellar implants failed due to multiple reasons including implant design, use of first-generation polyethylene, and surgical technique. This study evaluates clinical outcomes and survivorship of total knee arthroplasty (TKA) using a current generation highly porous metal-backed patellar component. One-hundred twenty-five consecutive primary cementless TKAs with a compression molded highly porous metal-backed patella were reviewed. One-hundred three TKAs (82.4%) with 5-year clinical and radiographic follow-up were available for review. These were matched with 103 consecutive TKAs using a cemented patella of the same implant design. The cementless cohort had a mean age of 65.5 years, body mass index (BMI) of 33.0, and follow-up of 64.4 months. Indications for cementless TKA were based on multiple factors including age, BMI, and bone quality. There were no revisions for loosening or mechanical failure of the cementless patella compared with two cemented patellae revised for aseptic loosening. Eight patients required revisions in the cementless cohort: three for prosthetic joint infection (PJI), two for instability, one periprosthetic femur fracture, one for patella instability, and one for extensor mechanism rupture. Five patients required revisions in the cemented cohort: two for aseptic patellar loosening, one for aseptic femoral loosening, one for PJI, and one for instability. All-cause survivorship at 5 years was 92.2 and 95.1% for the cementless metal-backed implant and cemented implant cohorts, respectively. Use of a compression molded highly porous metal-backed patella component demonstrated excellent clinical and radiographic results at 5-year follow-up. Longer follow-up is required to evaluate the ability of highly porous cementless patella implants to provide durable long-term fixation.

Cementless metal-backed patellar components in primary total knee arthroplasty using an implant of modern design.

Aims: The use of cementless total knee arthroplasty (TKA) components has increased during the past decade. The initial design of cementless metal-backed patellar components had shown high failure rates due to many factors. The aim of this study was to evaluate the clinical results of a second-generation cementless, metal-backed patellar component of a modern design. Methods: This was a retrospective review of 707 primary TKAs in 590 patients from a single institution, using a cementless, metal-backed patellar component with a mean follow-up of 6.9 years (2 to 12). A total of 409 TKAs were performed in 338 females and 298 TKAs in 252 males. The mean age of the patients was 63 years (34 to 87) and their mean BMI was 34.3 kg/m2 (18.8 to 64.5). The patients were chosen to undergo a cementless procedure based on age and preoperative radiological and intraoperative bone quality. Outcome was assessed using the Knee Society knee and function scores and range of motion (ROM), complications, and revisions. Results: A total of 24 TKAs (3.4%) in 24 patients failed and required revision surgery, of which five were due to patellar complications (0.71%): one for aseptic patellar loosening (0.14%) and four for polyethylene dissociation (0.57%). A total of 19 revisions (2.7%) were undertaken in 19 patients for indications which did not relate to the patella: four for aseptic tibial loosening (0.57%), one for aseptic femoral loosening (0.14%), nine for periprosthetic infection (1.3%), one for popliteus impingement (0.14%), and four for instability (0.57%). Knee Society knee and function scores, and ROM, improved significantly when comparing pre- and postoperative values. Survival of the metal-backed patellar component for all-cause failure was 97.5% (95% confidence interval 94.9% to 100%) at 12 years. Conclusion: The second-generation cementless TKA design of metal-backed patellar components showed a 97.5% survival at 12 years, with polyethylene dissociation from the metal-backing being the most common cause of patellar failure. In view of the increased use of TKA, especially in younger, more active, or obese patients, these findings are encouraging at mean follow-up of seven years.

The Claustrum in the Squirrel Monkey.

The claustrum (CLA) is a subcortical structure that is reciprocally and topographically connected with the cerebral cortex. The complexity of the cerebral cortex varies dramatically across mammals, raising the question of whether there might also be differences in CLA organization, circuitry, and function. Species variations in the shape of the CLA are well documented. Studies in multiple species have identified subsets of neurochemically distinct interneurons; some data suggest species variations in the nature, distribution, and numbers of different neurochemically identified neuronal types. We have studied the CLA in a smooth-brained primate, the squirrel monkey, using Nissl-stained sections and immunohistochemistry. We found that the shape of the CLA is different from that in other primates. We found several different neurochemically defined populations of neurons equally distributed throughout the CLA. Immunoreactivity to GAD65/67 and GABAA receptors suggest that GABAergic interneurons provide widespread inhibitory input to CLA neurons. Immunoreactivity to glutamate transporters suggests widespread and overlapping excitatory input from cortical and possibly subcortical sources. Comparison of CLA organization in different species suggests that there may be major species differences both in the organization and in the functions of the CLA. Anat Rec, 303:1439-1454, 2020. © 2019 American Association for Anatomy.

Can Revision TKA Patients Achieve Similar Clinical Functional Improvement Compared to Primaries?

The etiology of failure following primary total knee arthroplasty (TKA) leading to revision surgery are multifactorial, including infection, instability, loosening, contracture, and wear. Although the majority of patients have successful outcomes following revision TKA, postoperative complications are still increased in these patients when compared to primary patients. For this reason, there has been a continued search to identify options, including prosthesis types, to potentially improve outcomes. Therefore, the purpose of this study was to determine if the clinical results achieved following revision TKA are comparatively similar to primaries using the same implant design. Specifically, we compared (1) Knee Society Functional and Range-of-Motion Knee Scores and (2) component survivorship. This was a retrospective analysis of 100 patients undergoing revision TKA due to an aseptic etiology, who were matched to a cohort of 100 patients who underwent primaries with the same prosthesis. There were no differences in the groups with respect to age at surgery, sex, and body mass index. The mean follow-up was 57 months in the revision group (range 24-105 months) and 67 months in the primary TKA group (range 55-123 months). American Knee Society Scores (KSS) and range of motion measurements recorded preoperatively and at the most recent postoperative visit were compared between both cohorts in order to compare postoperative outcomes. A p value of 0.05 was used for significance. The average improvement between the pre- and postoperative KSS function scores in both groups was similar, with both cohorts demonstrating a 28-point improvement. At 2-year follow-up, all-cause survivorship of the aseptic revision surgeries was 87%. Patients undergoing revision TKA for aseptic loosening can potentially expect similar improvements in clinical function scores and survivorship compared to primary TKA when controlling for implant type.

Risk of Reinfection after Irrigation and Debridement of Acute Periprosthetic Joint Infection following TKA.

The purpose of this study was to determine the risk factors associated with reinfection in patients treated with irrigation and debridement (I&D) with liner exchange for an acute (less than 3 months) prosthetic joint infection following the index primary total knee arthroplasty (TKA). Medicare claims database was queried to identify patients with periprosthetic joint infection within 3 months of their index TKA who underwent I&D with tibial polyethylene liner exchange. Exclusion criteria included age < 65 years and < 1 year of claims prior to TKA. A total of 341 patients met our criteria and were analyzed by age, sex, diabetes, obesity, Charlson comorbidity score, and time between TKA and I&D with liner exchange. Average time to I&D with liner exchange following primary TKA was 38.5 ± 21.3 days and multivariate analysis showed a significantly higher risk of reinfection within 1 year in patients > 85 years old (p < 0.001) and diabetes (p < 0.02). The risk of reinfection was lowest for patients treated with I&D with liner exchange within 14 days after TKA (p = 0.028). The incidence of reinfection was 223% greater if I&D with liner exchange was performed 2 to 4 weeks after primary TKA (p < 0.03), and 277% higher if performed > 6 weeks after index procedure compared with those performed within 2 weeks. Patients older than 85 years, diabetics, or treated with I&D with liner exchange > 14 days following the primary TKA had a significantly higher risk of reinfection within 1 year. Patients should be cautioned on the risk of reinfection prior to proceeding with I&D with liner exchange > 2 weeks following the index procedure.

Cost-effectiveness of different strategies for amplified Mycobacterium tuberculosis direct testing for cases of pulmonary tuberculosis.

We conducted a decision analysis to assess and compare four algorithms for amplified Mycobacterium tuberculosis direct (MTD) testing of respiratory specimens in terms of cost-effectiveness. The most cost-effective strategy was one in which smear-positive specimens but not smear-negative specimens were diluted prior to MTD testing.

Specimen dilution improves sensitivity of the amplified Mycobacterium tuberculosis direct test for smear microscopy-positive respiratory specimens.

Specimen dilution has been proposed as a strategy to minimize amplified Mycobacterium tuberculosis direct (MTD) test inhibition (N. Pollock, J. Westerling, and A. Sloutsky, Am. J. Clin. Pathol. 126:142-147, 2006; A. Sloutsky, L. L. Han, and B. G. Werner, J. Clin. Microbiol. 42:1547-1551, 2004). We evaluated the impact of respiratory specimen dilution on MTD test accuracy in a public health laboratory. The difference in MTD test sensitivity between the dilution and conventional methods was 15.9% (P = 0.001) for smear microscopy-positive specimens and -3.6% (P = 0.38) for smear microscopy-negative specimens.

Species Differences in the Organization of the Ventral Cochlear Nucleus.

The mammalian cochlear nuclei (CN) consist of two major subdivisions, the dorsal (DCN) and ventral (VCN) nuclei. We previously reported differences in the structural and neurochemical organization of the human DCN from that in several other species. Here we extend this analysis to the VCN, considering both the organization of subdivisions and the types and distributions of neurons. Classically, the VCN in mammals is composed of two subdivisions, the anteroventral (VCA) and posteroventral cochlear nuclei (VCP). Anatomical and electrophysiological data in several species have defined distinct neuronal types with different distributions in the VCA and VCP. We asked if VCN subdivisions and anatomically defined neuronal types might be distinguished by patterns of protein expression in humans. We also asked if the neurochemical characteristics of the VCN are the same in humans as in other mammalian species, analyzing data from chimpanzees, macaque monkeys, cats, rats and chinchillas. We examined Nissl- and immunostained sections, using antibodies that had labeled neurons in other brainstem nuclei in humans. Nissl-stained sections supported the presence of both VCP and VCA in humans and chimpanzees. However, patterns of protein expression did not differentiate classes of neurons in humans; neurons of different soma shapes and dendritic configurations all expressed the same proteins. The patterns of immunostaining in macaque monkey, cat, rat, and chinchilla were different from those in humans and chimpanzees and from each other. The results may correlate with species differences in auditory function and plasticity. Anat Rec, 301:862-886, 2018. © 2017 Wiley Periodicals, Inc.

Description and Early Outcomes of a Comprehensive Curriculum Redesign at the Northwestern University Feinberg School of Medicine.

In 2012, the Northwestern University Feinberg School of Medicine launched a redesigned curriculum addressing the four primary recommendations in the 2010 Carnegie Foundation for the Advancement of Teaching report on reforming medical education. This new curriculum provides a more standardized evaluation of students' competency achievement through a robust portfolio review process coupled with standard evaluations of medical knowledge and clinical skills. It individualizes learning processes through curriculum flexibility, enabling students to take electives earlier and complete clerkships in their preferred order. The new curriculum is integrated both horizontally and vertically, combining disciplines within organ-based modules and deliberately linking elements (science in medicine, clinical medicine, health and society, professional development) and threads (medical decision making, quality and safety, teamwork and leadership, lifestyle medicine, advocacy and equity) across the three phases that replaced the traditional four-year timeline. It encourages students to conduct research in an area of interest and commit to lifelong learning and self-improvement. The curriculum formalizes the process of professional identity formation and requires students to reflect on their experiences with the informal and hidden curricula, which strongly shape their identities.The authors describe the new curriculum structure, explain their approach to each Carnegie report recommendation, describe early outcomes and challenges, and propose areas for further work. Early data from the first cohort to progress through the curriculum show unchanged United States Medical Licensing Examination Step 1 and 2 scores, enhanced student research engagement and career exploration, and improved student confidence in the patient care and professional development domains.

Use of the amplified mycobacterium tuberculosis direct test in a public health laboratory: test performance and impact on clinical care.

BACKGROUND: The Amplified Mycobacterium tuberculosis Direct Test (MTD; Gen-Probe; San Diego, CA) is a nucleic-acid amplification test for rapid pulmonary tuberculosis (PTB) diagnosis. In a routine public health setting, test accuracy and impact on clinical decisions are unknown. METHODS: Retrospectively, we evaluated MTD accuracy and impact on clinical decisions in a public health setting. To estimate MTD accuracy, mycobacterial culture was used as the "gold standard." To evaluate MTD impact on clinical decisions, concordance of clinician presumptive diagnosis (at time of MTD and smear availability) and definitive diagnosis, and duration of nonindicated tuberculosis therapy were determined for smear-positive PTB suspects in a period of MTD availability (MTD group) and a prior period of MTD nonavailability (non-MTD group). RESULTS: A total of 1,151 respiratory specimens from 638 PTB suspects were analyzed. MTD sensitivity, specificity, positive predictive value, and negative predictive value were 91.7%, 98.7%, 96.7%, and 96.5% overall, respectively; and 98.7%, 97.8%, 98.7%, and 97.8% for smear-positive patients; and 62.2%, 98.9%, 85.2%, and 96.1% for smear-negative patients. In the MTD group, concordance between definitive and clinician presumptive diagnoses was 78% (95% confidence interval [CI], 64 to 88%), similar to that for the non-MTD group (79%; 95% CI, 68.4 to 89.6%). However, concordance between definitive diagnosis and the MTD test was 98% (95% CI, 94.1 to 100%). Median duration of nonindicated tuberculosis treatment was 6 days for the MTD group vs 31 days for the non-MTD group (p = 0.002). CONCLUSION: In this public health setting, MTD was accurate and rapidly detected more than half of the smear-negative PTB cases. For smear-positive PTB suspects, MTD had excellent concordance with definitive diagnosis, but clinicians often inappropriately initiated TB therapy despite a negative MTD result.

Neurochemically defined cell columns in the nucleus prepositus hypoglossi of the cat and monkey.

Many studies have shown that the nucleus prepositus hypoglossi (PH) participates with the vestibular nuclear complex, the cerebellum and the oculomotor nuclei in the control of eye movements. We have looked at the neurochemical organization of PH in the cat and monkey using a recently developed antibody, 8B3, that recognizes a chondroitin sulfate proteoglycan. In the cat, immunoreactivity to 8B3 labels a set of cells in PH. On frontal sections, these cells form a cluster that is seen over the entire anterior-posterior (A-P) extent of PH, but the number of cells in the cluster changes with A-P level. Earlier studies have identified an A-P cell column in PH of the cat whose neurons synthesize nitric oxide. We have used both single- and double-label protocols to investigate the relation between the two cell groups. Single-label studies show spatial overlap but that the cells immunoreactive to nitric oxide synthase (nNOS) are more numerous than cells immunoreactive to 8B3. Double-label studies show that all cells immunoreactive to 8B3 were also immunoreactive to nNOS, but, as suggested by the single-label data, there are many nNOS-immunoreactive cells not immunoreactive to 8B3. Populations of 8B3 and nNOS-immunoreactive cells are also found in PH of squirrel and macaque monkeys. The results suggest that nNOS-immunoreactive cells in PH may consist of two functionally different populations.

Anterior canal neurons in cat vestibular nuclei have large phase leads during low frequency vertical axis pitch.

Vestibulo-ocular and second-order neurons in medial and superior vestibular nuclei of alert cats were identified by antidromic and orthodromic electrical stimulation, and their responses to whole body rotations were recorded in the dark. Neurons that had spatial sensitivity most closely aligned with the anterior canal (anterior canal neurons) were compared with neurons that had spatial sensitivity most closely aligned with the posterior canal (posterior canal neurons). Responses were recorded during low frequency earth-horizontal axis pitch rotations in the normal upright posture, and during earth-vertical axis pitch with the head and body lying on the left side. During upright pitch, response phases of anterior canal neurons slightly lagged those of posterior canal neurons or primary vestibular afferents, as previously reported. During on-side pitch, anterior canal neurons showed far greater phase leads with respect to head velocity than posterior canal neurons, primary vestibular afferents, or previously reported vestibulo-ocular reflex eye movements. These results provide challenges for vestibulo-ocular reflex models to incorporate central mechanisms for phase leads among the inputs to anterior canal neurons and to explain how the anterior canal neuron signals reported here combine with other signals to produce observed vestibulo-ocular reflex behavior.

Ascending vestibular drive is asymmetrically distributed to the inferior oblique motoneuron pools in a subset of hemispheric stroke survivors.

OBJECTIVE: Aberrant vestibular nuclear function is proposed to be a principle driver of limb muscle spasticity after stroke. Although spasticity does not manifest in ocular muscles, we sought to determine whether altered cortical modulation of ascending vestibuloocular pathways post-stroke could impact the excitability of ocular motoneurons. METHODS: Nineteen chronic stroke survivors, aged 49-68 yrs. were enrolled. Vestibular evoked myogenic potentials (VEMPs) were recorded from the inferior oblique muscles of the eye using surface EMG electrodes. We assessed the impact of ascending otolith pathways on eye muscle activity and evaluated the relationship between otolith-ocular function and the severity of spasticity. RESULTS: VEMP responses were recorded bilaterally in 14/19 subjects. Response magnitude on the affected side was significantly larger than on the spared side. In a subset of subjects, there was a strong relationship between affected response amplitude and the severity of limb spasticity, as estimated using a standard clinical scale. CONCLUSIONS: This study suggests that alterations in ascending vestibular drive to ocular motoneurons contribute to post-stroke spasticity in a subset of spastic stroke subjects. We speculate this imbalance is a consequence of the unilateral disruption of inhibitory corticobulbar projections to the vestibular nuclei. SIGNIFICANCE: This study potentially sheds light on the underlying mechanisms of post-stroke spasticity.

Pharmacokinetics and safety of the MRI contrast agent gadoversetamide injection (OptiMARK) in healthy pediatric subjects.

RATIONALE AND OBJECTIVE: This clinical trial examined the pharmacokinetics of gadoversetamide, a magnetic resonance imaging contrast agent, in normal pediatric subjects. MATERIALS AND METHODS: Seventeen healthy pediatric subjects received a single intravenous injection of gadoversetamide (0.1 mmol/kg, 0.2 mL/kg). Sixteen subjects that were evaluable for pharmacokinetic analysis fell into 2 stratified age groups: 2 years to <5 years and 5 years to <18 years of age. Serum samples were analyzed for total gadolinium as a measure of gadoversetamide concentration. RESULTS: Statistical analysis demonstrated significant (P < 0.05) age-related trends in the mean elimination half-life (t 1/2) of gadolinium with the older group having a slightly longer t 1/2 (1.39 hours) than the younger group (1.19 hours). No age-related changes occurred in volume of distribution or total body clearance, when normalized to body weight or body surface area. CONCLUSIONS: Based on this preliminary pharmacokinetic assessment, no adjustment from the approved adult gadoversetamide dose of 0.1 mmol/kg should be necessary for children aged 2 or older.

The vestibulo ocular reflex (VOR) in otoconia deficient head tilt (het) mutant mice versus wild type C57BL/6 mice.

The horizontal and vertical vestibulo ocular reflex (VOR) of head tilted (het) mutant mice was compared to C57BL/6 controls. Eye movements were recorded in darkness using a temporarily attached search coil. Contributions of semicircular canal versus otolith organ signals were investigated by providing a canal only (vertical axis) or canal plus otolith organ (horizontal axis) stimulus. In controls, rotations that stimulated only the canals (upright yaw and on tail roll) produced accurate VOR timing during middle frequency rotations at 0.5 Hz (gain 0.27, phase error 6 degrees), and a phase advanced VOR during low frequency rotations at 0.05 Hz (0.05, 115 degrees). In het mutant mice, these rotations produced a highly attenuated VOR response and phase errors at both 0.5 Hz (0.11, 42 degrees) and 0.05 Hz (0.01, 36 degrees). In controls, rotations that stimulated both the otolith organs and semicircular canals (upright roll and on tail yaw) produced higher VOR gains overall than were elicited during vertical axis rotations, with phase accurate VOR at both 0.5 Hz (0.52, 4 degrees) and 0.05 Hz (0.34, 9 degrees). In het mutant mice, these rotations produced a highly attenuated VOR response and phase errors at both 0.5 Hz (0.14, 51 degrees) and 0.05 Hz (0.01, 43 degrees). During constant velocity rotations about an earth horizontal axis, eye velocity bias and modulation were virtually absent in het mutant mice, while robust in controls. Control mice produced compensatory ocular deviations in response to static head tilt, but responses in het mice were weak and inconsistent. These results show that het mice not only lack all aspects of otolith mediated VOR, but also are deficient in canal mediated VOR. Because semicircular canals are normal in het mice, we conclude that central neurons of the canal VOR are dependent on otolith organ signals for normal performance.

Laminar and neurochemical organization of the dorsal cochlear nucleus of the human, monkey, cat, and rodents.

The dorsal cochlear nucleus (DCN) is a brainstem structure that receives input from the auditory nerve. Many studies in a diversity of species have shown that the DCN has a laminar organization and identifiable neuron types with predictable synaptic relations to each other. In contrast, studies on the human DCN have found a less distinct laminar organization and fewer cell types, although there has been disagreement among studies in how to characterize laminar organization and which of the cell types identified in other animals are also present in humans. We have reexamined DCN organization in the human using immunohistochemistry to analyze the expression of several proteins that have been useful in delineating the neurochemical organization of other brainstem structures in humans: nonphosphorylated neurofilament protein (NPNFP), nitric oxide synthase (nNOS), and three calcium-binding proteins. The results for humans suggest a laminar organization with only two layers, and the presence of large projection neurons that are enriched in NPNFP. We did not observe evidence in humans of the inhibitory interneurons that have been described in the cat and rodent DCN. To compare humans and other animals directly we used immunohistochemistry to examine the DCN in the macaque monkey, the cat, and three rodents. We found similarities between macaque monkey and human in the expression of NPNFP and nNOS, and unexpected differences among species in the patterns of expression of the calcium-binding proteins.

Otolith stimulation induces c-Fos expression in vestibular and precerebellar nuclei in cats and squirrel monkeys.

Vestibular information is critical for the control of balance, posture, and eye movements. Signals from the receptors, the semicircular canals and otoliths, are carried by the eighth nerve and distributed to the four nuclei of the vestibular nuclear complex, the VNC. However, anatomical and physiological data suggest that many additional brainstem nuclei are engaged in the processing of vestibular signals and generation of motor responses. To assess the role of these structures in vestibular functions, we have used the expression of the immediate early gene c-Fos as a marker for neurons activated by stimulation of the otoliths or the semicircular canals. Excitation of the otolith organs resulted in widespread c-Fos expression in the VNC, but also in other nuclei, including the external cuneate nucleus, the postpyramidal nucleus of the raphé, the nucleus prepositus hypoglossi, the subtrigeminal nucleus, the pontine nuclei, the dorsal tegmental nucleus, the locus coeruleus, and the reticular formation. Rotations that excited the semicircular canals were much less effective in inducing c-Fos expression. The large number of brainstem nuclei that showed c-Fos expression may reflect the multiple functions of the vestibular system. Some of these neurons may be involved in sensory processing of the vestibular signals, while others provide input to the vestibulo-ocular, vestibulocollic, and vestibulospinal reflexes or mediate changes in autonomic function. The data show that otolith stimulation engages brainstem structures both within and outside of the VNC, many of which project to the cerebellum.