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Background: Revision of a total hip arthroplasty in a patient who has had congenital hip dysplasia or dislocation is often more difficult than a standard revision operation. The purpose of this study was to assess the efficacy and complications of use of a cementless hemispherical acetabular component for revision of an acetabular component of a failed total hip replacement in patients whose initial problem was arthritis secondary to congenital dislocation or dysplasia. The mean duration of follow-up was approximately eight years.Methods: We reviewed a consecutive series of sixty-one hips in fifty-three patients who underwent a cementless acetabular revision with use of a hemispherical acetabular component, with or without concurrent femoral revision. Data were collected prospectively. The mean age of the patients at the time of the index operation was fifty-six years. A mean of 1.9 ipsilateral hip operations had been performed previously. Thirty-nine hips (64 percent) had a so-called high hip center prior to the index revision. With one exception, the uncemented acetabular component was fixed with screws. Fifty-one acetabular components were placed with so-called line-to-line fit, and ten were oversized by one to three millimeters. In thirty-eight hips, the femoral component was revised as well. Twenty-nine femora were reconstructed with use of a cemented device, and nine were revised with an uncemented patch-porous-coated femoral stem (a stem on which the porous coating appears in patches).Results: Four patients (five hips) died prior to the five-year minimum follow-up interval. With the exception of one hip treated with resection arthroplasty because of deep infection, none of the hips in these deceased patients had been revised or had a loose component. One living patient (one hip) had a resection arthroplasty, and one additional patient (two hips) had both stable acetabular components rerevised at the time of femoral rerevision at another institution because of loosening and osteolysis. One patient refused to return for follow-up, but the components had not been revised. The remaining fifty-two hips in forty-six patients were followed for a mean of 8.6 years (range, 5.0 to 12.7 years). The mean Harris hip score was 80 points (range, 56 to 100 points) at the time of the latest follow-up. No acetabular component had been revised, although two had migrated. No other acetabular component was loose according to our radiographic criteria. Thus, the mechanical failure rate on the acetabular side was 3 percent (two of sixty-one) for the entire series and 4 percent (two of fifty-two) for the patients who had been followed for a mean of 8.6 years. On the femoral side, the mechanical failure rate was 3 percent (one of twenty-nine) for the cemented stems and six of nine for the uncemented patch-porous-coated stems.Conclusions: Of the approaches used in this difficult series of patients requiring revision, the hybrid arthroplasty (a cementless acetabular component and a cemented femoral component) yielded overall good results after an intermediate duration of follow-up. [ABSTRACT FROM AUTHOR]

Although a disease-modifying therapy for classic late infantile neuronal ceroid lipofuscinosis (CLN2 disease) exists, poor understanding of cellular pathophysiology has hampered the development of more effective and persistent therapies. Here, we investigated the nature and progression of neurological and underlying neuropathological changes in Cln2R207X mice, which carry one of the most common pathogenic mutations in human patients but are yet to be fully characterized. Long-term electroencephalography recordings revealed progressive epileptiform abnormalities, including spontaneous seizures, providing a robust, quantifiable, and clinically relevant phenotype. These seizures were accompanied by the loss of multiple cortical neuron populations, including those stained for interneuron markers. Further histological analysis revealed early localized microglial activation months before neuron loss started in the thalamocortical system and spinal cord, which was accompanied by astrogliosis. This pathology was more pronounced and occurred in the cortex before the thalamus or spinal cord and differed markedly from the staging seen in mouse models of other forms of neuronal ceroid lipofuscinosis. Neonatal administration of adeno-associated virus serotype 9-mediated gene therapy ameliorated the seizure and gait phenotypes and prolonged the life span of Cln2R207X mice, attenuating most pathological changes. Our findings highlight the importance of clinically relevant outcome measures for judging preclinical efficacy of therapeutic interventions for CLN2 disease.

CLN1 disease, also called infantile neuronal ceroid lipofuscinosis (NCL) or infantile Batten disease, is a fatal neurodegenerative lysosomal storage disorder resulting from mutations in the CLN1 gene encoding the soluble lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1). Therapies for CLN1 disease have proven challenging because of the aggressive disease course and the need to treat widespread areas of the brain and spinal cord. Indeed, gene therapy has proven less effective for CLN1 disease than for other similar lysosomal enzyme deficiencies. We therefore tested the efficacy of enzyme replacement therapy (ERT) by administering monthly infusions of recombinant human PPT1 (rhPPT1) to PPT1-deficient mice (Cln1-/-) and CLN1R151X sheep to assess how to potentially scale up for translation. In Cln1-/- mice, intracerebrovascular (i.c.v.) rhPPT1 delivery was the most effective route of administration, resulting in therapeutically relevant CNS levels of PPT1 activity. rhPPT1-treated mice had improved motor function, reduced disease-associated pathology, and diminished neuronal loss. In CLN1R151X sheep, i.c.v. infusions resulted in widespread rhPPT1 distribution and positive treatment effects measured by quantitative structural MRI and neuropathology. This study demonstrates the feasibility and therapeutic efficacy of i.c.v. rhPPT1 ERT. These findings represent a key step toward clinical testing of ERT in children with CLN1 disease and highlight the importance of a cross-species approach to developing a successful treatment strategy.

Cannabidiol (CBD) has gained attention as a therapeutic agent and is purported to have immunomodulatory, neuroprotective, and anti-seizure effects. Here, we determined the effects of chronic CBD administration in a mouse model of CLN1 disease (Cln1 -/- ) that simultaneously exhibits neuroinflammation, neurodegeneration, and spontaneous seizures. Proteomic analysis showed that putative CBD receptors are expressed at similar levels in the brains of Cln1 -/- mice compared to normal animals. Cln1 -/- mice received an oral dose (100 mg/kg/day) of CBD for six months and were evaluated for changes in pathological markers of disease and seizures. Chronic cannabidiol administration was well-tolerated, high levels of CBD were detected in the brain, and markers of astrocytosis and microgliosis were reduced. However, CBD had no apparent effect on seizure frequency or neuron survival. These data are consistent with CBD having immunomodulatory effects. It is possible that a higher dose of CBD could also reduce neurodegeneration and seizure frequency., (© 2022. The Author(s).)

Human genetics have defined a new neurodevelopmental syndrome caused by loss-of-function mutations in MYT1L, a transcription factor known for enabling fibroblast-to-neuron conversions. However, how MYT1L mutation causes intellectual disability, autism, ADHD, obesity, and brain anomalies is unknown. Here, we developed a Myt1l haploinsufficient mouse model that develops obesity, white-matter thinning, and microcephaly, mimicking common clinical phenotypes. During brain development we discovered disrupted gene expression, mediated in part by loss of Myt1l gene-target activation, and identified precocious neuronal differentiation as the mechanism for microcephaly. In contrast, in adults we discovered that mutation results in failure of transcriptional and chromatin maturation, echoed in disruptions in baseline physiological properties of neurons. Myt1l haploinsufficiency also results in behavioral anomalies, including hyperactivity, muscle weakness, and social alterations, with more severe phenotypes in males. Overall, our findings provide insight into the mechanistic underpinnings of this disorder and enable future preclinical studies., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aim: To understand the progression of CLN1 disease and develop effective therapies we need to characterize early sites of pathology. Therefore, we performed a comprehensive evaluation of the nature and timing of early CLN1 disease pathology in the spinal cord, which appears especially vulnerable, and how this may affect behaviour., Methods: We measured the spinal volume and neuronal number, and quantified glial activation, lymphocyte infiltration and oligodendrocyte maturation, as well as cytokine profile analysis during the early stages of pathology in Ppt1-deficient (Ppt1 -/- ) mouse spinal cords. We then performed quantitative gait analysis and open-field behaviour tests to investigate the behavioural correlates during this period., Results: We detected significant microglial activation in Ppt1 -/- spinal cords at 1 month. This was followed by astrocytosis, selective interneuron loss, altered spinal volumes and oligodendrocyte maturation at 2 months, before significant storage material accumulation and lymphocyte infiltration at 3 months. The same time course was apparent for inflammatory cytokine expression that was altered as early as one month. There was a transient early period at 2 months when Ppt1 -/- mice had a significantly altered gait that resembles the presentation in children with CLN1 disease. This occurred before an anticipated decline in overall locomotor performance across all ages., Conclusion: These data reveal disease onset 2 months (25% of life-span) earlier than expected, while spinal maturation is still ongoing. Our multi-disciplinary data provide new insights into the spatio-temporal staging of CLN1 pathogenesis during ongoing postnatal maturation, and highlight the need to deliver therapies during the presymptomatic period., (© 2020 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)

Lysosomal storage diseases (LSDs) are typically caused by a deficiency in a soluble acid hydrolase and are characterized by the accumulation of undegraded substrates in the lysosome. Determining the role of specific cell types in the pathogenesis of LSDs is a major challenge due to the secretion and subsequent uptake of lysosomal hydrolases by adjacent cells, often referred to as "cross-correction." Here we create and validate a conditional mouse model for cell-autonomous expression of galactocerebrosidase (GALC), the lysosomal enzyme deficient in Krabbe disease. We show that lysosomal membrane-tethered GALC (GALCLAMP1) retains enzyme activity, is able to cleave galactosylsphingosine, and is unable to cross-correct. Ubiquitous expression of GALCLAMP1 fully rescues the phenotype of the GALC-deficient mouse (Twitcher), and widespread deletion of GALCLAMP1 recapitulates the Twitcher phenotype. We demonstrate the utility of this model by deleting GALCLAMP1 specifically in myelinating Schwann cells in order to characterize the peripheral neuropathy seen in Krabbe disease., Competing Interests: The authors declare no competing interest.

Infantile globoid cell leukodystrophy (GLD, Krabbe disease) is a fatal demyelinating disorder caused by a deficiency in the lysosomal enzyme galactosylceramidase (GALC). GALC deficiency leads to the accumulation of the cytotoxic glycolipid, galactosylsphingosine (psychosine). Complementary evidence suggested that psychosine is synthesized via an anabolic pathway. Here, we show instead that psychosine is generated catabolically through the deacylation of galactosylceramide by acid ceramidase (ACDase). This reaction uncouples GALC deficiency from psychosine accumulation, allowing us to test the long-standing "psychosine hypothesis." We demonstrate that genetic loss of ACDase activity (Farber disease) in the GALC-deficient mouse model of human GLD (twitcher) eliminates psychosine accumulation and cures GLD. These data suggest that ACDase could be a target for substrate reduction therapy (SRT) in Krabbe patients. We show that pharmacological inhibition of ACDase activity with carmofur significantly decreases psychosine accumulation in cells from a Krabbe patient and prolongs the life span of the twitcher (Twi) mouse. Previous SRT experiments in the Twi mouse utilized l-cycloserine, which inhibits an enzyme several steps upstream of psychosine synthesis, thus altering the balance of other important lipids. Drugs that directly inhibit ACDase may have a more acceptable safety profile due to their mechanistic proximity to psychosine biogenesis. In total, these data clarify our understanding of psychosine synthesis, confirm the long-held psychosine hypothesis, and provide the impetus to discover safe and effective inhibitors of ACDase to treat Krabbe disease., Competing Interests: Conflict of interest statement: Y.X., J.C.W., A.G., B.K.Y., J.E., M.C.B., M.L., and B.E.C. are employees of BioMarin Pharmaceutical. The remaining authors declare no conflict of interest.

Here we have characterized the functional impairments resulting from conditional knockout of the ubiquitin-conjugating E2 enzyme (UBC13) in rodent cerebellar granule neurons, which greatly increases the parallel fiber presynaptic boutons and functional parallel fiber/Purkinje cell synapses. We report that conditional UBC13 knockout mice exhibit reliable deficits on several gait-related variables when their velocity of ambulation is tightly controlled by a moving treadmill and by restricting space for movement. Selected gait parameters and movement patterns related to spontaneous exploration in an open field may also be affected in conditional UBC13 knockout mice. Analysis of open-field data as a function of test session half using force-plate actometer instrumentation suggest that conditional UBC13 knockout mice have alterations in emotionality, possibly affecting gait and movement variables. These findings suggest that conditional UBC13 knockout mice represent a valuable platform for assessing the effects of disturbances in cerebellar granule cell circuitry on gait and other aspects of locomotion. Also, the possibility that psychological factors such as altered emotionality may impact gait and movement patterns in these mice suggest that these mice may provide a useful model for evaluating analogous behavioral impairments in autism spectrum disorders and other neurodevelopmental syndromes associated with deregulation of ubiquitin signaling.

Infantile neuronal ceroid lipofuscinosis (INCL, or CLN1 disease) is an inherited neurodegenerative storage disorder caused by a deficiency of the lysosomal enzyme palmitoyl protein thioesterase 1 (PPT1). It was widely believed that the pathology associated with INCL was limited to the brain, but we have now found unexpectedly profound pathology in the human INCL spinal cord. Similar pathological changes also occur at every level of the spinal cord of PPT1-deficient ( Ppt1 -/- ) mice before the onset of neuropathology in the brain. Various forebrain-directed gene therapy approaches have only had limited success in Ppt1 -/- mice. Targeting the spinal cord via intrathecal administration of an adeno-associated virus (AAV) gene transfer vector significantly prevented pathology and produced significant improvements in life span and motor function in Ppt1 -/- mice. Surprisingly, forebrain-directed gene therapy resulted in essentially no PPT1 activity in the spinal cord, and vice versa. This leads to a reciprocal pattern of histological correction in the respective tissues when comparing intracranial with intrathecal injections. However, the characteristic pathological features of INCL were almost completely absent in both the brain and spinal cord when intracranial and intrathecal injections of the same AAV vector were combined. Targeting both the brain and spinal cord also produced dramatic and synergistic improvements in motor function with an unprecedented increase in life span. These data show that spinal cord pathology significantly contributes to the clinical progression of INCL and can be effectively targeted therapeutically. This has important implications for the delivery of therapies in INCL, and potentially in other similar disorders., Competing Interests: The authors declare no conflict of interest.

"Cross-correction," the transfer of soluble lysosomal enzymes between neighboring cells, forms the foundation for therapeutics of lysosomal storage disorders (LSDs). However, "cross-correction" poses a significant barrier to studying the role of specific cell types in LSD pathogenesis. By expressing the native enzyme in only one cell type, neighboring cell types are invariably corrected. In this study, we present a strategy to limit "cross-correction" of palmitoyl-protein thioesterase-1(PPT1), a lysosomal hydrolase deficient in Infantile Neuronal Ceroid Lipofuscinosis (INCL, Infantile Batten disease) to the lysosomal membrane via the C-terminus of lysosomal associated membrane protein-1 (LAMP1). Tethering PPT1 to the lysosomal membrane prevented "cross-correction" while allowing PPT1 to retain its enzymatic function and localization in vitro. A transgenic line harboring the lysosomal membrane-tethered PPT1 was then generated. We show that expression of lysosome-restricted PPT1 in vivo largely rescues the INCL biochemical, histological, and functional phenotype. These data suggest that lysosomal tethering of PPT1 via the C-terminus of LAMP1 is a viable strategy and that this general approach can be used to study the role of specific cell types in INCL pathogenesis, as well as other LSDs. Ultimately, understanding the role of specific cell types in the disease progression of LSDs will help guide the development of more targeted therapeutics. One Sentence Synopsis: Tethering PPT1 to the lysosomal membrane is a viable strategy to prevent "cross-correction" and will allow for the study of specific cellular contributions in INCL pathogenesis.

Infantile neuronal ceroid lipofuscinosis (INCL, Infantile Batten disease) is an invariably fatal neurodegenerative pediatric disorder caused by an inherited mutation in the PPT1 gene. Patients with INCL lack the lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1, EC 3.1.2.22), resulting in intracellular accumulation of autofluorescent storage material and subsequent neuropathology. The Ppt1(-/-) mouse is deficient in PPT1 activity and represents a useful animal model of INCL that recapitulates most of the clinical and pathological aspects of the disease. Preclinical therapeutic experiments performed in the INCL mouse include CNS-directed gene therapy and recombinant enzyme replacement therapy; both seek to re-establish therapeutic levels of the deficient enzyme. We present a novel method for the histochemical localization of PPT1 activity in the Ppt1(-/-) mouse. By utilizing the substrate CUS-9235, tissues known to be positive for PPT1 activity turn varying intensities of blue. Presented here are histochemistry data showing the staining pattern in Ppt1(-/-), wild type, and Ppt1(-/-) mice treated with enzyme replacement therapy or AAV2/9-PPT1-mediated gene therapy. Results are paired with quantitative biochemistry data that confirm the ability of CUS-9235 to detect and localize PPT1 activity. This new method complements the current tools for the study of INCL and evaluation of effective therapies., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Infantile neuronal ceroid lipofuscinosis (INCL, Infantile Batten disease) is a neurodegenerative lysosomal storage disease caused by a deficiency in palmitoyl protein thioesterase-1 (PPT1). The PPT1-deficient mouse (Cln1(-/-)) is a useful phenocopy of human INCL. Cln1(-/-) mice display retinal dysfunction, seizures, motor deficits, and die at ~8 months of age. However, little is known about the cognitive and behavioral functions of Cln1(-/-) mice during disease progression. In the present study, younger (~1-2 months of age) Cln1(-/-) mice showed minor deficits in motor/sensorimotor functions while older (~5-6 months of age) Cln1(-/-) mice exhibited more severe impairments, including decreased locomotor activity, inferior cued water maze performance, decreased running wheel ability, and altered auditory cue conditioning. Unexpectedly, certain cognitive functions such as some learning and memory capabilities seemed intact in older Cln1(-/-) mice. Younger and older Cln1(-/-) mice presented with walking initiation defects, gait abnormalities, and slowed movements, which are analogous to some symptoms reported in INCL and parkinsonism. However, there was no evidence of alterations in dopaminergic markers in Cln1(-/-) mice. Results from this study demonstrate quantifiable changes in behavioral functions during progression of murine INCL and suggest that Parkinson-like motor/sensorimotor deficits in Cln1(-/-) mice are not mediated by dopamine deficiency.

Infantile neuronal ceroid lipofuscinosis (INCL) is an inherited neurodegenerative lysosomal storage disease (LSD) caused by a deficiency in palmitoyl protein thioesterase-1 (PPT1). Studies in Ppt1(-/-) mice demonstrate that glial activation is central to the pathogenesis of INCL. Astrocyte activation precedes neuronal loss, while cytokine upregulation associated with microglial reactivity occurs before and concurrent with neurodegeneration. Therefore, we hypothesized that cytokine cascades associated with neuroinflammation are important therapeutic targets for the treatment of INCL. MW01-2-151SRM (MW151) is a blood-brain barrier penetrant, small-molecule anti-neuroinflammatory that attenuates glial cytokine upregulation in models of neuroinflammation such as traumatic brain injury, Alzheimer's disease, and kainic acid toxicity. Thus, we used MW151, alone and in combination with CNS-directed, AAV-mediated gene therapy, as a possible treatment for INCL. MW151 alone decreased seizure susceptibility. When combined with AAV-mediated gene therapy, treated INCL mice had increased life spans, improved motor performance, and eradication of seizures. Combination-treated INCL mice also had decreased brain atrophy, astrocytosis, and microglial activation, as well as intermediary effects on cytokine upregulation. These data suggest that MW151 can attenuate seizure susceptibility but is most effective when used in conjunction with a therapy that targets the primary genetic defect., (Copyright © 2014 the authors 0270-6474/14/3413077-06$15.00/0.)

Apolipoprotein E (apoE) is the strongest known genetic risk factor for late onset Alzheimer's disease (AD). It influences amyloid-β (Aβ) clearance and aggregation, which likely contributes in large part to its role in AD pathogenesis. We recently found that HJ6.3, a monoclonal antibody against apoE, significantly reduced Aβ plaque load when given to APPswe/PS1ΔE9 (APP/PS1) mice starting before the onset of plaque deposition. To determine whether the anti-apoE antibody HJ6.3 affects Aβ plaques, neuronal network function, and behavior in APP/PS1 mice after plaque onset, we administered HJ6.3 (10 mg/kg/week) or PBS intraperitoneally to 7-month-old APP/PS1 mice for 21 weeks. HJ6.3 mildly improved spatial learning performance in the water maze, restored resting-state functional connectivity, and modestly reduced brain Aβ plaque load. There was no effect of HJ6.3 on total plasma cholesterol or cerebral amyloid angiopathy. To investigate the underlying mechanisms of anti-apoE immunotherapy, HJ6.3 was applied to the brain cortical surface and amyloid deposition was followed over 2 weeks using in vivo imaging. Acute exposure to HJ6.3 affected the course of amyloid deposition in that it prevented the formation of new amyloid deposits, limited their growth, and was associated with occasional clearance of plaques, a process likely associated with direct binding to amyloid aggregates. Topical application of HJ6.3 for only 14 d also decreased the density of amyloid plaques assessed postmortem. Collectively, these studies suggest that anti-apoE antibodies have therapeutic potential when given before or after the onset of Aβ pathology., (Copyright © 2014 the authors 0270-6474/14/347281-12$15.00/0.)

Nicotinamide adenine dinucleotide (NAD(+)) is an enzyme cofactor or cosubstrate in many essential biological pathways. To date, the primary source of neuronal NAD(+) has been unclear. NAD(+) can be synthesized from several different precursors, among which nicotinamide is the substrate predominantly used in mammals. The rate-limiting step in the NAD(+) biosynthetic pathway from nicotinamide is performed by nicotinamide phosphoribosyltransferase (Nampt). Here, we tested the hypothesis that neurons use intracellular Nampt-mediated NAD(+) biosynthesis by generating and evaluating mice lacking Nampt in forebrain excitatory neurons (CaMKIIαNampt(-/-) mice). CaMKIIαNampt(-/-) mice showed hippocampal and cortical atrophy, astrogliosis, microgliosis, and abnormal CA1 dendritic morphology by 2-3 months of age. Importantly, these histological changes occurred with altered intrahippocampal connectivity and abnormal behavior; including hyperactivity, some defects in motor skills, memory impairment, and reduced anxiety, but in the absence of impaired sensory processes or long-term potentiation of the Schaffer collateral pathway. These results clearly demonstrate that forebrain excitatory neurons mainly use intracellular Nampt-mediated NAD(+) biosynthesis to mediate their survival and function. Studying this particular NAD(+) biosynthetic pathway in these neurons provides critical insight into their vulnerability to pathophysiological stimuli and the development of therapeutic and preventive interventions for their preservation.

Brain aging is associated with diminished circadian clock output and decreased expression of the core clock proteins, which regulate many aspects of cellular biochemistry and metabolism. The genes encoding clock proteins are expressed throughout the brain, though it is unknown whether these proteins modulate brain homeostasis. We observed that deletion of circadian clock transcriptional activators aryl hydrocarbon receptor nuclear translocator-like (Bmal1) alone, or circadian locomotor output cycles kaput (Clock) in combination with neuronal PAS domain protein 2 (Npas2), induced severe age-dependent astrogliosis in the cortex and hippocampus. Mice lacking the clock gene repressors period circadian clock 1 (Per1) and period circadian clock 2 (Per2) had no observed astrogliosis. Bmal1 deletion caused the degeneration of synaptic terminals and impaired cortical functional connectivity, as well as neuronal oxidative damage and impaired expression of several redox defense genes. Targeted deletion of Bmal1 in neurons and glia caused similar neuropathology, despite the retention of intact circadian behavioral and sleep-wake rhythms. Reduction of Bmal1 expression promoted neuronal death in primary cultures and in mice treated with a chemical inducer of oxidative injury and striatal neurodegeneration. Our findings indicate that BMAL1 in a complex with CLOCK or NPAS2 regulates cerebral redox homeostasis and connects impaired clock gene function to neurodegeneration.

Children with neurofibromatosis type 1 (NF1) frequently have cognitive and behavioral deficits. Some of these deficits have been successfully modeled in Nf1 genetically-engineered mice that develop optic gliomas (Nf1 OPG mice). In the current study, we show that abnormal motivational influences affect the behavior of Nf1 OPG mice, particularly with regard to their response to novel environmental stimuli. For example, Nf1 OPG mice made fewer spontaneous alternations in a Y-maze and fewer arm entries relative to WT controls. However, analysis of normalized alternation data demonstrated that these differences were not due to a spatial working memory deficit. Other reported behavioral results (e.g., open-field test, below) suggest that differential responses to novelty and/or other motivational influences may be more important determinants of these kinds of behavior than simple differences in locomotor activity/spontaneous movements. Importantly, normal long-term depression was observed in hippocampal slices from Nf1 OPG mice. Results from elevated plus maze testing showed that differences in exploratory activity between Nf1 OPG and WT control mice may be dependent on the environmental context (e.g., threatening or non-threatening) under which exploration is being measured. Nf1 OPG mice also exhibited decreased exploratory hole poking in a novel holeboard and showed abnormal olfactory preferences, although L-dopa (50 mg/kg) administration resolved the abnormal olfactory preference behaviors. Nf1 OPG mice displayed an attenuated response to a novel open field in terms of decreased ambulatory activity and rearing but only during the first 10 min of the session. Importantly, Nf1 OPG mice demonstrated investigative rearing deficits with regard to a novel hanging object suspended on one side of the field which were not rescued by L-dopa administration. Collectively, our results provide new data important for evaluating therapeutic treatments aimed at ameliorating NF1-associated cognitive/behavioral deficits.

The androgenic adrenal steroids dehydroepiandrosterone (DHEA) and 4α-androstenedione (4-A) have significant biological activity, but it is unclear if the behavioral effects are unique or only reflections of the effects of testosterone (TS). Gonadally intact male Long-Evans rats were assigned to groups to receive supplements of DHEA, 4-A, TS, corticosteroid (CORT), all at 400 µg steroid/kg of body weight, or vehicle only for 5 weeks. All males were tested in a paradigm for sexual motivation that measures time and urinary marks near an inaccessible receptive female. It was found that DHEA and 4-A supplements failed to influence time near the estrous female in the same way TS supplements did, and, indeed, 5 weeks of 4-A administration reduced the time similar to the suppressive effects of CORT after 3 weeks. Further, animals treated with DHEA or 4-A left fewer urinary marks near an estrous female than TS and control groups. These results suggest that DHEA and 4-A are not merely precursors of sex hormones, and provide support for these steroids influencing the brain and behavior in a unique fashion that is dissimilar from the effects of TS on male sexual behavior.

Tremor is a prominent phenotype of the twitcher mouse, an authentic genetic model of Globoid-Cell Leukodystrophy (GLD, Krabbe's disease). In the current study, the tremor was quantified using a force-plate actometer designed to accommodate low-weight mice. The actometer records the force oscillations caused by a mouse's movements, and the rhythmic structure of the force variations can be revealed. Results showed that twitcher mice had significantly increased power across a broad band of higher frequencies compared to wildtype mice. Bone marrow transplantation (BMT), the only available therapy for GLD, worsened the tremor in the twitcher mice and induced a measureable alteration of movement phenotype in the wildtype mice. These data highlight the damaging effects of conditioning radiation and BMT in the neonatal period. The behavioral methodology used herein provides a quantitative approach for assessing the efficacy of potential therapeutic interventions for Krabbe's disease.

Previous studies suggest that loss of γ-secretase activity in postnatal mouse brains causes age-dependent memory impairment and neurodegeneration. Due to the diverse array of γ-secretase substrates, it remains to be demonstrated whether loss of cleavage of any specific substrate(s) is responsible for these defects. The bulk of the phenotypes observed in mammals deficient for γ-secretase or exposed to γ-secretase inhibitors are caused by the loss of Notch receptor proteolysis. Accordingly, inhibition of Notch signaling is the main cause for untoward effects for γ-secretase inhibitors as therapeutics for Alzheimer's disease. Therefore, we wished to determine if loss of canonical Notch signaling is responsible for the age-dependent neurodegeneration observed upon γ-secrectase deficiency in the mouse brain. We generated postnatal forebrain-specific RBPj conditional knockout (cKO) mice using the CamKII-Cre driver and examined behavior and brain pathology in 12-18 month old animals. Since all four mammalian Notch receptor homologues signal via this DNA binding protein, these mice lack canonical Notch signaling. We found that loss of RBPj in mature excitatory neurons was well tolerated, with no evidence for neurodegeneration or of learning and memory impairment in mice aged up to 18 months. The only phenotypic deficit we observed in the RBPj-deficient mice was a subtle abnormality in olfactory preferences, particularly in females. We conclude that the loss of canonical Notch signaling through the four receptors is not responsible for age-dependent neurodegeneration or learning and memory deficits seen in γ-secretase deficient mice.

Frontotemporal dementia (FTD) is typified by behavioral and cognitive changes manifested as altered social comportment and impaired memory performance. To investigate the neurodegenerative consequences of progranulin gene (GRN) mutations, which cause an inherited form of FTD, we used previously generated progranulin knockout mice (Grn-/-). Specifically, we characterized two cohorts of early and later middle-aged wild type and knockout mice using a battery of tests to assess neurological integrity and behavioral phenotypes analogous to FTD. The Grn-/- mice exhibited reduced social engagement and learning and memory deficits. Immunohistochemical approaches were used to demonstrate the presence of lesions characteristic of frontotemporal lobar degeneration (FTLD) with GRN mutation including ubiquitination, microgliosis, and reactive astrocytosis, the pathological substrate of FTD. Importantly, Grn-/- mice also have decreased overall survival compared to Grn+/+ mice. These data suggest that the Grn-/- mouse reproduces some core features of FTD with respect to behavior, pathology, and survival. This murine model may serve as a valuable in vivo model of FTLD with GRN mutation through which molecular mechanisms underlying the disease can be further dissected., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The optimal technique for acetabular revision surgery in the face of major bone stock deficiency remains controversial. One subset of these problem cases consists of hips that are amenable to reconstruction using a large, hemispherical cementless acetabular component, the so-called jumbo acetabular component. We report the intermediate-term experience of 24 hips in 24 patients who underwent an uncemented acetabular revision using a hemispherical acetabular component of > or = 66 mm diameter. In 16 hips, the femoral component was replaced as well. Of the 18 hips in patients alive after 5 years, 15 were assessed at a mean follow-up of 7.0 years (range, 5.0-10.3 years). The mean final Harris Hip Score was 86 points (range, 45-100 points). No acetabular component had been revised, and none were loose radiographically. In this difficult group, a bimodal distribution resulted. The complication rate was high. In those without infection, the results were excellent.

Study Design: Adult spinal surgery patients were studied prospectively to determine the incidence of subclinical deep venous thrombosis. An overlapping group of patients was reviewed retrospectively for symptomatic thromboembolism., Objectives: To determine the incidence of symptomatic and asymptomatic thromboembolism in spinal surgery patients., Summary of Background Data: Although thromboembolic complications are known to occur after spinal operations, there are limited published data on the incidence of pulmonary embolus or deep venous thrombosis after major spinal surgery., Methods: One hundred sixteen adult spinal surgery patients were examined with duplex ultrasound to determine the incidence of deep venous thrombosis. Seventy-three of these patients also underwent lung perfusion scans to look for subclinical pulmonary embolism. A retrospective review was conducted of symptomatic thromboembolic complications occurring in a 2-year period at the authors' center. Three hundred and eighteen major spinal reconstructive procedures were performed during the period reviewed, which included the period of the prospective study and therefore the patients of the prospective group. Thigh-length compression stockings and pneumatic compression leggings were used for prophylaxis in all patients., Results: One patient had an asymptomatic iliac vein thrombosis, and seven patients had symptomatic pulmonary embolism (2.2%). Six of the symptomatic pulmonary emboli occurred after combined anterior/posterior spinal fusions (6%), whereas only one occurred after posterior decompression and fusion (0.5%)., Conclusions: Duplex ultrasound appeared insensitive for diagnosing clots before embolization in this patient group. Simple mechanical prophylaxis for thromboembolism, which may be adequate for patients undergoing posterior procedures, may not be as protective for patients undergoing combined anterior/posterior spine surgery.

Background: Revision of an acetabular component in a patient who has severe periacetabular bone loss is a complex problem, particularly when there is not enough bone stock to allow placement of an acetabular component near the normal anatomical hip center. A valuable option for revision in such a situation is placement of a hemispherical shell, fixed with screws and without cement, against the superior margin of the acetabular defect. The resulting hip center is more proximal than that seen following a typical primary total hip replacement., Methods: Forty-six hips in forty-four patients were treated consecutively, between July 1984 and February 1988, with a revision in which a hemispherical acetabular component was fixed with screws and without cement. All shells but one were placed with a so-called line-to-line fit. The procedures resulted in a so-called high hip center--that is, the center of rotation of the revised hip was located at least thirty-five millimeters proximal to the interteardrop line. The mean age of the patients at the time of the index procedure was fifty-two years (range, twenty-five to eighty-one years). The most common diagnosis for which the original arthroplasty was performed was osteoarthritis secondary to congenital hip dysplasia or dislocation (twenty-two hips). Thirty-four hips had had a high hip center before the index revision, and most patients had had a substantial limb-length discrepancy, with a mean of 1.6 centimeters of shortening on the side of the operation. In thirty-three hips, the femoral component was replaced as well, with a long-neck or calcar-replacement stem used when necessary to maintain or increase the length of the limb., Results: Six patients (six hips) died before the minimum eight-year follow-up interval; none had had another revision or loosening of the revised acetabular component. Of the remaining patients, four (four hips) had the implant removed. One of them had a resection arthroplasty and one of them had a hip disarticulation because of infection after a subsequent femoral reoperation. Another had a hip disarticulation because of late infection. The fourth implant was removed because it had displaced into the pelvis at approximately six years; this was the only reoperation for aseptic loosening in the series. The remaining thirty-six hips (thirty-four patients) were followed for a mean of 10.4 years (range, 8.5 to 12.7 years). One acetabular component migrated medially and was scheduled for revision. No other acetabular component was loose or had been revised. The mean Harris hip score was 81 points (range, 56 to 100 points) at the time of the most recent follow-up. Despite the use of a high hip center, the prevalence of a positive Trendelenburg sign was reduced from 98 percent (forty-five of forty-six hips) preoperatively to 44 percent (sixteen of thirty-six hips) at the time of the most recent follow-up. The short limbs were lengthened a mean of seven millimeters (range, five millimeters of shortening to forty millimeters of lengthening)., Conclusions: In this study of acetabular revisions with use of a high hip center in patients who had major periacetabular bone loss, mechanical failure occurred in 4 percent (two) of the forty-six hips in the entire series and in 6 percent (two) of the thirty-six hips in patients who were alive and still had the implant in place after a mean of 10.4 years of follow-up. The use of a high hip center did not adversely affect function of the abductor muscles, and the mean limb-length discrepancy was reduced by the femoral reconstruction.

We retrospectively determined the prevalence and nature of mortality as many as ninety days after 2736 primary and revision total hip arthroplasties performed in 2002 patients by one surgeon at a teaching hospital between January 1969 and December 1996. All but seventy-one of the patients had received prophylaxis against venous thromboembolic disease. There were no intraoperative deaths, and no events during the operation could be linked directly to postoperative mortality. Eight deaths (mortality rate, 0.3 per cent) occurred within ninety days after the 2736 procedures. Four deaths (mortality rate, 0.15 per cent) occurred during the initial hospitalization. The cause of seven of the deaths was determined. Three patients died as a result of preexisting disease (severe hepatorenal disease, metastatic esophageal cancer, or severe cardiac disease), and one patient died from sepsis with a gram-negative organism during a thoracotomy eight days postoperatively. A bleeding complication that occurred while the patient was receiving warfarin therapy led to the death of two other patients; one of these deaths occurred in 1974 and the other, in 1982. At the time that these patients were managed, the desired prothrombin time was considered to be twice the control value. The remaining patient, who had had a clip placed on the inferior vena cava after a pulmonary embolus occurred in 1970, died secondary to acute, severe thrombosis of this vessel after a total hip arthroplasty in 1971. The patient for whom the cause of death was not determined had had an artificial aortic valve and had been receiving chronic warfarin therapy. She died suddenly eighty-nine days postoperatively; no autopsy was performed. No patient died as the direct result of a known pulmonary embolus. No deaths related to venous thromboembolic disease or its prophylaxis or treatment occurred after 1982 (1458 operations). We attribute this, in part, to reduced levels of warfarin prophylaxis and improved management with warfarin. The ninety-day postoperative mortality rate after 2736 procedures performed over nearly three decades was low (0.3 per cent). This span of time included the period before the introduction of many current improvements in perioperative care, such as routine intubation of patients under general anesthesia, continuous monitoring of the electrocardiogram intraoperatively, and blood-gas determinations. When the patients who died as a result of known, severe preexisting disease were excluded, the mortality rate was 0.18 per cent (five of 2733).

The first 100 consecutive primary hip arthroplasties with the Arthopor 2 acetabular component (Joint Medical Products, Stamford, CT) with supplemental screw fixation performed by the senior author were prospectively studied. The mean patient age was 57 years. Seventy-seven cemented and 23 cementless stems were placed, with 32-mm femoral heads used in most of the patients. Eighty-six hips were reviewed at 7-8.8 years (mean, 7.8 years). The mean Harris hip score at final follow-up evaluation was 94 points. No cups have been revised, although 2 cups in patients with radiation osteonecrosis were loose radiographically. One patient underwent revision of a severely worn liner. Despite a relatively high mean linear wear rate of 0.27 mm/y (range, 0.13-0.57 mm/y), no radiographic evidence of pelvic osteolysis was seen. The Arthopor 2 cup performed well with respect to pelvic osteolysis, despite the presence of substantial polyethylene debris. The relatively high polyethylene wear rate is attributed in part to the younger patient population and the use of 32-mm femoral heads paired with thin polyethylene liners.

This article reviews the appropriate workup of the patient presenting with complaints referable to a joint, including the important information to be obtained during the interview and physical examination, as well as from laboratory and imaging studies. The clinical presentation of osteoarthritis, rheumatoid arthritis, gout, and joint sepsis are discussed, and the treatment approach for each is outlined. The specific indications for surgical intervention in the course of arthritis also are detailed.

When the resultant forces on the tibial plateau are displaced medially, compressive stresses cause apposition of bony tissue, thus thickening the dense subchondral bone underlying the medial plateau. Loss of the articular cartilage and an increase in subchondral bone density facilitate the progression of osteoarthrosis. Surgical management is dependent on the presence of a varus deformity; patients with medial compartment disease and varus alignment should be considered for high tibial osteotomy (HTO) or unicondylar or total knee arthroplasty (TKA), depending on their age and activity level. Patients without varus deformity and with mechanical symptoms, only mild joint-space narrowing, and pain less than 1 year are likely to benefit from arthroscopic débridement. Patients without varus alignment but with chronic pain associated with loading and more pronounced joint-space loss should be considered for HTO, or unicondylar or TKA.