Reliability and validity of self-reported questionnaires to measure pain and disability in adults with neck pain and its associated disorders: part 3-a systematic review from the CADRE Collaboration.

PURPOSE: To determine the reliability and validity of self-reported questionnaires to measure pain and disability in adults with grades I-IV neck pain and its associated disorders (NAD). METHODS: We updated the systematic review of the 2000-2010 Bone and Joint Decade Task Force on Neck Pain and its Associated Disorders and systematically searched databases from 2005 to 2017. Independent reviewers screened and critically appraised studies using standardized tools. Evidence from low-risk-of-bias studies was synthesized according to best evidence synthesis principles. Validity studies were ranked according to the Sackett and Haynes classification. RESULTS: We screened 2823 articles, and 26 were eligible for critical appraisal; 18 were low risk of bias. Preliminary evidence suggests that the Neck Disability Index (original and short versions), Whiplash Disability Questionnaire, Neck Pain Driving Index, and ProFitMap-Neck may be valid and reliable to measure disability in patients with NAD. We found preliminary evidence for the validity and reliability of pain measurements including the Body Pain Diagram, Visual Analogue Scale, the Numeric Rating Scale and the Pain-DETECT Questionnaire. CONCLUSION: The evidence supporting the validity and reliability of instruments used to measure pain and disability is preliminary. Further validity studies are needed to confirm the clinical utility of self-reported questionnaires to assess pain and disability in patients with NAD. These slides can be retrieved under Electronic Supplementary Material.

Validity and reliability of clinical prediction rules used to screen for cervical spine injury in alert low-risk patients with blunt trauma to the neck: part 2. A systematic review from the Cervical Assessment and Diagnosis Research Evaluation (CADRE) Collaboration.

PURPOSE: To update findings of the 2000-2010 Bone and Joint Decade Task Force on Neck Pain and its Associated Disorders (Neck Pain Task Force) on the validity and reliability of clinical prediction rules used to screen for cervical spine injury in alert low-risk adult patients with blunt trauma to the neck. METHODS: We searched four databases from 2005 to 2015. Pairs of independent reviewers critically appraised eligible studies using the modified QUADAS-2 and QAREL criteria. We synthesized low risk of bias studies following best evidence synthesis principles. RESULTS: We screened 679 citations; five had a low risk of bias and were included in our synthesis. The sensitivity of the Canadian C-spine rule ranged from 0.90 to 1.00 with negative predictive values ranging from 99 to 100%. Inter-rater reliability of the Canadian C-spine rule varied from k = 0.60 between nurses and physicians to k = 0.93 among paramedics. The inter-rater reliability of the Nexus Low-Risk Criteria was k = 0.53 between resident physicians and faculty physicians. CONCLUSIONS: Our review adds new evidence to the Neck Pain Task Force and supports the use of clinical prediction rules in emergency care settings to screen for cervical spine injury in alert low-risk adult patients with blunt trauma to the neck. The Canadian C-spine rule consistently demonstrated excellent sensitivity and negative predictive values. Our review, however, suggests that the reproducibility of the clinical predictions rules varies depending on the examiners level of training and experience.

Reliability and validity of clinical tests to assess the anatomical integrity of the cervical spine in adults with neck pain and its associated disorders: Part 1-A systematic review from the Cervical Assessment and Diagnosis Research Evaluation (CADRE) Collaboration.

OBJECTIVE: To determine the reliability and validity of clinical tests to assess the anatomical integrity of the cervical spine in adults with neck pain and its associated disorders. METHODS: We updated the systematic review of the 2000-2010 Bone and Joint Decade Task Force on Neck Pain and its Associated Disorders. We also searched the literature to identify studies on the reliability and validity of Doppler velocimetry for the evaluation of cervical arteries. Two independent reviewers screened and critically appraised studies. We conducted a best evidence synthesis of low risk of bias studies and ranked the phases of investigations using the classification proposed by Sackett and Haynes. RESULTS: We screened 9022 articles and critically appraised 8 studies; all 8 studies had low risk of bias (three reliability and five validity Phase II-III studies). Preliminary evidence suggests that the extension-rotation test may be reliable and has adequate validity to rule out pain arising from facet joints. The evidence suggests variable reliability and preliminary validity for the evaluation of cervical radiculopathy including neurological examination (manual motor testing, dermatomal sensory testing, deep tendon reflexes, and pathological reflex testing), Spurling's and the upper limb neurodynamic tests. No evidence was found for doppler velocimetry. CONCLUSIONS: Little evidence exists to support the use of clinical tests to evaluate the anatomical integrity of the cervical spine in adults with neck pain and its associated disorders. We found preliminary evidence to support the use of the extension-rotation test, neurological examination, Spurling's and the upper limb neurodynamic tests.

Early Initiation Rather Than Prolonged Duration of Antiretroviral Therapy in HIV Infection Contributes to the Normalization of CD8 T-Cell Counts.

BACKGROUND: CD8 T-cell counts remain elevated in human immunodeficiency virus (HIV) infection even after long-term antiretroviral therapy (ART), which is associated with an increased risk of non-AIDS-related events. We assessed the impact of ART initiation in early versus chronic HIV infection on trajectories of CD8 cell counts over time. METHODS: Of 280 individuals enrolled during primary HIV infection (PHI), 251 were followed up for 24 months; 84 started ART before 6 months of infection (eART), 49 started between 6 and 24 months, and 118 remained untreated. Plasma HIV viral load (VL), CD4 and CD8 cell counts were assessed at each study visit. CD8 counts were also examined in 182 age-matched HIV-infected individuals who started ART during chronic infection and maintained undetectable plasma VL for ≥5 years. RESULTS: At PHI baseline, higher CD8 cell counts were associated with more recent infection (P = .02), higher CD4 cell counts (P < .001), and higher VL (P < .001). The CD8 count in the eART group decreased from 797 to 588 cells/µL over 24 months (P < .001), to a level lower than that in untreated PHI (834 cells/µL; P = .004) or in long-term-treated patients with chronic HIV infection (743 cells/µL; P = .047). More prominent CD4 T-cell recovery was observed in the eART group than in the delayed ART group. CONCLUSIONS: ART initiated in early HIV infection is associated with improved resolution of CD8 T-cell elevation compared with long-term ART initiated in chronic infection. Early ART may help reduce the risk of non-AIDS-related events by alleviating this elevation.

HIV and hepatitis C virus coinfection in Canada: challenges and opportunities for reducing preventable morbidity and mortality.

OBJECTIVES: Hepatitis C virus (HCV) has emerged as an important health problem in the era of effective HIV treatment. However, very few data exist on the health status and disease burden of HIV/HCV-coinfected Canadians. METHODS: HIV/HCV-coinfected patients were enrolled prospectively in a multicentre cohort from 16 centres across Canada between 2003 and 2010 and followed every 6 months. We determined rates of a first liver fibrosis or endstage liver disease (ESLD) event and all-cause mortality since cohort enrolment and calculated standardized mortality ratios compared with the general Canadian population. RESULTS: A total of 955 participants were enrolled in the study and followed for a median of 1.4 (interquartile range 0.5-2.3) years. Most were male (73%) with a median age of 44.5 years; 13% self-identified as aboriginal. There were high levels of current injecting drug and alcohol use and poverty. Observed event rates [per 100 person-years; 95% confidence interval (CI)] were: significant fibrosis (10.21; 8.49, 12.19), ESLD (3.16; 2.32, 4.20) and death (3.72; 2.86, 4.77). The overall standardized mortality ratio was 17.08 (95% CI 12.83, 21.34); 12.80 (95% CI 9.10, 16.50) for male patients and 28.74 (95% CI 14.66, 42.83) for female patients. The primary causes of death were ESLD (29%) and overdose (24%). CONCLUSIONS: We observed excessive morbidity and mortality in this HIV/HCV-coinfected population in care. Over 50% of observed deaths may have been preventable. Interventions aimed at improving social circumstances, reducing harm from drug and alcohol use and increasing the delivery of HCV treatment in particular will be necessary to reduce adverse health outcomes among HIV/HCV-coinfected persons.

Chimaeric mice deficient in dystroglycans develop muscular dystrophy and have disrupted myoneural synapses.

Mutations in the dystrophin gene (DMD) and in genes encoding several dystrophin-associated proteins result in Duchenne and other forms of muscular dystrophy. alpha-Dystroglycan (Dg) binds to laminins in the basement membrane surrounding each myofibre and docks with beta-Dg, a transmembrane protein, which in turn interacts with dystrophin or utrophin in the subplasmalemmal cytoskeleton. alpha- and beta-Dgs are thought to form the functional core of a larger complex of proteins extending from the basement membrane to the intracellular cytoskeleton, which serves as a superstructure necessary for sarcolemmal integrity. Dgs have also been implicated in the formation of synaptic densities of acetylcholine receptors (AChRs) on skeletal muscle. Here we report that chimaeric mice generated with ES cells targeted for both Dg alleles have skeletal muscles essentially devoid of Dgs and develop a progressive muscle pathology with changes emblematic of muscular dystrophies in humans. In addition, many neuromuscular junctions are disrupted in these mice. The ultrastructure of basement membranes and the deposition of laminin within them, however, appears unaffected in Dg-deficient muscles. We conclude that Dgs are necessary for myofibre survival and synapse differentiation or stability, but not for the formation of the muscle basement membrane, and that Dgs may have more than a purely structural function in maintaining muscle integrity.

The trajectory of recovery and the inter-relationships of symptoms, activity and participation in the first year following total hip and knee replacement.

OBJECTIVE: Primary total hip (THR) and knee (TKR) replacement outcomes typically include pain and function with a single time of follow-up post-surgery. This research evaluated the trajectory of recovery and inter-relationships within and across time of physical impairments (PI) (e.g., symptoms), activity limitations (AL), and social participation restrictions (PR) in the year following THR and TKR for osteoarthritis. DESIGN: Participants (hip: n=437; knee: 494) completed measures pre-surgery and at 2 weeks, 1, 3, 6 and 12 months post-surgery. These included PI (Hip Disability and Osteoarthritis Outcome Score (HOOS)/Knee Injury and Osteoarthritis Outcome Score (KOOS) symptoms and Chronic Pain Grade); AL (HOOS/KOOS activities of daily living and sports/leisure activities); and, PR (Late Life Disability and the Calderdale community mobility). Repeated measures analysis of variance (RANOVA) was used to evaluate the trajectory of recovery of outcomes and the inter-relationships of PI, AL and PR were evaluated using path analysis. All analyses were adjusted for age, sex, obesity, THR/TKR, low back pain and mood. RESULTS: THR: age 31-86 years with 55% female; TKR: age 35-88 years with 65% female. Significant improvements in outcomes were observed over time. However, improvements were lagged over time with earlier improvements in PI and AL and later improvements in PR. Within and across time, PI was associated with AL and AL was associated with PR. The magnitude of these inter-relationships varied over time. CONCLUSION: Given the lagged inter-relationship of PI, AL and PR, the provision and timing of interventions targeting all constructs are critical to maximizing outcome. Current care pathways focusing on short-term follow-up with limited attention to social and community participation should be re-evaluated.

The dystroglycan complex is necessary for stabilization of acetylcholine receptor clusters at neuromuscular junctions and formation of the synaptic basement membrane.

The dystrophin-associated protein (DAP) complex spans the sarcolemmal membrane linking the cytoskeleton to the basement membrane surrounding each myofiber. Defects in the DAP complex have been linked previously to a variety of muscular dystrophies. Other evidence points to a role for the DAP complex in formation of nerve-muscle synapses. We show that myotubes differentiated from dystroglycan-/- embryonic stem cells are responsive to agrin, but produce acetylcholine receptor (AChR) clusters which are two to three times larger in area, about half as dense, and significantly less stable than those on dystroglycan+/+ myotubes. AChRs at neuromuscular junctions are similarly affected in dystroglycan-deficient chimeric mice and there is a coordinate increase in nerve terminal size at these junctions. In culture and in vivo the absence of dystroglycan disrupts the localization to AChR clusters of laminin, perlecan, and acetylcholinesterase (AChE), but not rapsyn or agrin. Treatment of myotubes in culture with laminin induces AChR clusters on dystroglycan+/+, but not -/- myotubes. These results suggest that dystroglycan is essential for the assembly of a synaptic basement membrane, most notably by localizing AChE through its binding to perlecan. In addition, they suggest that dystroglycan functions in the organization and stabilization of AChR clusters, which appear to be mediated through its binding of laminin.

Mitogen-induced replication of woodchuck hepatitis virus in cultured peripheral blood lymphocytes.

Peripheral blood lymphocytes (PBLs) isolated from woodchucks chronically infected with the woodchuck hepatitis virus (WHV) carry low levels of nonreplicating WHV DNA. When PBLs from chronic carrier woodchucks were activated in culture with the generalized mitogen lipopolysaccharide (LPS), WHV DNA replication was initiated in cells obtained from one of three animals examined. Intracellular WHV core particles, containing WHV DNA replication intermediates, RNA/DNA hybrid molecules, and an active endogenous DNA polymerase, appeared 3 days after the start of LPS stimulation. After 5 to 7 days of LPS stimulation, WHV DNA-containing particles, which displayed the properties of intact, mature virions, were released into the culture medium. These studies provide evidence for reactivation of a latent WHV infection of circulating lymphoid cells and indicate that the presence of nonreplicating hepadnaviral DNA in lymphoid cells represents a potentially active infection following cellular activation.

Identifying phases of investigation helps planning, appraising, and applying the results of explanatory prognosis studies.

OBJECTIVE: To present an explanatory framework for understanding prognosis and illustrate it using data from a systematic review. STUDY DESIGN AND SETTING: A framework including three phases of explanatory prognosis investigation was adapted from earlier work and a discussion of causal understanding was integrated. For illustration, prognosis studies were identified from electronic and supplemental searches of literature between 1966 and December 2006. We extracted characteristics of the populations, exposures, and outcomes and identified three phases of explanatory prognosis investigation: Phase 1, identifying associations; Phase 2, testing independent associations; and Phase 3, understanding prognostic pathways. The purpose of each phase is exploration, confirmation, and development of understanding, respectively. RESULTS: It is important to consider a framework of explanatory prognosis studies for: (1) defining the study objectives, (2) presenting the study methods and data, and (3) interpreting and applying the results of the study. CONCLUSION: When conducting and reporting prognosis studies, researchers should consider the approach to prognosis (explanatory or outcome prediction) and phase of investigation, use best methods to limit biases, report completely, and cautiously interpret results. Readers of health care research will then be better able to evaluate the goals and interpret and appropriately use the results of prognosis studies.

Serologic survey of woodchuck hepatitis virus in North Carolina woodchucks (Marmota monax).

The prevalence of woodchuck hepatitis virus (WHV) in wild populations of woodchucks is understudied and therefore unclear. Although infection is common in the southeastern region of Pennsylvania and surrounding states, it is virtually absent in New York and New England. Sera were collected from wild woodchucks from Orange County, North Carolina and tested for the presence of markers of current or previous infection with WHV. Of the 24 woodchucks tested, there were three animals (12.5%) with WHV surface antigen as well as antibodies to woodchuck hepatitis core antigen in their serum, indicative of active infection. There were four (17%) animals with antibodies to WHV core antigen but no woodchuck hepatitis surface antigen, indicative of prior infections. The remaining 17 animals had no detectable markers of WHV infection. These data indicate that WHV is present in central North Carolina at rates approaching those seen in endemic areas, such as the mid-Atlantic region of the United States.

Clinical practice guidelines for the noninvasive management of low back pain: A systematic review by the Ontario Protocol for Traffic Injury Management (OPTIMa) Collaboration.

We conducted a systematic review of guidelines on the management of low back pain (LBP) to assess their methodological quality and guide care. We synthesized guidelines on the management of LBP published from 2005 to 2014 following best evidence synthesis principles. We searched MEDLINE, EMBASE, CINAHL, PsycINFO, Cochrane, DARE, National Health Services Economic Evaluation Database, Health Technology Assessment Database, Index to Chiropractic Literature and grey literature. Independent reviewers critically appraised eligible guidelines using AGREE II criteria. We screened 2504 citations; 13 guidelines were eligible for critical appraisal, and 10 had a low risk of bias. According to high-quality guidelines: (1) all patients with acute or chronic LBP should receive education, reassurance and instruction on self-management options; (2) patients with acute LBP should be encouraged to return to activity and may benefit from paracetamol, nonsteroidal anti-inflammatory drugs (NSAIDs), or spinal manipulation; (3) the management of chronic LBP may include exercise, paracetamol or NSAIDs, manual therapy, acupuncture, and multimodal rehabilitation (combined physical and psychological treatment); and (4) patients with lumbar disc herniation with radiculopathy may benefit from spinal manipulation. Ten guidelines were of high methodological quality, but updating and some methodological improvements are needed. Overall, most guidelines target nonspecific LBP and recommend education, staying active/exercise, manual therapy, and paracetamol or NSAIDs as first-line treatments. The recommendation to use paracetamol for acute LBP is challenged by recent evidence and needs to be revisited. SIGNIFICANCE: Most high-quality guidelines recommend education, staying active/exercise, manual therapy and paracetamol/NSAIDs as first-line treatments for LBP. Recommendation of paracetamol for acute LBP is challenged by recent evidence and needs updating.

Chemical anatomy of primate basal ganglia.

This paper provides an overview of the anatomical and functional organization of the most prominent chemospecific neuronal systems that compose the basal ganglia in primates. Emphasis is placed on the heterogeneity and diversity of small-molecule transmitters, neuroactive peptides and proteins used by basal ganglia neurons. Dopaminergic, serotoninergic and cholinergic neuronal systems are shown to comprise multiple subsystems organized according to highly specific patterns. These subsystems differentially regulate gene expression of several neuroactive peptides, including tachykinins, enkephalins, dynorphin, somatostatin, and neuropeptide Y, that are used by distinct subsets of basal ganglia neurons. Glutamatergic excitatory inputs establish distinct functional territories within the basal ganglia, and neurons in each of these territories act upon other brain neuronal systems through a GABAergic disinhibitory output mechanism. A striking complementary pattern of distribution of the calcium-binding proteins parvalbumin and calbindin D-28k is noted in all basal ganglia components. The limbic system-associated membrane protein (LAMP) is confined chiefly to basal ganglia sectors that are anatomically and functionally related to limbic system structures; these may serve as functional interfaces between the basal ganglia and the limbic system. The functional status of the various basal ganglia chemospecific systems in neurodegenerative diseases, such as Parkinson's disease and Huntington's chorea, is examined. It is concluded that these multiple transmitter-related systems cannot be analyzed separately as they form highly complex and interactive neuronal networks. These complexities should be taken into account to reach a better understanding of the functions of primate basal ganglia in health and disease.

Alpha-fetoprotein in the woodchuck model of hepadnavirus infection and disease: normal physiological patterns and responses to woodchuck hepatitis virus infection and hepatocellular carcinoma.

Persistent infection of the eastern woodchuck (Marmota monax) with the woodchuck hepatitis virus (WHV) produces disease sequelae similar to those observed in humans with persistent hepatitis B virus infection, including hepatocellular carcinoma (HCC). To further characterize serological markers of HCC in the woodchuck, serum alpha-fetoprotein (AFP) was measured under normal physiological conditions and following infection with WHV. Serum AFP was elevated in association with WHV-induced hepatitis and HCC and was a useful indicator of hepatic responses in individual animals throughout the course of experimental WHV infection. The frequent occurrence of normal elevations in serum AFP during the fall and winter, however, limits the use of AFP as a marker for early detection of HCC. The present temporal studies of AFP responses in WHV-infected woodchucks have identified several stages of infection where virological and cellular interactions can be investigated at the molecular level. Studies of AFP in the woodchuck model should provide opportunities to further elucidate the physiological and immunological functions of AFP and to understand virus-host cell interactions during the course of experimental hepadnavirus infection leading to HCC.

Prevalence of HIV-1 resistant to antiretroviral drugs in 81 individuals newly infected by sexual contact or injecting drug use. Investigators of the Quebec Primary Infection Study.

OBJECTIVE: Prolonged treatment with antiretroviral drugs results in the selection of HIV-1 variants with mutations conferring resistance to nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTI and NNRTI) or to protease inhibitors (PI). There is serious concern about transmission of resistant viruses to newly infected persons. This study monitored the prevalence of resistant viruses in individuals undergoing primary HIV infection. DESIGN: Resistance testing was performed on 81 individuals infected between 1997 and 1999 by injecting drug use (n =21), sexual (n = 56), or unknown (n = 4) transmission. METHODS: Automated sequencing was used to genotype the reverse transcriptase (RT) and protease regions of virus isolated from patients' plasma. The phenotypic susceptibility of stimulated peripheral blood mononuclear cells to antiretroviral drugs was assayed. Line probe assays detected quasispecies variations in wild-type and mutated RT codons. RESULTS: A high prevalence of PI and RT genotypic variants, associated with high-level resistance to antiretroviral drugs, was observed in individuals newly infected by injecting drug use (PI = 24%, RT = 24%) or sexual transmission (PI = 12%, RT = 22%). The PI mutations, L101, V82A, and L90M, were found in 10.5, 3 and 4% of cases, respectively; whereas for RT, primary mutations at positions T215Y (zidovudine), M184V (lamivudine), T69D/A (zalcitabine), and K103N (multi-NNRTI) were present in 8, 5, 4, and 4% of subjects, respectively. Resistance to NRTI was demonstrated by phenotypic, genotypic, and line probe analyses. Transmission of multidrug (NRTI/NNRTI/PI) resistance in eight subjects (9.9%) was confirmed by showing that source partners possessed viruses of similar genotype. CONCLUSIONS: The transmission of drug-resistant HIV is a serious problem that merits further attention by public health officials as well as virologists and clinicians.

Enhanced antiviral benefit of combination therapy with lamivudine and alpha interferon against WHV replication in chronic carrier woodchucks.

Cell culture studies in our laboratory previously demonstrated synergistic antiviral activity for the combinations of lamivudine and a novel recombinant hybrid human alpha B/D interferon (rHu alpha B/D IFN) against hepatitis B virus (HBV) replication. Based on these results, a study was designed to determine if an enhanced antiviral effect with this drug combination could be demonstrated in vivo using the woodchuck hepatitis virus (WHV)/woodchuck experimental model of chronic HBV infection. Both antiviral agents have been shown to be effective against WHV replication in WHV chronic carriers during previous studies by our laboratories. Two combination treatment regimens were compared to matched monotherapies in a placebo-controlled trial. The first used simultaneous administration of rHu alpha B/D IFN and lamivudine for 24 weeks. The other combination treatment regimen used a staggered dosing schedule of 12 weeks of administration of lamivudine alone, followed by 12 weeks of simultaneous dosing with both drugs, followed by 12 weeks of therapy with rHu alpha B/D IFN alone. Both treatment regimens with combinations of lamivudine and rHu alpha B/D IFN were more effective at reducing WHV replication in chronically infected wood-chucks than the corresponding monotherapies. Both combination treatments produced antiviral effects that were at least equal to that expected for additive activity based on estimations generated by Bliss Independence calculations. The staggered treatment regimen reduced viraemia and intrahepatic WHV replication significantly more than that expected for additive interactions, indicating synergistic antiviral effects. These studies demonstrate that combination therapy of chronic WHV infection has enhanced antiviral benefit over corresponding monotherapies and indicate that combination treatment of chronic HBV infection can be superior to therapies using a single antiviral agent.

Preclinical investigation of L-FMAU as an anti-hepatitis B virus agent.

Preclinical aspects of a potent anti-hepatitis B virus (HBV) L-nucleoside, 1-(2-fluoro-5-methyl-beta-L-arabino-furanosyl)uracil (L-FMAU) are described. L-FMAU was prepared from L-ribose derivatives via either L-xylose or L-arabinose. L-FMAU shows potent antiviral activity against hepatitis B virus (EC50 5.0 microM in H1 cells) with high selectivity in vitro. L-FMAU is not incorporated into mitochondrial DNA and no significant lactic acid production was observed in vitro. L-FMAU is phosphorylated by thymidine kinase as well as deoxycytidine kinase, ultimately to the triphosphate, which inhibits HBV DNA polymerase as the mechanism of antiviral action. Preliminary in vivo toxological studies suggest no apparent toxicity for 30 days at 50 mg/kg/day in mice and for 3 months in woodchucks (10 mg/kg/day). L-FMAU also has respectable bioavailability in rats. L-FMAU shows potent anti-HBV activity in vivo against woodchuck hepatitis virus in chronically infected woodchucks and there is no significant virus rebound after cessation of the drug treatment.

Distribution of limbic system-associated membrane protein immunoreactivity in primate basal ganglia.

The limbic system-associated membrane protein is a 64,000-68,000 mol.wt molecule known to be preferentially expressed by neurons in limbic structures of rats and cats. The present immunohistochemical study describes the distribution of this protein in the basal ganglia of Macaca fascicularis. The ventral striatum of the cynomolgus monkey displays a very intense immunostaining, whereas the dorsal striatum is much more weakly stained, except for some small zones scattered in the caudate nucleus and, to a lesser extent, in the putamen. These protein-rich zones are in register with striosomes, as visualized on adjacent sections immunostained for calbindin. At pallidal levels, immunostaining for the protein is observed only in the subcommissural regions, at the ventromedial tip of the internal pallidum, and in the caudoventral portion of the external pallidum. At nigral levels, the immunostaining is highly heterogeneous with a marked decreasing rostrocaudal gradient. The staining is most intense in nigral regions that receive striatal inputs and are enriched with calbindin. Nigral sectors populated by dopaminergic neurons, as visualized on adjacent sections immunostained for tyrosine hydroxylase, are largely devoid of immunoreactivity. In contrast, the immunostaining is uniformly intense in the ventral tegmental area. This study provides the first neuroanatomical evidence for teh existence of the limbic system-associated membrane protein in primate brain. It reveals that this glycoprotein is distributed in a highly heterogeneous manner in primate basal ganglia, where it preferentially labels regions that are anatomically and functionally linked to the limbic system.

Mesencephalic grafts partially restore normal nigral dynorphin levels in 6-hydroxydopamine-lesioned rats treated chronically with L-dihydroxyphenylalanine.

An increase of dynorphin levels is commonly observed in the substantia nigra of 6-hydroxydopamine-lesioned rats chronically treated with daily injections of L-DOPA. This study investigates the potential of fetal mesencephalic grafts to restore normal levels of dynorphin in such cases. After 19 consecutive days of treatment with L-DOPA, lesioned rats with the most severe nigral cell loss showed increased levels of dynorphin in the substantia nigra ipsilateral to the lesion, as expected. The changes were assessed by standard immunohistochemical techniques combined with the use of an image analysis system. Such changes were not observed in the substantia nigra of rats that received fetal mesencephalic cells in the striatum six months prior to the beginning of the chronic treatment. However, only animals displaying heavy loss of dopaminergic neurons in the substantia nigra pars compacta showed significant changes of dynorphin levels in the substantia nigra following drug treatment. Our results show that fetal nigral cells transplanted into the striatum have the potential to prevent biochemical changes observed in the basal ganglia induced by the lesion of the nigrostriatal pathway and chronic treatment with L-DOPA. It is still hypothesized from studies in rodents that this peptide may play a role in the appearance of DOPA-induced dyskinesia, because dynorphin levels increase in the substantia nigra pars reticulata after L-DOPA treatment. If this happens to be the case, then the use of fetal nigral grafts could therefore be an important step to prevent the induction of dyskinesia after chronic L-DOPA treatment.