Immediately restored single implants in the aesthetic zone of the maxilla using a novel design: 5-year results from a prospective single-arm clinical trial.

BACKGROUND: Single implant crowns have become the preferred rehabilitation treatment option for replacing a missing tooth. PURPOSE: This study evaluates 5-year clinical success of using tilted implants placed immediately after extraction followed by rehabilitation with all-ceramic crowns. MATERIALS AND METHODS: Twenty-seven participants requiring 28 single implant crowns in the aesthetic zone of maxilla were recruited to participate in a single-arm clinical trial. All participants were rehabilitated according to immediate implant placement using CP grade 4 titanium implants with roughened surfaces and a 12°-angled platform. Provisional implant crowns were connected within 4 hours of implant placement and loaded according to progressive loading protocol. At 8 weeks (baseline), definitive screw-retained crowns fabricated using densely sintered zirconia abutments with the veneering porcelain were delivered. Participants were followed up to 5 years and 16 participants with 17 single implant crowns attended Year 5 recall. Data collection included changes in marginal bone levels (MBLs), mid-buccal mucosal levels (MBMLs), implant stability quotient (ISQ) values, and any prosthodontic maintenance issues. RESULTS: The mean changes in MBLs at each recall was bone fill of 0.5 ± 1.18 mm (surgery-baseline), increase of 0.1 ± 0.57 mm (baseline-Year 1), and marginal bone loss of 0.1 ± 0.25 mm (Years 1-5). A minimal change occurred with the MBMLs during the observation period. The mean ISQ value at each time point increased from 65.1 (implant placement), to 67.4 (baseline) and 69.9 (Years 1 and 5). Prosthodontic maintenance issues occurred only during the first year which included fracture of veneering ceramic and zirconia abutment as well as aesthetic concerns. CONCLUSIONS: Within the limitations of this study, the data collected would suggest that replacing a single missing tooth using titanium oral implants with 12° platform tilt and zirconia abutments can be a successful rehabilitation option in the esthetically demanding zone of anterior maxilla.

Clinical vignettes in Parkinson's disease: a collection of unusual medication-induced hallucinations, delusions, and compulsive behaviours.

Hallucinations, delusions, and compulsive behaviors are frequent iatrogenic complications of the treatment of motor dysfunction in Parkinson's disease (PD). Although these have been studied, and the phenomenology described, there are few detailed descriptions of the various psychiatric problems our treated PD patients live with that allow physicians who do not have a great deal of experience with PD patients to appreciate the extent of their altered lives. This report is a compilation of vignettes describing these behavioral problems that the treating neurologist or psychiatrist attributed to the medications used for treating PD.

Immediately restored single implants in the aesthetic zone of the maxilla using a novel design: 1-year report.

OBJECTIVES: To evaluate immediate placement and immediate restoration of a novel implant with a 12°-angled prosthodontic platform, in fresh extraction sockets of the aesthetic zone of the maxilla. MATERIALS AND METHODS: Tapered, roughened surface implants of 4 mm (n=15) or 5 mm (n=13) diameter were placed in 27 participants (mean age: 47.1 years; range: 21-71 years) requiring an immediate replacement of single anterior maxillary teeth. Provisional screw-retained all-ceramic crowns were placed within 4 h following optical impressions. At 8 weeks (baseline), definitive screw-retained all-ceramic crowns were placed in occlusion. RESULTS: Twenty-six of the 28 implants met the inclusion criteria at surgery. Marginal bone levels revealed bone gain between surgery and baseline, and between baseline and 1 year of 0.2 mm (SD 0.75) and 0.78 mm (SD 2.45). Mean mid-buccal mucosal margins showed gains of 0.2 mm (SD 0.44). Prosthodontic maintenance and the aesthetics of the screw-retained implant crowns were facilitated by the external hex 12°-angled prosthodontic platform on the novel implant design, re-orientating the access cavity to the palatal or occlusal surfaces. All-ceramic implant crowns showed a high success rate with low maintenance issues over 1 year. CONCLUSION: Tapered, roughened-surfaced implants with a novel 12°-angled prosthodontic platform immediately placed in fresh extraction sockets, immediately restored with provisional crowns and subsequent definitive crowns at 8 weeks were successful for 1 year.

Mitochondrial DNA haplogroups and mutations in children with acquired central demyelination.

OBJECTIVE: We investigated mitochondrial DNA (mtDNA) variants in children with a first episode of acquired demyelinating syndromes (PD-ADS) of the CNS and their relationship to disease phenotype, including subsequent diagnosis of multiple sclerosis (MS). METHODS: This exploratory analysis included the initial 213 children with PD-ADS in the prospective Canadian Pediatric Demyelinating Study and 166 matched healthy sibling controls from the Canadian Autism Genome Project. A total of 31 single nucleotide polymorphisms (SNPs) were analyzed, including haplogroup-defining SNPs and mtDNA variants previously reported to be associated with MS. RESULTS: Primary Leber hereditary optic neuropathy (LHON) mutations and other known pathogenic mtDNA mutations were absent in both patients with pediatric acquired demyelinating syndromes and controls. The 13708A haplogroup J-associated variant, previously linked to adult MS, was more frequent among subjects with PD-ADS (13.0%) compared to controls (6.2%; odds ratio [OR] 2.27; 95% confidence interval [CI] 1.06 to 4.83) and haplogroup M was associated with an earlier age at onset of PD-ADS (-1.74 years; 95% CI -3.33 to -0.07). In contrast, the haplogroup cluster UKJT, as well as 3 other SNPs, were each associated with a lower risk of PD-ADS. A total of 33 subjects with PD-ADS were diagnosed with MS during a mean follow-up period of 3.11 ± 1.14 (SD) years. No single SNP was associated with the risk of subsequent diagnosis of MS. However, haplogroup H was associated with an increased risk of MS (OR 2.60; 95% CI 1.21 to 5.55). CONCLUSION: These data suggest an association between mtDNA variants and the risk of PD-ADS and of a subsequent MS diagnosis. Replication of these findings in an independent population of subjects with PD-ADS is required.

Laserlight cues for gait freezing in Parkinson's disease: an open-label study.

Freezing of gait (FOG) and falls are major sources of disability for Parkinson's disease (PD) patients, and show limited responsiveness to medications. We assessed the efficacy of visual cues for overcoming FOG in an open-label study of 26 patients with PD. The change in the frequency of falls was a secondary outcome measure. Subjects underwent a 1-2 month baseline period of use of a cane or walker without visual cues, followed by 1 month using the same device with the laserlight visual cue. The laserlight visual cue was associated with a modest but significant mean reduction in FOG Questionnaire (FOGQ) scores of 1.25 ± 0.48 (p = 0.0152, two-tailed paired t-test), representing a 6.6% improvement compared to the mean baseline FOGQ scores of 18.8. The mean reduction in fall frequency was 39.5 ± 9.3% with the laserlight visual cue among subjects experiencing at least one fall during the baseline and subsequent study periods (p = 0.002; two-tailed one-sample t-test with hypothesized mean of 0). Though some individual subjects may have benefited, the overall mean performance on the timed gait test (TGT) across all subjects did not significantly change. However, among the 4 subjects who underwent repeated testing of the TGT, one showed a 50% mean improvement in TGT performance with the laserlight visual cue (p = 0.005; two-tailed paired t-test). This open-label study provides evidence for modest efficacy of a laserlight visual cue in overcoming FOG and reducing falls in PD patients.

Novel THAP1 sequence variants in primary dystonia.

BACKGROUND: THAP1 encodes a transcription factor (THAP1) that harbors an atypical zinc finger domain and regulates cell proliferation. An exon 2 insertion/deletion frameshift mutation in THAP1 is responsible for DYT6 dystonia in Amish-Mennonites. Subsequent screening efforts in familial, mainly early-onset, primary dystonia identified additional THAP1 sequence variants in non-Amish subjects. OBJECTIVE: To examine a large cohort of subjects with mainly adult-onset primary dystonia for sequence variants in THAP1. METHODS: With high-resolution melting, all 3 THAP1 exons were screened for sequence variants in 1,114 subjects with mainly adult-onset primary dystonia, 96 with unclassified dystonia, and 600 controls (400 neurologically normal and 200 with Parkinson disease). In addition, all 3 THAP1 exons were sequenced in 200 subjects with dystonia and 200 neurologically normal controls. RESULTS: Nine unique melting curves were found in 19 subjects from 16 families with primary dystonia and 1 control. Age at dystonia onset ranged from 8 to 69 years (mean 48 years). Sequencing identified 6 novel missense mutations in conserved regions of THAP1 (G9C [cervical, masticatory, arm], D17G [cervical], F132S [laryngeal], I149T [cervical and generalized], A166T [laryngeal], and Q187K [cervical]). One subject with blepharospasm and another with laryngeal dystonia harbored a c.-42C>T variant. A c.57C>T silent variant was found in 1 subject with segmental craniocervical dystonia. An intron 1 variant (c.71+9C>A) was present in 7 subjects with dystonia (7/1,210) but only 1 control (1/600). CONCLUSIONS: A heterogeneous collection of THAP1 sequence variants is associated with varied anatomical distributions and onset ages of both familial and sporadic primary dystonia.

Non-invasive brain stimulation for Parkinson's disease: a systematic review and meta-analysis of the literature.

A systematic review and meta-analysis were conducted to quantify the efficacy of transcranial magnetic stimulation (TMS) and electroconvulsive therapy (ECT) for the treatment of motor dysfunction in patients with Parkinson's disease (PD). Prospective studies which evaluated the effects of either TMS (12 studies) or ECT (five studies) on motor function in PD using the motor subscale of the Unified Parkinson's Disease Rating Scale (UPDRS) for TMS studies and any continuous measures of motor function in PD for ECT studies were included. The pooled effect size (standardised mean difference between pre-treatment versus post-treatment means) from a random effects model was 0.62 (95% confidence interval: 0.38, 0.85) for TMS treatment and 1.68 (0.79, 2.56) for ECT treatment, and from a fixed effects model was 0.59 (0.39, 0.78) for TMS treatment and 1.55 (1.07, 2.03) for ECT treatment. TMS, across applied stimulation sites and parameters, can exert a significant, albeit modest, positive effect on the motor function of patients with PD. ECT also may exert a significant effect on motor function in PD patients.

Novel SCO2 mutation (G1521A) presenting as a spinal muscular atrophy type I phenotype.

Rare cases of suspected spinal muscular atrophy (SMA) have been found to have cytochrome c oxidase (COX) deficiency. To date, four cases with SMA features have been reported in children with mutations in the synthesis of cytochrome oxidase 2 (SCO2) gene. We report a male neonate who was born hypotonic, with persistent lactic acidosis, spontaneous activity with EMG testing, development of respiratory distress in the first few hours of life, and died at 30 days of age with progressive cardiomyopathy. Testing for survival motor neurone (smn) and NAIP deletions were negative and a skeletal muscle biopsy showed neurogenic features with severe reductions of COX enzymatic and histochemical staining intensity. Post-mortem muscle, heart, and liver biopsies showed severe, moderate, and mild reductions in COX activity, respectively, with parallel findings in the protein content for the mitochondrial DNA (COII) and nuclear DNA (COIV) encoded subunits. DNA sequencing of exon 2 of the SCO2 gene revealed compound heterozygosity with mutations at G1541A (common mutation, E140K) and also at a novel site in the copper binding region (G1521A in the current case (converting a highly conserved cysteine to tyrosine [corrected] (C133Y) [corrected]); mother heterozygous for G1521A; and father heterozygous for G1541A). This case provides strong support that SCO2 mutations can result in neonatal hypotonia with an SMA 1 phenotype. SCO2 mutations should be screened in suspected SMA cases with normal smn mutation analysis and any one of; cardiomyopathy, lactic acidosis, or COX deficiency in muscle.

Low mutational burden of individual acquired mitochondrial DNA mutations in brain.

Neurons may be particularly susceptible to oxidative damage, which has been proposed to induce somatic mutations, particularly in mitochondrial DNA (mtDNA). Therefore, acquired mtDNA mutations might preferentially accumulate in the brain and could play a role in aging and neurodegenerative disorders. Recently, a somatic T to G mtDNA mutation at noncoding nucleotide position 414 was reported in fibroblasts specifically from elderly subjects, with mutational burdens of up to 50%. We screened for this mutation in brain-derived mtDNA from 8 Alzheimer's disease patients, 27 Parkinson's disease patients, 4 multiple system atrophy patients, and 44 controls using up to three RFLP analyses. A total of 73 of these subjects were over the age of 65. The 414 mutation was absent in all cases. Next, individual mtDNA fragments from 6 elderly subjects were cloned, and a total of 70 clones were sequenced. The 414 mutation was absent in all clones, though occasional sequence variations were identified at other sites in single clones. The 414 mutation also was absent in blood (n = 6) and fibroblasts (n = 11) from elderly subjects. Our data suggest that it is rare for any one particular acquired mtDNA mutation to reach levels in the brain that are functionally significant. This does not exclude the possibility that the cumulative burden of multiple, individually rare, acquired mutations impairs mitochondrial function.

Mitochondrial DNA mutations in complex I and tRNA genes in Parkinson's disease.

OBJECTIVE: To identify mitochondrial DNA (mtDNA) mutations that predispose to PD. BACKGROUND: Mitochondrial complex I activity is deficient in PD. mtDNA mutations may account for the defect, but the specific mutations have not been identified. METHODS: Complete sequencing was performed of all mtDNA-encoded complex I and transfer RNA (tRNA) genes in 28 PD patients and 8 control subjects, as well as screening of up to 243 additional PD patients and up to 209 control subjects by restriction digests for selected mutations. RESULTS: In the PD patients, 15 complex I missense mutations and 9 tRNA mutations were identified. After screening additional subjects, rare PD patients were found to carry complex I mutations that altered highly conserved amino acids. However, no significant differences were found in the frequencies of any mutations in PD versus control groups. The authors were unable to confirm previously reported associations of mutations at nucleotide positions (np) 4336, 5460, and 15927/8 with PD. Complex I mutations previously linked to Leber's hereditary optic neuropathy, one of which has been linked to atypical parkinsonism, were not associated with PD. CONCLUSIONS: mtDNA mutations with a high mutational burden (present in a high percentage of mtDNA molecules in an individual) in complex I or tRNA genes do not play a major role in the risk of PD in most PD patients. Further investigations are necessary to determine if any of the rare mtDNA mutations identified in PD patients play a role in the pathogenesis of PD in those few cases.

Familial multisystem degeneration with parkinsonism associated with the 11778 mitochondrial DNA mutation.

OBJECTIVE: To investigate a family with maternally inherited, adult-onset multisystem degeneration including prominent parkinsonism to determine whether clinical features can result from a mitochondrial DNA (mtDNA) mutation. The parkinsonism was levodopa responsive and was associated with the loss of pigmented neurons in the substantia nigra in at least one patient. BACKGROUND: Mitochondrial dysfunction is hypothesized to play a role in late-onset neurodegenerative diseases including PD and AD. Mitochondrial genetic mutations are hypothesized to account for these defects, but attempts to identify specific mtDNA mutations have been inconclusive. METHODS: Clinical examinations, DNA sequencing, and restriction digestion and biochemical analyses were performed. RESULTS: Maternal relatives harbor a G-to-A missense mutation, heteroplasmic in some patients, at nucleotide position 11778 of the mitochondrial ND4 gene of complex I that converts a highly conserved arginine to a histidine. Sequencing of the entire mitochondrial genome in an affected family member reveals no other mutations likely to be pathogenic. This mutation has been identified previously only in families with Leber's hereditary optic neuropathy-a disorder also linked to complex I dysfunction but usually limited clinically to optic atrophy. CONCLUSIONS: These data reveal previously unsuspected clinical heterogeneity of the G11778A mutation, and suggest that an inherited mtDNA mutation can contribute to the development of adult-onset parkinsonism and multisystem degeneration.

Neuroprotective therapies.

Though effective symptomatic therapies for Parkinson's disease exist, currently no treatment is proven to slow the progression of the underlying disease. Our growing understanding of the mechanisms of neuronal models, however, offers hope that neuroprotective strategies will soon be a standard part of the treatment of PD. Current approaches to the development of neuroprotective strategies are based on the hypothesized roles of oxidative stress and excitotoxicity in the degenerative process. In this article, we review evidence in support of these hypotheses as well as attempts to achieve neuroprotection in PD based on these and other mechanisms.

Mitochondrial disorders: clinical and genetic features.

Virtually all cells in humans depend on mitochondrial oxidative phosphorylation to generate energy, accounting for the remarkable diversity of clinical disorders associated with mitochondrial DNA mutations. However, certain tissues are particularly susceptible to mitochondrial dysfunction, resulting in recognizable clinical syndromes. Mitochondrial DNA mutations have been linked to seizures, strokes, optic atrophy, neuropathy, myopathy, cardiomyopathy, sensorineural hearing loss, diabetes mellitus, and other clinical features. Mitochondrial DNA mutations also may play an important role in aging, as well as in common age-related neurodegenerative disorders such as Parkinson's disease. Therefore, it is becoming increasingly important for clinicians to recognize the clinical syndromes suggestive of a mitochondrial disorder, and to understand the unique features of mitochondrial genetics that complicate diagnosis and genetic counseling.

A unique familial leukodystrophy with adult onset dementia and abnormal glycolipid storage: a new lysosomal disease?

Two adult siblings with early onset dementia are described. At presentation, in their early 30s, they showed poor judgment and disinhibition. A progressive dementia ensued over several years. Brain MRI disclosed diffusely increased T2 signal in the cerebral white matter, suggestive of a leukodystrophy. Numerous lysosomal enzyme assays including leucocyte arylsulphatase A and galactocerebrosidase activities, plasma and fibroblast very long chain fatty acid concentrations, and urinary sulphatide concentrations were normal, as were CSF analyses. A brain biopsy disclosed periodic acid Schiff (PAS) and Sudan black positive material in perivascular macrophages which, by electron microscopy, consisted of stacks of straight or curvilinear paired membranes within angulate lysosomes, indicative of abnormal glycolipid accumulation. The combination of clinical, radiological, biochemical, and pathological features of this degenerative disease is not consistent with that of any of the known leukodystrophies or lysosomal storage disorders. These findings suggest a previously undescribed familial glycolipid storage disorder causing an adult onset leukodystrophy and presenting with behavioural symptoms that mimic a psychiatric disorder.

Plasticity in the development of topographic order in the mammalian retinocollicular projection.

The topographically ordered retinocollicular projection in rats emerges from an initially diffuse projection present in neonates through the elimination of aberrantly positioned axons and arbors. We explore developmental plasticity in this process by making partial retinal lesions at birth and determining the topographic mapping of the remaining retina at later ages when the map normally has a mature, retinotopic order. In normal mature rats, DiI focally injected into the retina labels axons that form a dense focus of overlapping arbors at the topographically correct location in the superior colliculus (SC). Similar injections in rats with partial retinal lesions label axons that form two discrete foci of arborizations; one at the topographically appropriate region of the SC and another in the region of the SC deprived of its normal retinal input by the retinal lesion. A focal injection of DiI into the "deprived" SC region retrogradely labels ganglion cells widely scattered in the retina. Therefore, a partial retinal lesion in developing rats does not lead to an orderly expansion of the remaining retinal projection to cover the entire SC, as it does in amphibians and fish following optic nerve regeneration. Rather, in rats, the remaining partial retina forms two distinct, contiguous projections to the SC: a retinotopically ordered one that retains normal topographic relationships and an aberrant, diffusely ordered one to the SC region topographically matched with the lesioned part of the retina. This abnormal persistence of topographically aberrant axons and arbors indicates that competitive interactions between retinal axons drive the remodeling of the initially diffuse retino-collicular projection into a topographically ordered one.

Responses of retinal axons in vivo and in vitro to position-encoding molecules in the embryonic superior colliculus.

We show that rat retinal ganglion cell axons exhibit no topographic specificity in growth along the rostral-caudal axis of the embryonic superior colliculus (SC). Position-related, morphological differences are not found between temporal and nasal axon growth cones. However, embryonic retinal axons respond in vitro to a position-dependent molecular property of SC membranes. In vivo, regional specificity in side branching is the earliest indication that axons make topographic distinctions along the rostral-caudal SC axis. Our contrasting in vivo and in vitro results indicate that molecules encoding rostral-caudal position in the SC neither guide nor restrict retinal axon growth, but may promote the development of topographic connections by controlling specificity in the extension or stabilization of branches.