Prevalence of transactive response DNA-binding protein 43 (TDP-43) proteinopathy in cognitively normal older adults: systematic review and meta-analysis.

OBJECTIVE: To perform a systematic review and meta-analysis on the prevalence of transactive response DNA-binding protein 43 (TDP-43) proteinopathy in cognitively normal older adults. METHODS: We systematically reviewed and performed a meta-analysis on the prevalence of TDP-43 proteinopathy in older adults with normal cognition, evaluated by the Mini-Mental State Examination or the Clinical Dementia Rating. We estimated the overall prevalence of TDP-43 using random-effect models, and stratified by age, sex, sample size, study quality, antibody used to assess TDP-43 aggregates, analysed brain regions, Braak stage, Consortium to Establish a Registry for Alzheimer's Disease score, hippocampal sclerosis and geographic location. RESULTS: A total of 505 articles were identified in the systematic review, and 7 were included in the meta-analysis with 1196 cognitively normal older adults. We found an overall prevalence of TDP-43 proteinopathy of 24%. Prevalence of TDP-43 proteinopathy varied widely across geographic location (North America: 37%, Asia: 29%, Europe: 14%, and Latin America: 11%). Estimated prevalence of TDP-43 proteinopathy also varied according to study quality (quality score >7: 22% vs. quality score <7: 42%), antibody used to assess TDP-43 proteinopathy (native: 18% vs. hyperphosphorylated: 24%) and presence of hippocampal sclerosis (without 24% vs. with hippocampal sclerosis: 48%). Other stratified analyses by age, sex, analysed brain regions, sample size and severity of AD neuropathology showed similar pooled TDP-43 prevalence. CONCLUSIONS: Different methodology to access TDP-43, and also differences in lifestyle and genetic factors across different populations could explain our results. Standardization of TDP-43 measurement, and future studies about the impact of genetic and lifestyle characteristics on the development of neurodegenerative diseases are needed.

Magnetic resonance diffusion tensor imaging for the pedunculopontine nucleus: proof of concept and histological correlation.

The pedunculopontine nucleus (PPN) has been proposed as target for deep brain stimulation (DBS) in patients with postural instability and gait disorders due to its involvement in muscle tonus adjustments and control of locomotion. However, it is a deep-seated brainstem nucleus without clear imaging or electrophysiological markers. Some studies suggested that diffusion tensor imaging (DTI) may help guiding electrode placement in the PPN by showing the surrounding fiber bundles, but none have provided a direct histological correlation. We investigated DTI fractional anisotropy (FA) maps from in vivo and in situ post-mortem magnetic resonance images (MRI) compared to histological evaluations for improving PPN targeting in humans. A post-mortem brain was scanned in a clinical 3T MR system in situ. Thereafter, the brain was processed with a special method ideally suited for cytoarchitectonic analyses. Also, nine volunteers had in vivo brain scanning using the same MRI protocol. Images from volunteers were compared to those obtained in the post-mortem study. FA values of the volunteers were obtained from PPN, inferior colliculus, cerebellar crossing fibers and medial lemniscus using histological data and atlas information. FA values in the PPN were significantly lower than in the surrounding white matter region and higher than in areas with predominantly gray matter. In Nissl-stained histologic sections, the PPN extended for more than 10 mm in the rostro-caudal axis being closely attached to the lateral parabrachial nucleus. Our DTI analyses and the spatial correlation with histological findings proposed a location for PPN that matched the position assigned to this nucleus in the literature. Coregistration of neuroimaging and cytoarchitectonic features can add value to help establishing functional architectonics of the PPN and facilitate neurosurgical targeting of this extended nucleus.

Quantifying the accretion of hyperphosphorylated tau in the locus coeruleus and dorsal raphe nucleus: the pathological building blocks of early Alzheimer's disease.

AIMS: Hyperphosphorylated tau neuronal cytoplasmic inclusions (ht-NCI) are the best protein correlate of clinical decline in Alzheimer's disease (AD). Qualitative evidence identifies ht-NCI accumulating in the isodendritic core before the entorhinal cortex. Here, we used unbiased stereology to quantify ht-NCI burden in the locus coeruleus (LC) and dorsal raphe nucleus (DRN), aiming to characterize the impact of AD pathology in these nuclei with a focus on early stages. METHODS: We utilized unbiased stereology in a sample of 48 well-characterized subjects enriched for controls and early AD stages. ht-NCI counts were estimated in 60-µm-thick sections immunostained for p-tau throughout LC and DRN. Data were integrated with unbiased estimates of LC and DRN neuronal population for a subset of cases. RESULTS: In Braak stage 0, 7.9% and 2.6% of neurons in LC and DRN, respectively, harbour ht-NCIs. Although the number of ht-NCI+ neurons significantly increased by about 1.9× between Braak stages 0 to I in LC (P = 0.02), we failed to detect any significant difference between Braak stage I and II. Also, the number of ht-NCI+ neurons remained stable in DRN between all stages 0 and II. Finally, the differential susceptibility to tau inclusions among nuclear subdivisions was more notable in LC than in DRN. CONCLUSIONS: LC and DRN neurons exhibited ht-NCI during AD precortical stages. The ht-NCI increases along AD progression on both nuclei, but quantitative changes in LC precede DRN changes.

Brazilian psychiatric brain bank: a new contribution tool to network studies.

There is an urgent need for expanding the number of brain banks serving psychiatric research. We describe here the Psychiatric Disorders arm of the Brain Bank of the Brazilian Aging Brain Study Group (Psy-BBBABSG), which is focused in bipolar disorder (BD) and obsessive compulsive disorder (OCD). Our protocol was designed to minimize limitations faced by previous initiatives, and to enable design-based neurostereological analyses. The Psy-BBBABSG first milestone is the collection of 10 brains each of BD and OCD patients, and matched controls. The brains are sourced from a population-based autopsy service. The clinical and psychiatric assessments were done by an expert team including psychiatrists, through an informant. One hemisphere was perfused-fixed to render an optimal fixation for conducting neurostereological studies. The other hemisphere was comprehensively dissected and frozen for molecular studies. In 20 months, we collected 36 brains. A final report was completed for 14 cases: 3 BDs, 4 major depressive disorders, 1 substance use disorder, 1 mood disorder NOS, 3 obsessive compulsive spectrum symptoms, 1 OCD and 1 schizophrenia. The majority were male (64%), and the average age at death was 67.2 ± 9.0 years. The average postmortem interval was 16 h. Three matched controls were collected. The pilot stage confirmed that the protocols are well fitted to reach our goals. Our unique autopsy source makes possible to collect a fairly number of high quality cases in a short time. Such a collection offers an additional to the international research community to advance the understanding on neuropsychiatric diseases.

Concurrent ipsilateral fractures of the hip and femoral shaft: a meta-analysis of 659 cases

Structured abstract from the article published on Acta Orthopaedica Scandinavica in which the author compare the different methods of treatment for concurrent ipsilateral fractures of the hip and femur.

Smoking and intervertebral disc degeneration.

Cigarette smokers have an increased risk of low back pain which may be caused by disc degeneration and spinal instability, for example. Ischemia, apoptosis, faulty synthesis of disc macromolecules, and an imbalance between disc matrix proteinases and their inhibitors may be involved in the pathogenesis of disc degeneration. Along with degeneration, the primary avascular disc turns vascular. There is some evidence that disc degeneration of cigarette smokers is of more severe degree than that of non-smokers.Cigarette-smoking increases serum proteolytic activity by releasing proteolytic enzymes from neutrophils in alveolar capillaries, and by inhibiting the activity of alpha-1-antiprotease, the most potent protease inhibitor. We hypothesize that the high serum proteolytic activity of cigarette-smokers gets access to a previously degenerated neovascularized disc and speeds up the degerative process. The increased proteolytic activity may also weaken the spinal ligaments resulting in spinal instability. These processes may explain the increased risk of low back pain of cigarette smokers.

Cemented Lubinus and Furlog total hip endoprosthesis: a 12-year follow-up study of 175 hips comparing the cementing technique.

We analyzed 175 total hip replacements with cemented Lubinus and Furlong arthroplasties in 164 patients with a median age of 65 (32-80) years and followed them for 12 years to evaluate and compare the efficacy of total hip prosthesis designs. Survival analysis was combined with an analysis of radiological findings and a study of functional outcome of the patients. The 12-year survival of Furlong arthroplasty in patients of 60 years of age and older was O.85 (95% CI 1.00-0.52). The survival of Lubinus arthroplasty in patients younger than 60 years of age was 0.70 (0.91-0.48), while the survival in older patients was 0.75 (0.89-0.61). The 12-year survival of well-cemented Lubinus prosthesis was 0.91 (1.00-0.79), indicating the importance of the cementing technique. The survival of the cups was marginally better than that of the stems. In the 12-year follow-up study, the clinical state and function varied from hips ready for revision to hips where a continuously long survival could be predicted. Harris hip score did not differentiate between patients who had intact and loose components. We conclude that cemented arthroplasty affords a notable alternative with satisfactory long-term survival and function. The better survival of cemented cup than the stem may be utilized as a basis for "reverse" hybrid arthroplasty. Adequate long-term follow-up of all arthroplasties as a quality maintenance and to prevent difficult revisions is a major challenge.

Impaction bone grafting in revision hip surgery. A high incidence of complications.

We have reviewed retrospectively 68 revisions of the femoral component in arthroplasties of the hip in 65 patients, using impaction bone grafting, at a median of three years (1 month to 6 years). We employed the cemented Exeter X-Change technique in 36 patients and the uncemented Bi-Metric allografting method in 32. The 37 bone defects were grade 3 or grade 4 on the Endo-Klinik classification. The Mayo hip score improved from a mean of 32 (SD +/- 18) to 62 (SD +/- 15). Most (25) of the 34 complications occurred in grade-3 and grade-4 defects; nine were intraoperative diaphyseal fractures and eight fractures of the greater trochanter. All the fractures united. The risk of intraoperative fracture was prevented by supporting the bone with wires in 16 hips, with reinforcement mesh in 18 and by a plate in six. Early migration of the stem of more than 10 mm during the first year indicated rotational instability; it occurred in three cases. In difficult revision cases with large defects of the femoral bone, bone-impaction techniques carry a high risk of complications.

Mutational analysis of the HGO gene in Finnish alkaptonuria patients.

Alkaptonuria (AKU), the prototypic inborn error of metabolism, has recently been shown to be caused by loss of function mutations in the homogentisate-1,2-dioxygenase gene (HGO). So far 17 mutations have been characterised in AKU patients of different ethnic origin. We describe three novel mutations (R58fs, R330S, and H371R) and one common AKU mutation (M368V), detected by mutational and polymorphism analysis of the HGO gene in five Finnish AKU pedigrees. The three novel AKU mutations are most likely specific for the Finnish population and have originated recently.

A prospective study of teleconferencing for orthopaedic consultations.

We carried out a prospective study of teleconsulting in orthopaedics. A commercial videoconferencing system was connected by three ISDN lines between the Satakunta Central Hospital in Pori and the Orton Orthopaedic Hospital in Helsinki, 240 km away. A document camera was used to transfer radiographic images and paper documents. Twenty-nine patients who needed an orthopaedic consultation were studied over three months. They were examined by a surgeon in Pori with the aid of teleconferencing and again later in a traditional, face-to-face appointment in Helsinki. Patients and doctors completed questionnaires after the consultations. Technically, the videoconferencing system functioned reliably and the quality of the video was judged to be good. Twenty patients (69%) would not have needed to travel for a face-to-face appointment, because the teleconsultation afforded a definite treatment decision. The orthopaedic surgeons considered all the treatment decisions arising from the teleconsultation good, except in one case which was considered satisfactory. The quality of the radiographic images transferred with the document camera was good or very good in 17 cases and satisfactory in three cases. None of the patients had experienced videoconferencing before; 87% of them thought that teleconsultation was a good or very good method and the rest felt that it was satisfactory. All patients wanted to participate in teleconsultations again and most would have recommended it to other patients.

Internally fixed femoral neck fractures. Early prediction of failure in 203 elderly patients with displaced fractures.

After internal fixation of a femoral neck fracture, 3 months is the critical time for planning rehabilitation of the patient. Most failures in the elderly occur within this time. In a series of 165 patients, we followed 127 women and 38 men with a median age of 81 (63-97) years from an examination at 3 months to reoperation or survival of the hip. 36 patients had radiographic signs of disturbed healing at the 3-month follow-up--change in fracture position by 10 mm, change in screw position by 5%, backing of the screws by 20 mm, or perforation of the femoral head by the screw. These signs had a high association with local complications and need for a later reoperation. High age and male sex increased this association. Signs of impaired healing made nonunion likely, but did not predict late segmental collapse of the femoral head. Patients with signs of disturbed healing and those closest to them should be informed about the value of early check-ups in case of pain and impaired function.

Recovery of sciatic nerve injuries in association with total hip arthroplasty in 27 patients.

We analyzed 27 sciatic nerve injuries associated with total hip arthroplasty (THA). The patients were 23 women and 4 men, and their median age was 55 years (range, 28-75 years). In 1987 to 1995, 4,339 THAs were performed. Primary arthroplasties accounted for 3,471 and 868 were revisions. Nine patients had developmental dysplasia of the hip. Six operations were revisions. Radiologic lengthening was median 1.4 cm (range, -1 to 4.1 cm); in 8 cases, lengthening was greater than 2 cm. The median follow-up period was 58 months (range, 24-110 months). Eight patients recovered fully, the recovery of 7 patients was fair, and 12 patients had a considerable permanent disability. The risk of nerve injury was not related to the extent of lengthening. The recovery of the nerve injury was only weakly correlated to its primary postoperative extent. The sciatic nerve injury rate was 0.6%.

Biases in a randomized comparison of three types of screw fixation in displaced femoral neck fractures.

We studied fixation of displaced femoral neck fractures prospectively in a randomized multicenter study, comparing 2 Olmed screws, 2 Tronzo screws and 3 Ullevaal hip screws. The study population consisted of 482 women and 125 men, of whom 432 women and 100 men were older than 65 years of age. Their median age was 80 (54-97) years. Despite agreement on criteria, the rates of reoperations for pain and failure--salvage (prosthesis replacement) and other reoperations (removal of implant)--differed significantly between the 3 hospitals regardless of type of fixation. In total, the percentages of salvage operations were: Olmed screw 17/175, Tronzo 17/130 and Ullevaal screw 11/302 (n.s.); the percentages of other reoperations were 11, 6 and 13, respectively (n.s.). In the whole series, the 2-year rate of salvage operations was 14%. No differences between the implants were found in patients older than 65 years of age. We conclude that an agreed, common definition of a hard end-point (reoperation) does not ensure comparability of results, because of differences in clinical decision making.

Treatment of periprosthetic fractures in association with total hip arthroplasty--a retrospective comparison between revision stem and plate fixation.

BACKGROUND AND AIMS: In periprosthetic fracture associated with hip arthroplasty, no consensus exists about the use of plate fixation or revision stem except for cases where the stem is loose in a young patient and a revision is made. The aim of the present retrospective study was to compare two commonly used alternatives for treatment of the fracture--revision arthroplasty and plate fixation. MATERIAL AND METHODS: Seventy-five fractures associated with total hip arthroplasty were treated with revision arthroplasty (N = 40) or compression plate fixation (N = 35). Twenty-one fractures were intraoperative and 54 were postoperative. In revision arthroplasty, cemented (N = 11) and porous-coated (N = 29) stems were sued. Autologous bone grafts were used in 15 revision arthroplasties and 20 plate fixations. The follow-up time was median 20 months (range 12-96 months). RESULTS: Bone grafting at the time of fracture treatment had no significant effect on fracture healing in the present setting. One patient in both groups was operated secondarily because of fracture instability. Five nonunions in the former and 9 nonunions in the latter group were treated by repeated revision and bone graft. In two revision arthroplasties and nine cases with plate fixation, a secondary bone grafting operation was performed for delayed union. In all, 20 secondary operations were needed after prosthesis stem revision and 27 secondary operations after plate fixation (p = 0.014). The need for reoperations was similar in fractures at different levels of the femur. Fracture healing was finally obtained in 39 revision arthroplasties and 34 cases with plate fixation during the follow-up period. CONCLUSIONS: Cases where the prosthesis stem is stable, where its removal would include great risks and, where the biomechanical conditions are optimal, are best treated with plate fixation. In cases where the stem is loose and where a choice is possible, stem revision is preferable to plate fixation.

Dynamic hip screw with trochanteric stabilizing plate in the treatment of unstable proximal femoral fractures: a comparative study with the Gamma nail and compression hip screw.

OBJECTIVE: To compare the results after operative treatment of unstable per- and subtrochanteric fractures with the Gamma nail, compression hip screw (CHS), or dynamic hip screw with a laterally mounted trochanteric stabilizing plate (DHS/TSP). DESIGN: Prospective. PATIENTS: One hundred seventy patients with unstable trochanteric femoral fractures surviving six months after operation. Eighty-five patients were randomized to treatment with the Gamma nail (n = 50, Gamma group) or the compression hip screw (n = 35, CHS group) and compared with a consecutive series of eighty-five patients operated with the dynamic hip screw with a laterally mounted trochanteric stabilizing plate (DHS/TSP group) MAIN OUTCOME MEASUREMENTS: Radiographs were analyzed for fracture classification, evaluation of fracture reduction, implant positioning, later fracture dislocation, and other complications. Pre- and postoperative functional status of the patients were recorded, with a minimum of six months follow-up. RESULTS: Eighteen percent of the patients in the Gamma group, 34 percent in the CHS group, and 9 percent in the DHS/TSP group suffered significant secondary fracture dislocation during the six months follow-up, leading to a varus malunion, lag screw cutout, or excessive lag screw sliding with medialization of the distal fracture fragment. Two patients (4.0 percent) in the Gamma group suffered an implant-related femoral fracture below the nail, and one had a deep infection. The reoperation rates were 8.0 percent in the Gamma group, 2.9 percent in the CHS group, and 5.9 percent in the DHS/TSP group. All but one fracture in the Gamma and CHS groups and two fractures in the DHS/TSP group healed within six months. Approximately three-fourths of the patients had returned to their preoperative walking ability after six months, with a trend toward better functional outcome in the DHS/TSP group. Use of a TSP reduced the secondary lag screw sliding as compared with the conventional CHS, without affecting fracture healing. CONCLUSION: The TSP may be an aid in the treatment of these difficult fractures because the problem with femoral shaft fractures using the Gamma nail is avoided and the medialization of the distal fracture fragment frequently associated with the CHS is prevented.

Improved diagnostic assessment of major depression in psychiatric outpatient care in Finland.

The accuracy of diagnosis of major depression by psychiatrists, psychiatric residents, and other physicians in outpatient psychiatric care settings in Finland was examined. A total of 232 patients who visited four mental health centers in the hospital district of Satakunta during three years (1989, 1992, and 1995) were retrospectively given a diagnosis of first-episode major depression by researchers, based on chart reviews. These diagnoses were compared with those made by the evaluating clinicians. Accurate diagnosis was associated with the specialty of the physician and the location of the mental health center. Recognition of major depression significantly improved over the time period, which could be attributed to educational efforts, increasing familiarity with DSM-III-R criteria, and use of new antidepressants.

Anomalous nerve anatomy at the wrist?

BACKGROUND AND AIMS: The common course of the ulnar and median nerve in the carpal tunnel has been described previously on two occasions. The aim of the study was to explain the cause of two main nerve trunks in the carpal tunnel found at an operation. MATERIAL AND METHODS: A patient was treated with open reduction and internal fixation for a volar Barton's fracture of the distal radius. Later, compression syndrome of the ulnar and median nerves developed. At operation, two nerves were found in the carpal tunnel. Electroneuromyography (ENMG) and magnetic resonance imaging (MRI) confirmed a divided median nerve. RESULT AND CONCLUSION: No anomaly of the ulnar nerve was confirmed. Deviation from the common clinical and ENMG picture of the carpal tunnel syndrome should result in thorough evaluation of possible anomalous nerve anatomy at the wrist. When at operation findings are suspicious of anomalous anatomy of the median or ulnar nerves in the carpal tunnel, Guyon's canal should also be explored to clarify the anatomy of the nerves. In cases with previous carpal collapse or other space occupying lesions we recommend division of the whole transverse carpal ligament in connection with a volar osteosynthesis, because the operative trauma may cause elevation of pressure in both the carpal and Guyon's canals.