Is it safe to preserve the deltoid when resecting the proximal humerus for a primary malignant bone tumour? A comparative study.

AIMS: Resection of the proximal humerus for the primary malignant bone tumour sometimes requires en bloc resection of the deltoid. However, there is no information in the literature which helps a surgeon decide whether to preserve the deltoid or not. The aim of this study was to determine whether retaining the deltoid at the time of resection would increase the rate of local recurrence. We also sought to identify the variables that persuade expert surgeons to choose a deltoid sparing rather than deltoid resecting procedure. PATIENTS AND METHODS: We reviewed 45 patients who had undergone resection of a primary malignant tumour of the proximal humerus. There were 29 in the deltoid sparing group and 16 in the deltoid resecting group. Imaging studies were reviewed to assess tumour extension and soft-tissue involvement. The presence of a fat rim separating the tumour from the deltoid on MRI was particularly noted. The cumulative probability of local recurrence was calculated in a competing risk scenario. RESULTS: There was no significant difference (adjusted p = 0.89) in the cumulative probability of local recurrence between the deltoid sparing (7%, 95% confidence interval (CI) 1 to 20) and the deltoid resecting group (26%, 95% CI 8 to 50). Patients were more likely to be selected for a deltoid sparing procedure if they presented with a small tumour (p = 0.0064) with less bone involvement (p = 0.032) and a continuous fat rim on MRI (p = 0.002) and if the axillary nerve could be identified (p = 0.037). CONCLUSION: A deltoid sparing procedure can provide good local control after resection of the proximal humerus for a primary malignant bone tumour. A smaller tumour, the presence of a continuous fat rim and the identification of the axillary nerve on pre-operative MRI will persuade surgeons to opt for a deltoid resecting procedure. Cite this article: Bone Joint J 2017;99-B:1244-9.

Flatfoot in children and adolescents. Analysis of imaging findings and therapeutic implications.

INTRODUCTION: Pes planovalgus (PPV) is a complex three-dimensional deformity of which routine radiographs provide only a two-dimensional analysis. HYPOTHESIS: Angles and other radiographic parameters of the foot in children and adolescents, when studied on both the dorsoplantar and the lateral view, can be used to establish a radiographic classification system for PPV that provides useful therapeutic guidance in clinical practice. MATERIALS AND METHODS: A retrospective single-centre study was conducted on 65 feet in 35 patients aged 7 to 18 years and having adequate ossification. All patients had a clinical diagnosis of idiopathic or neurologic PPV and available weight-bearing dorsoplantar and strict lateral radiographs. We excluded pes planus due to tarsal coalition, congenital bone deformities, or overcorrection of talipes equinovarus (n=25). All possible axes were drawn and angles measured after an evaluation of interindividual agreement. RESULTS: We identified four patterns of PPV: subtalar pes planus (n=16) with marked subtalar valgus and longitudinal sag predominating at the talonavicular joint, midtarsal pes planus (n=12) without subtalar valgus but with marked midtarsal abduction and sag predominating at the cuneonavicular joint, mixed pes planus (n=28) with subtalar valgus, midtarsal abduction, and sag at both the talonavicular and cuneonavicular joints, and pes planocavus (n=9) with sag of the medial arch and cavus deformity of the lateral arch. CONCLUSION: This original classification system provides therapeutic guidance by helping to match the surgical procedure to the nature and location of the deformities. LEVEL OF EVIDENCE: Level IV.

Chronic high dose transdermal nicotine in Parkinson's disease: an open trial.

Whether nicotine has therapeutic effects on Parkinson's disease (PD) symptoms is controversial, but high doses and chronic treatment have never been tested. We report the results of a pilot, open-label trial to assess the safety and possible efficacy of chronic high doses of nicotine. Six patients with advanced idiopathic PD received increasing daily doses of transdermal nicotine up to 105 mg/day over 17 weeks. All patients but one accepted the target dose. Nausea and vomiting were frequent but moderate, and occurred in most of the patients (four of six) who received over 90 mg/day and 14 weeks of nicotine treatment. During the plateau phase, patients improved their motor scores and dopaminergic treatment was reduced. These results confirm the feasibility of chronic high dose nicotinic treatment in PD but warrant validation of the beneficial effects by a randomized controlled trial.

Neuroprotective gene therapy for Huntington's disease, using polymer-encapsulated cells engineered to secrete human ciliary neurotrophic factor: results of a phase I study.

Huntington's disease (HD) is a monogenic neurodegenerative disease that affects the efferent neurons of the striatum. The protracted evolution of the pathology over 15 to 20 years, after clinical onset in adulthood, underscores the potential of therapeutic tools that would aim at protecting striatal neurons. Proteins with neuroprotective effects in the adult brain have been identified, among them ciliary neurotrophic factor (CNTF), which protected striatal neurons in animal models of HD. Accordingly, we have carried out a phase I study evaluating the safety of intracerebral administration of this protein in subjects with HD, using a device formed by a semipermeable membrane encapsulating a BHK cell line engineered to synthesize CNTF. Six subjects with stage 1 or 2 HD had one capsule implanted into the right lateral ventricle; the capsule was retrieved and exchanged for a new one every 6 months, over a total period of 2 years. No sign of CNTF-induced toxicity was observed; however, depression occurred in three subjects after removal of the last capsule, which may have correlated with the lack of any future therapeutic option. All retrieved capsules were intact but contained variable numbers of surviving cells, and CNTF release was low in 13 of 24 cases. Improvements in electrophysiological results were observed, and were correlated with capsules releasing the largest amount of CNTF. This phase I study shows the safety, feasibility, and tolerability of this gene therapy procedure. Heterogeneous cell survival, however, stresses the need for improving the technique.

Motor and cognitive improvements in patients with Huntington's disease after neural transplantation.

BACKGROUND: Huntington's disease is a neurodegenerative disease of genetic origin that mainly affects the striatum. It has severe motor and cognitive consequences and, up to now, no treatment. Motor and cognitive functions can be restored in experimental animal models by means of intrastriatal transplantation of fetal striatal neuroblasts. We explored whether grafts of human fetal striatal tissue could survive and have detectable effects in five patients with mild to moderate Huntington's disease. METHODS: After 2 years of preoperative assessment, patients were grafted with human fetal neuroblasts into the right striatum then, after a year, the left striatum. Final results were assessed 1 year later on the basis of neurological, neuropsychological, neurophysiological, and psychiatric tests. The results obtained were compared with those of a cohort of 22 untreated patients at similar stages of the disease who were followed up in parallel. Repeated magnetic resonance imaging (MRI) and positron emission tomography (PET) scanning with fluorine-18-labelled fluorodeoxyglucose was also done to assess metabolic activity. FINDINGS: The final PET-scan assessment showed increased metabolic activity in various subnuclei of the striatum in three of five patients, contrasting with the progressive decline recorded in the two other patients in the series, as seen in patients with untreated Huntington's disease. Small areas of even higher metabolic activity, coregistering with spherical hyposignals on MRI were also present in the same three patients, suggesting that grafts were functional. Accordingly, motor and cognitive functions were improved or maintained within the normal range, and functional benefits were seen in daily-life activities in these three patients, but not in the other two. INTERPRETATION: Fetal neural allografts could be associated with functional, motor, and cognitive improvements in patients with Huntington's disease.

Neuroprotective gene therapy for Huntington's disease using a polymer encapsulated BHK cell line engineered to secrete human CNTF.

Huntington's disease (HD) is an autosomal dominant genetic disease with devastating clinical effects on cognitive, psychological, and motor functions. These clinical symptoms primarily relate to the progressive loss of medium-spiny GABA-ergic neurons of the striatum. There is no known treatment to date. Several neurotrophic factors have, however, demonstrated the capacity to protect striatal neurons in various experimental models of HD. This includes the ciliary neurotrophic factor (CNTF), the substance examined in this protocol. An ex vivo gene therapy approach based on encapsulated genetically modified BHK cells will be used for the continuous and long-term intracerebral delivery of CNTF. A device, containing up to 106 human CNTF-producing BHK cells surrounded by a semipermeable membrane, will be implanted into the right lateral ventricle of 6 patients. Capsules releasing 0.15-0.5 microg CNTF/day will be used. In this phase I study, the principal goal will be the evaluation of the safety and tolerability of the procedure. As a secondary goal, HD symptoms will be analyzed using a large battery of neuropsychological, motor, neurological, and neurophysiological tests and the striatal pathology monitored using MRI and PET-scan imaging. It is expected that the gene therapy approach described in this protocol will mitigate the side effects associated with the peripheral administration of recombinant hCNTF and allow a well-tolerated, continuous intracerebroventricular delivery of the neuroprotective factor.

Safety and tolerability assessment of intrastriatal neural allografts in five patients with Huntington's disease.

This study describes issues related to the safety and tolerability of fetal striatal neural allografts as assessed in five patients with Huntington's disease. Huntington's disease (HD) is characterized by motor, cognitive, and behavioral disturbances. The latter include psychological disturbances and, as a consequence, we took particular care to analyze behavioral changes, in addition to the usual "safety" follow-up. We conducted multidisciplinary follow-up at least 2 years before and 1 year after grafting. Psychological care extended to close relatives. The grafting procedure itself was altogether safe and uneventful, and there were no apparent clinical deleterious effects for 1 year. The immunosuppressive treatment, however, was complicated by various problems (irregular compliance, errors of handling, side effects). Direct psychological consequences of the transplantation procedure were rare and not worrisome, although mood alteration requiring treatment was observed in one patient. Indirectly, however, the procedure required patients and relatives to accept constraints that tended to complicate familial situations already marred by aggressivity and depression. All patients and close relatives expressed major expectations, in spite of our strong and repeated cautioning. It is clearly important to be aware of these particular conditions since they may eventually translate into psychological difficulties in coping with the long-term clinical outcome of the procedure, if not beneficial. Despite an overall good tolerance, therefore, this follow-up calls for caution regarding the involvement of HD patients in experimental surgical protocols.

Distribution of visual callosal neurons in normal and strabismic cats.

It has been suggested that synchronous activation of cortical loci in the two cerebral hemispheres during development leads to the stabilization of juvenile callosal connections in some areas of the visual cortex. One way in which loci in opposite hemispheres can be synchronously activated is if they receive signals generated by the same stimulus viewed through different eyes. These ideas lead to the prediction that shifts in the cortical representation of the visual field caused by misalignment of the visual axes (strabismus) should change the width of the callosal zone in the striate cortex. We tested this prediction by using quantitative techniques to compare the tangential distribution of callosal neurons in the striate cortex of strabismic cats to that in normally reared cats. Animals were rendered strabismic surgically at 8-10 days of age and were allowed to survive a minimum of 18 weeks, at which time multiple intracortical injections of the tracer horseradish peroxidase (HRP) were used to reveal the distribution of callosally projecting cells in the contralateral striate cortex. HRP-labeled cells were counted in coronal sections, and data from four animals with divergent strabismus (exotropia) and four with convergent strabismus (esotropia) were compared to those from four normally reared animals. Although our data from strabismic cats do not differ markedly from those reported previously, we find that the distribution of callosal cells in the striate cortex of these cats does not differ significantly from that in our normally reared control cats. These results do not bear out the prediction that surgically shifting the visual axes leads to stabilization of juvenile callosal axons in anomalous places within the striate cortex.

Cell-type-specific expression and regulation of a c-fos-NGF fusion gene in neurons and astrocytes of transgenic mice.

A mouse line transgenic for nerve growth factor (NGF) was developed using the mouse prepro-NGF cDNA inserted within a plasmid containing the proximal region (-10 to -550 bp) of the c-fos promoter and the transcription termination and polyadenylation signals of the rabbit beta-globin gene. No significant modification of gross behavior or central nervous system anatomy was detected in adult animals as assessed by immunohistochemistry and in situ hybridization for NGF and choline acetyltransferase. The expression of the transgene and the possible regulation of its expression by agents acting on the promoter were investigated in vitro. Despite the presence of an additional pool of NGF mRNA specific to the transgene, basal levels of NGF in the supernatant of transgenic astrocytes were similar to normal ones. On the other hand, transgenic neurons spontaneously synthesized and released levels of NGF two to three times higher than normal neurons, while mRNA levels were barely detectable by conventional Northern blotting. The tissue-specificity of NGF expression was respected, with higher levels in hippocampal than neocortical neurons. Increases of NGF mRNA by agents acting on the promoter could be observed in normal and transgenic astrocytes only after inhibition of the protein synthesis by cycloheximide, suggesting a similar rapid turnover of normal and transgenic transcripts. Cyclic AMP agonists specifically increased the secretion of NGF protein by transgenic astrocytes and neurons, while activators of the protein kinase C had a similar effect on transgenic and normal cells. Differences between amounts of NGF secreted by neurons and astrocytes with regards to their respective content in mRNA suggest that transgenic transcripts are subject to normal cell- and tissue-specific post-transcriptional regulations. Agents acting on the c-fos promoter through the protein kinase C or cyclic AMP routes differentially increased the secretion of NGF by transgenic astrocytes or neurons, supporting this hypothesis.

Insomnia in anxiety: sleep EEG changes.

Anxiety is often paired with sleep disturbances and both interact in a quite complex manner. Sleep (and vigilance) problems are often included in the descriptive definition or in the diagnostic criteria for anxiety disorders. Nevertheless, if anxiety may cause sleep disturbances, it is also known that sleep deprivation may produce symptoms which fall within the symptom complex of anxiety. In this paper, some of the methodological issues encountered when studying sleep and anxiety are discussed. Polygraphic recordings of sleep in anxious patients have consistently shown an increased sleep latency and, quite often, also exhibited a reduced sleep time, a reduced total sleep time, less slow-wave sleep, a greater arousal index and an increased duration of wakefulness during sleep. From our own study, we also report anomalies of the first night cycle in anxious poor sleepers who are otherwise indistinguishable from normal controls (with regard to the 'classical' sleep parameters). We have also observed the large interindividual variability of numbers of sleep parameters in anxious people. The question of a potential heterogeneity of the studied groups with regard to their clinical presentation as well as their sleep profile has been raised through our research as well. It is apparent that strategies for exploring the source of the potential heterogeneity of anxiety disorders are still needed.

[11C]L-methionine uptake in gliomas.

Treatment of gliomas remains disappointing in spite of a great number of experimental biological data and of randomized therapeutic studies. This could be partly explained by the inefficiency of our conventional methods to assess the regional metabolism of these tumors. The use of positron emission tomography (PET) brings encouraging possibilities in this field. We report our preliminary experience of measuring regional cerebral methionine uptake with PET after intravenous injection of [11C]L-methionine. Twenty-two patients with histologically confirmed gliomas were studied. An ECAT II positron emission tomograph was used for scanning. The position of the plane was chosen to include a major section of the tumor in the reconstructed brain slice. The protocol required a two-step examination: 1) after injection of 15 to 25 mCi of [11C]L-methionine, 12 scans were performed over a period of 46 minutes; and 2) 18 hours later, regional cerebral blood volume was measured in the same slice after intravenous injection of 2 to 4 mCi of 68GaCl3. The tumoral region of interest was determined as being the area of maximum activity. For each patient we calculated the ratio, R, between the activity in this tumor region of interest and the activity in the contralateral healthy symmetric region of interest which was used as an "internal standard" for the same patient. We correlated the ratio R with the histological grading. In 22 patients, mean values of R were calculated for each tumor: Grade II (n = 5): R = 1.04 +/- 0.27; Grade III (n = 5): R = 1.68 +/- 0.22; and Grade IV (n = 12): R = 2.33 +/- 0.86.(ABSTRACT TRUNCATED AT 250 WORDS)