Predictors of medication adherence in patients with schizophrenia and bipolar disorder.

OBJECTIVE: To investigate potential risk factors for medication non-adherence in patients with schizophrenia and bipolar disorder. METHOD: A total of 255 patients underwent clinical assessments, neurocognitive testing and blood sampling. The patients were divided into groups of 'No', 'Partial' or 'Full' adherence. Relationships to different risk factors were analyzed. RESULTS: In schizophrenia, use of illicit substances, alcohol and poor insight were related to worse adherence. Schizophrenia patients with No adherence did better on tests of executive functioning, verbal learning and memory and had higher IQ than patients with better adherence. There were higher levels of autonomic side effects in the non-adherence group, but body mass index was lower in the Partial adherence group than in the Full adherence group. In the bipolar disorder patients, there was an association between the use of illicit substances and alcohol and poor adherence. We found no relationship between adherence behavior and neurocognition in the bipolar disorder group. CONCLUSION: Substance use is an important risk factor for non-adherence in patients with schizophrenia and bipolar disorder. Poor insight is also a risk factor in schizophrenia. The results suggest that cognitive dysfunction is not a risk factor for non-adherence in these diagnostic groups.

Animal model for endoscopic neurosurgical training: technical note.

OBJECTIVE: The learning curve for endonasal endoscopic and neuroendoscopic port surgery is long and often associated with an increase in complication rates as surgeons gain experience. We present an animal model for laboratory training aiming to encourage the young generation of neurosurgeons to pursue proficiency in endoscopic neurosurgical techniques. METHODS: 20 Wistar rats were used as models. The animals were introduced into a physical trainer with multiple ports to carry out fully endoscopic microsurgical procedures. The vertical and horizontal dimensions of the paired ports (simulated nostrils) were: 35×20 mm, 35×15 mm, 25×15 mm, and 25×10 mm. 2 additional single 11.5 mm endoscopic ports were added. Surgical depth varied as desired between 8 and 15 cm. The cervical and abdominal regions were the focus of the endoscopic microsurgical exercises. RESULTS: The different endoscopic neurosurgical techniques were effectively trained at the millimetric dimension. Levels of progressive surgical difficulty depending upon the endoneurosurgical skills set needed for a particular surgical exercise were distinguished. LEVEL 1 is soft-tissue microdissection (exposure of cervical muscular plane and retroperitoneal space); LEVEL 2 is soft-tissue-vascular and vascular-capsule microdissection (aorto-cava exposure, carotid sheath opening, external jugular vein isolation); LEVEL 3 is artery-nerve microdissection (carotid-vagal separation); LEVEL 4 is artery-vein microdissection (aorto-cava separation); LEVEL 5 is vascular repair and microsuturing (aortic rupture), which verified the lack of current proper instrumentation. CONCLUSION: The animal training model presented here has the potential to shorten the length of the learning curve in endonasal endoscopic and neuroendoscopic port surgery and reduce the incidence of training-related surgical complications.

Opposite relationships between cannabis use and neurocognitive functioning in bipolar disorder and schizophrenia.

BACKGROUND: Cannabis use is associated with altered neurocognitive functioning in severe mental disorders, but data are still inconclusive and there are no studies of bipolar disorder. The aim of this study was to investigate the association between cannabis use and neurocognition in bipolar disorder compared with schizophrenia in a naturalistic setting. METHOD: A total of 133 patients with bipolar disorder and 140 patients with schizophrenia underwent neuropsychological assessments and clinical characterization including measures of substance use. Relationships between cannabis users and neurocognitive function were explored in the two diagnostic groups. Possible interactions between diagnosis and cannabis use were investigated, and findings were controlled for possible confounders. RESULTS: In bipolar disorder subjects, cannabis use was associated with better neurocognitive function, but the opposite was the case for the schizophrenia subjects. There was a statistically significant interaction effect of diagnosis and cannabis use on focused attention (p=0.019), executive functioning (verbal fluency--set shifting) (p=0.009), logical memory-learning (p=0.007) and on logical memory-recall (p=0.004). These differences in neurocognitive function could not be explained by putative confounders. CONCLUSIONS: The findings suggest that cannabis use may be related to improved neurocognition in bipolar disorder and compromised neurocognition in schizophrenia. The results need to be replicated in independent samples, and may suggest different underlying disease mechanisms in the two disorders.

Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1alpha.

Hypoxia contributes to the progression of a variety of cancers by activating adaptive transcriptional programs that promote cell survival, motility and tumor angiogenesis. Although the importance of hypoxia and subsequent hypoxia-inducible factor-1alpha (HIF-1alpha) activation in tumor angiogenesis is well known, their role in the regulation of glioma-derived stem cells is unclear. In this study, we show that hypoxia (1% oxygen) promotes the self-renewal capacity of CD133-positive human glioma-derived cancer stem cells (CSCs). Propagation of the glioma-derived CSCs in a hypoxic environment also led to the expansion of cells bearing CXCR4 (CD184), CD44(low) and A2B5 surface markers. The enhanced self-renewal activity of the CD133-positive CSCs in hypoxia was preceded by upregulation of HIF-1alpha. Knockdown of HIF-1alpha abrogated the hypoxia-mediated CD133-positive CSC expansion. Inhibition of the phosphatidylinositol 3-kinase(PI3K)-Akt or ERK1/2 pathway reduced the hypoxia-driven CD133 expansion, suggesting that these signaling cascades may modulate the hypoxic response. Finally, CSCs propagated at hypoxia robustly retained the undifferentiated phenotype, whereas CSCs cultured at normoxia did not. These results suggest that response to hypoxia by CSCs involves the activation of HIF-1alpha to enhance the self-renewal activity of CD133-positive cells and to inhibit the induction of CSC differentiation. This study illustrates the importance of the tumor microenvironment in determining cellular behavior.

The level of illicit drug use is related to symptoms and premorbid functioning in severe mental illness.

OBJECTIVE: There is conflicting data on drug abuse and outcome in severe mental illness. This study aims to investigate if the amount of illicit psychoactive drug use is related to symptom load or premorbid functioning across diagnosis in patients with severe mental illness. METHOD: Symptom load, sociodemographic status, premorbid functioning and the level of use of illicit psychoactive drugs were assessed in 423 subjects with schizophrenia or bipolar disorder in a cross-sectional study. RESULTS: High amount of illicit drug use was associated with poorer premorbid academic functioning. In schizophrenia, there was a significant positive association between amount of drug use and severity of psychiatric symptoms. The association between symptom load and drug use was significant after controlling for premorbid functioning. CONCLUSION: The results suggest a direct association between the quantity of current drug use and more severe symptoms in schizophrenia. Poor premorbid functioning was related to high amount of use, but did not explain the difference in symptom load.

Illicit drug use in patients with psychotic disorders compared with that in the general population: a cross-sectional study.

OBJECTIVE: Prevalence estimates of illicit drug use in psychotic disorders vary between studies, and only a few studies compared prevalence estimates with those in the general population. METHOD: Cross-sectional study comparing 148 stable-phase patients with schizophrenia or bipolar disorder with 329 representative general citizens of Oslo. A total of 849 patients from the same hospital department in the same time period constituted a patient reference group. RESULTS: Lifetime illicit drug use was 44% higher (P < 0.001) in study patients than in the general population sample; while lifetime use of amphetamine/cocaine was 160% higher (P < 0.001). No differences were found between user groups for sociodemographic characteristics. CONCLUSION: Patients with psychotic disorders in stable phase had a markedly higher lifetime use of any illicit substance, especially amphetamine/cocaine, than the general population. They also seemed to use drugs more periodically. The same sociodemographic characteristics were associated with increased illicit drug use in both groups.

The effect of gender on emotion perception in schizophrenia and bipolar disorder.

OBJECTIVE: Impaired emotion perception is documented for schizophrenia, but findings have been mixed for bipolar disorder. In healthy samples females perform better than males. This study compared emotion perception in schizophrenia and bipolar disorder and investigated the effects of gender. METHOD: Visual (facial pictures) and auditory (sentences) emotional stimuli were presented for identification and discrimination in groups of participants with schizophrenia, bipolar disorder and healthy controls. RESULTS: Visual emotion perception was unimpaired in both clinical groups, but the schizophrenia sample showed reduced auditory emotion perception. Healthy males and male schizophrenia subjects performed worse than their female counterparts, whereas there were no gender differences within the bipolar group. CONCLUSION: A disease-specific auditory emotion processing deficit was confirmed in schizophrenia, especially for males. Participants with bipolar disorder performed unimpaired.

Toward effective needle steering in brain tissue.

Recent research has exploited the inherent bending of a bevel-tipped needle during insertion, accomplishing steering of the needle by rotating the needle shaft. Combining this technique with the observation that a straight trajectory can be accomplished by spinning the needle at a constant rate during insertion, this paper presents a novel technique for proportional control of the curvature of the trajectory via duty-cycled spinning of the needle. In order to accommodate this technique to very soft tissues such as the brain, several custom needle prototypes have also been designed in order to increase the steering versatility of the system by maximizing the attainable curvature. The paper describes the needle-steering system and the needle prototypes, and presents preliminary results from tests in an artificial brain tissue substitute.

Repeat microvascular decompression for hemifacial spasm.

OBJECTIVE: To report our experience with repeat microvascular decompression (MVD) for hemifacial spasm (HFS) in patients who have failed their first operation. METHODS: The authors describe 41 redo MVDs for HFS in 36 patients performed over a 3 year period. Seven patients underwent early re-operation after an aborted seventh nerve decompression. Eight patients underwent early re-operation for clinical failure. Eighteen patients underwent late re-operation for spasm recurrence long after their original MVD. Eight MVDs were performed on patients who had already undergone at least two prior operations. RESULTS: Twenty four patients experienced complete spasm resolution (70.6%), eight patients had near total resolution (23.5%), and two patients failed re-operation (5.9%). Two patients were lost to follow up (5.6%). A favourable outcome was reported by 82.4% of patients at a mean follow up interval of 18 months. A total of 91.7% of patients 50 years of age or younger were cured at follow up versus 59.1% of patients older than 50 (p = 0.04). Patients undergoing early re-operation were significantly more likely to be cured or improved than patients undergoing late re-operation (p = 0.03). CONCLUSIONS: Repeat MVD for HFS is effective in experienced hands. Younger patients respond better to repeat MVD. Late repeat MVD for HFS is a reasonable treatment option, although results are less favourable than for early re-operation.

Morphologic analysis of BMP-9 gene therapy-induced osteogenesis.

The present study was performed to determine the histological, ultrastructural, and radiographic changes that occur over time at intramuscular BMP-9 gene therapy treatment sites. Several members of the bone morphogenetic protein (BMP) family have the potential to induce osteochondrogenesis when the protein is delivered to rodents, canines, rabbits, and nonhuman primates. Previous studies have also demonstrated that BMP gene therapy utilizing adenoviral vectors can also stimulate orthotopic and heterotopic bone formation in rodents and rabbits. Athymic nude and Sprague-Dawley rats were injected with Ad-BMP-9 or Ad-beta-Gal (3.75 x 10(9) particles) in their thigh musculature and light microscopic, electron microscopic, and computerized tomography analysis was performed 3, 6, 9, 12, 15, 18, 21, and 100 days later. To assess early mesenchymal cell proliferation, a bromodeoxyuridine (BrdU) immunohistochemical analysis was also performed 48, 60, and 72 hr postinjection in athymic nude rats. All animals demonstrated extensive endochondral bone formation at the Ad-BMP-9 treatment sites within 3 weeks. The Sprague-Dawley rats also exhibited a massive, acute inflammatory infiltrate during the first week. Proliferating mesenchymal stem cells were clearly evident as early as 2 days after treatment, which differentiated into small or hypertrophied chondrocytes during the next week. During the third week, the cartilaginous matrix mineralized and formed woven bone, which converted to lamellar bone by 3 months. No evidence of bone formation was demonstrated at the Ad-beta-Gal injection sites in the athymic nude or Sprague-Dawley rats. In addition, no cellular proliferation was seen at the Ad-beta-Gal treatment sites in the athymic nude animals as assessed by light microscopy and BrdU immunohistochemistry. The extensive bone formation induced by Ad-BMP-9 suggests that BMP gene therapy may have potential utility in the treatment of degenerative, rheumatic, or traumatic bone pathology.

Use of bone morphogenetic protein-9 gene therapy to induce spinal arthrodesis in the rodent.

OBJECT: Bone morphogenetic proteins (BMPs) have been shown to have significant osteoinductive activity in numerous in vitro and in vivo assay systems, and BMP-2 and BMP-7 are currently being evaluated in human clinical studies. In the spinal region, BMPs have been shown to promote spinal arthrodesis at a higher rate than autologous bone alone. The delivery of BMPs via direct or ex vivo gene therapy techniques is also currently being evaluated and has shown promise in several mammalian models. The present study was designed to evaluate the efficacy of the use of direct, percutaneous BMP-9 adenoviral gene therapy to promote spinal fusion in the rodent. METHODS: Each animal was injected with 7.5x10(8) pfu of a BMP-9 adenoviral vector in the lumbar paraspinal musculature and allowed to survive 16 weeks. Computerized tomography studies and histological analysis demonstrated massive bone induction at the injection sites, clearly leading to solid spinal arthrodesis, without evidence of pseudarthroses, nerve root compression, or systemic side effects. CONCLUSIONS: The results of this study strongly support the advancement of BMP gene therapy techniques toward clinical use.

The use of bone morphogenetic protein gene therapy in craniofacial bone repair.

Bone morphogenetic proteins (BMPs) are capable of inducing endochondral bone formation when applied on biologic carriers in numerous mammalian in vivo assay systems. Bone morphogenetic protein gene therapy is also currently being developed to promote osteogenesis for clinical indications such as spinal fusions, craniofacial bone loss, and osteoporosis. In this study, critical-sized mandibular defects were treated with a control adenoviral vector (Ad-beta-gal), a BMP-2 adenoviral vector (Ad-BMP-2), or a BMP-9 adenoviral vector (Ad-BMP-9). Gross tissue examination, radiographic analysis, and histologic analysis demonstrated significant bony healing in the BMP treated groups compared to controls. Osteogenesis was limited to the bony defect, without extension into the surrounding soft tissues. The study suggests that with further development, BMP gene therapy may be potentially useful for repair of bony defects in the craniofacial region.

In vivo endochondral bone formation using a bone morphogenetic protein 2 adenoviral vector.

Bone morphogenetic proteins (BMPs) are polypeptides that induce ectopic bone formation in standard rat in vivo assay systems. Previous studies have demonstrated the clinical utility of these proteins in spinal fusion, fracture healing, and prosthetic joint stabilization. Gene therapy is also a theoretically attractive technique to express BMPs clinically, since long-term, regulatable gene expression and systemic delivery with tissue-specific expression may be possible in future. This study was performed to determine whether an adenoviral vector containing the BMP-2 gene can be used to express BMP-2 in vitro and promote endochondral bone formation in vivo. In vitro, U87 MG cells transduced per cell with 20 MOI of an adenoviral construct containing the BMP-2 gene under the control of the universal CMV promoter (Ad-BMP-2) showed positive antibody staining for the BMP-2 protein at posttransfection day 2. The synthesis and secretion of active BMP-2 into the conditioned medium of Ad-BMP-2-transduced 293 cells were confirmed by Western blot analysis and the induction of alkaline phosphatase activity in a W-20 stromal cell assay. In vivo, Sprague-Dawley rats and athymic nude rats were injected with Ad-BMP-2 in the thigh musculature and were sacrificed on day 3, 6, 9, 12, 16, 21, 60, and 110 for histological analysis. The Sprague-Dawley rats showed evidence of acute inflammation, without ectopic bone formation, at the injection sites. In the athymic nude rats, BMP-2 gene therapy induced mesenchymal stem cell chemotaxis and proliferation, with subsequent differentiation to chondrocytes. The chondrocytes secreted a cartilaginous matrix, which then mineralized and was replaced by mature bone. This study demonstrates that a BMP-2 adenoviral vector can be utilized to produce BMP-2 by striated muscle cells in athymic nude rats, leading to endochondral bone formation. However, in immunocompetent animals the endochondral response is attenuated, secondary to the massive immune response elicited by the first-generation adenoviral construct.