Creation of an international registry to support discovery in schwannomatosis.

Schwannomatosis is a tumor suppressor syndrome that causes multiple tumors along peripheral nerves. Formal diagnostic criteria were first published in 2005. Variability in clinical presentation and a relative lack of awareness of the syndrome have contributed to difficulty recognizing affected individuals and accurately describing the natural history of the disorder. Many critical questions such as the mutations underlying schwannomatosis, genotype-phenotype correlations, inheritance patterns, pathologic diagnosis of schwannomatosis-associated schwannomas, tumor burden in schwannomatosis, the incidence of malignancy, and the effectiveness of current, or new treatments remain unanswered. A well-curated registry of schwannomatosis patients is needed to facilitate research in field. An international consortium of clinicians and scientists across multiple disciplines with expertise in schwannomatosis was established and charged with the task of designing and populating a schwannomatosis patient registry. The International Schwannomatosis Registry (ISR) was built around key data points that allow confirmation of the diagnosis and identification of potential research subjects to advance research to further the knowledge base for schwannomatosis. A registry with 389 participants enrolled to date has been established. Twenty-three additional subjects are pending review. A formal process has been established for scientific investigators to propose research projects, identify eligible subjects, and seek collaborators from ISR sites. Research collaborations have been created using the information collected by the registry and are currently being conducted. The ISR is a platform from which multiple research endeavors can be launched, facilitating connections between affected individuals interested in participating in research and researchers actively investigating a variety of aspects of schwannomatosis. © 2016 Wiley Periodicals, Inc.

Transanal endoscopic microsurgery: a new technique for completion proctectomy.

AIM: Following subtotal colectomy, the retained rectal stump is a potential source of morbidity. Although restorative ileal pouch-anal anastomosis is the gold standard for ulcerative colitis, up to 14% of patients will opt for a permanent ileostomy and undergo completion proctectomy, traditionally by an abdomino-perineal approach, which itself carries significant morbidity. We describe a new technique of perineal proctectomy using transanal endoscopic microsurgery (TEMS) equipment. To our knowledge, this technique has not previously been described in the literature. METHOD: Twelve patients, mean (SD) age 66 (±13) years, underwent TEMS proctectomy, performed by a single surgeon between January 2007 and October 2011. Excision began with an intersphincteric dissection following which the TEMS (WOLF) proctoscope was inserted and close rectal dissection was performed, entering the peritoneal cavity (if the top of the stump was intraperitoneal). Following perineal extraction of the specimen, the external sphincter and skin were closed with an absorbable suture. RESULTS: Nine patients had inflammatory bowel disease, two had neoplasia and one had intractable radiation proctitis. The mean (SD) rectal stump length was 17.8 (±6.1) cm and the peritoneal cavity was entered in nine patients, with no small-bowel injury. The median postoperative hospital stay was 5.5 days. In four patients there was delayed healing of the perineal wound. There was no perioperative mortality. CONCLUSION: TEMS perineal proctectomy is a novel, but safe, technique that may avoid the need for a traditional abdominoperineal approach in selected patients.

Reaction of the purple membrane with a carbodiimide.

Purple membrane was reacted with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide at pH 4.5 and 8.0. At pH 4.5, the reaction yields cross-linked bacteriorhodopsin. The cross-linking is inhibited by pretreatment of the membrane with papain, or by the presence of carbohydrazide or glycine ethyl ester in the reaction mixture. The product of the pH 8.0 reaction is not cross-linked, but it displays altered properties. Two measures of photochemical activity (light-induced change in proton binding (delta h) and decay of photointermediate M) show changes indicative of slowed proton uptake. The delta h is increased by ethyl dimethylaminopropylcarbodiimide. This increase is unaffected by pretreatment of the membrane with papain, and it is not reversed by NH2OH. However, the reaction is inhibited by millimolar concentrations of CaCl2. The altered delta h is not apparent in detergent-solubilized membranes. Ethyl dimethylaminopropylcarbodiimide does not appear to cause a large alteration in the membrane surface charge, as measured by Ca2+ binding. We conclude that (1) at acid pH, ethyl dimethylaminopropylcarbodiimide can be used for cross-linking or for attachment of specific probes to the C-terminal region of bacteriorhodopsin, and hence to the cytoplasmic side of the purple membrane, and (2) at alkaline pH, ethyl dimethylaminopropylcarbodiimide reacts at a diffent type of site and appears to inhibit the proton pump.

Fluorescent labeling of bacteriorhodopsin: implications for helix connections.

Purple membrane from Halobacterium halobium was reacted with dansyl (5-dimethylamino-1-naphthalenyl fluorescent labels that have specificity for different protein side chains of bacteriorhodopsin. Dansyl chloride was found to react primarily with Lys-41. Dansyl hydrazine was coupled, with water-soluble carbodiimide, to Glu-74 and/or Asp-85, which was the major modified site after papain-cleavage of the carboxyl-terminal 17 amino acids. Fluorescence energy transfer was used to probe the proximity of the modified sites to the retinal chromophore of bacteriorhodopsin. The dansyl group on Lys-41 was greater than 2.99 nm from retinal, while the dansyl group on Glu-74/Asp-85 was greater than 2.10 nm from retinal. Information available on the location of retinal in the transmembrane profile and probable surface locations of the fluorescent labels was combined with the energy transfer results to calculate distances projected in the plane of the membrane. The projected distances to retinal were 1.64 nm (Lys-41) and 1.65 nm (Gly-74). These measurements, combined with many other labeling experiments that have been reported, restrict the number of likely helix-connection models to only three: EDCABGF, FEDCBAG and FGEABDC (in the nomenclature of Engelman et al. (1980) Proc. Natl. Acad. Sci. USA 77, 2023-2027).

Comparison of diameter and perimeter methods for tumor volume calculation.

PURPOSE: Lesion volume is often used as an end point in clinical trials of oncology therapy. We sought to compare the common method of using orthogonal diameters to estimate lesion volume (the diameter method) with a computer-assisted planimetric technique (the perimeter method). METHODS: Radiologists reviewed 825 magnetic resonance imaging studies from 219 patients with glioblastoma multiforme. Each study had lesion volume independently estimated via the diameter and perimeter methods. Cystic areas were subtracted out or excluded from the outlined lesion. Inter- and intrareader variability was measured by using multiple readings on 48 cases. Where serial studies were available in noncystic cases, a mock response analysis was used. RESULTS: The perimeter method had a reduced interreader and intrareader variability compared with the diameter method (using SD of differences): intrareader, 1.76 mL v 7.38 mL (P < .001); interreader, 2.51 mL v 9.07 mL (P < .001) for perimeter and diameter results, respectively. Of the 121 noncystic cases, 23 had serial data. In six (26.1%) of those 23, a classification difference occurred when the perimeter method was used versus the diameter method. CONCLUSION: Variability of measurements was reduced with the computer-assisted perimeter method compared with the diameter method, which suggests that changes in volume can be detected more accurately with the perimeter method. The differences between these techniques seem large enough to have an impact on grading the response to therapy.

Quantitative changes in mesial temporal volume, regional cerebral blood flow, and cognition in Alzheimer's disease.

Twenty-six patients with moderately severe Alzheimer's disease (AD) and 16 normal control subjects were studied using either quantitative magnetic resonance imaging (MRI) measures of mesial temporal atrophy (15 patients with AD and 16 normal control subjects) and/or quantitative radioactive iodine 123-N-isopropyl-iodoamphetamine single-photon emission computed tomography (SPECT) assessment of regional cerebral blood flow (20 patients with AD and eight normal control subjects). Nine individuals with AD and eight normal control subjects underwent both structural and functional imaging. On MRI, patients and controls were best discriminated using left amygdala and entorhinal cortex volumes, and on SPECT they were best discriminated by relative left temporoparietal cortex blood flow. Combining these MRI and SPECT measures yielded 100% discrimination. Relative left temporoparietal SPECT regional cerebral blood flow and left superior temporal gyral MRI volume correlated best with severity of cognitive deficit in patients with AD. Mesial temporal MRI atrophy exceeded generalized cerebral shrinkage. Both SPECT and MRI regional changes accorded with areas known to be affected by AD neuropathology.

Normal caudate nucleus in obsessive-compulsive disorder assessed by quantitative neuroimaging.

BACKGROUND: Prior neuroimaging studies have not consistently demonstrated a structural or functional abnormality of the caudate nucleus in patients with obsessive-compulsive disorder (OCD). However, there is theoretical support for some associated dysfunction of the caudate nucleus. METHODS: We examined volumes of the caudate nucleus and putamen with magnetic resonance imaging in 24 patients with adult-onset OCD and 21 control subjects, group-matched on age, race, education, and sex. Patients were relatively free from tics. To evaluate function (metabolism or blood flow) of the caudate nucleus, we performed a quantitative review, including a meta-analysis, of normalized data from functional neuroimaging studies that compared patients who had OCD with normal control subjects. RESULTS: All structural basal ganglia measures failed to exhibit differences between patients with OCD and matched normal control subjects. Patients did not demonstrate evidence of ventricular enlargement. Quantitative meta-analysis of the functional neuroimaging literature did not demonstrate a consistent abnormality of the caudate nucleus. CONCLUSIONS: We did not observe evidence of a structural abnormality of the caudate nucleus in patients with OCD. Prior reports of a structural aberration of the caudate nucleus were mixed. We also did not find strong support for relative caudate metabolic or perfusion dysfunction in the literature, although increased function in the frontal cerebral cortex was identified. The heterogeneous nature of this disorder may account for inconsistencies between studies. For example, ventricular enlargement or reduced caudate volume or blood flow might be evident in patients with soft neurological signs (eg, tics), while patients in the current study were relatively free from tics. Although theories of OCD suggest a dysfunction of the caudate nucleus, the structural and functional neuroimaging literature has not consistently verified this.

Altered cortical blood flow in HIV-seropositive individuals with and without dementia: a single photon emission computed tomography study.

OBJECTIVE: To quantitatively demonstrate the pattern of cerebral perfusion abnormalities in HIV-1-infected individuals described as 'patchiness' or inhomogeneity in previous qualitative emission tomographic imaging studies. DESIGN: We aimed to create a quantitative measure of inhomogeneity in HIV-infected individuals. High-frequency variance in cortical profiles is an indication of inhomogeneity in the distribution of radiotracer in the cerebral cortex. Therefore, the study analysis was designed to enable the estimation of variance frequencies in cortical profiles. METHODS: Regional cerebral blood flow was examined in nine mildly demented and 10 cognitively normal HIV-1-seropositive individuals and eight seronegative normal controls using single photon emission computed tomography with the radiotracer [I-123]-N-isopropyl-p-iodoamphetamine. Quantitative analysis was performed using circumferential profiles of cerebral cortical perfusion. Fourier transform power spectra of the profiles were examined as an index of patchiness in tracer distribution. RESULTS: Normal controls were characterized by strong middle frequency and weak high-frequency power. Both HIV-1-infected groups showed a significant power shift from middle to high frequencies. CONCLUSIONS: Increased high-frequency variations in both HIV-1-infected groups indicates diffuse cortical perfusion changes compared with normal controls. This study suggests that there are cerebral bloodflow abnormalities in HIV-1-infected individuals both with and without clinically severe dementia.

Utility of perfusion-weighted CT imaging in acute middle cerebral artery stroke treated with intra-arterial thrombolysis: prediction of final infarct volume and clinical outcome.

BACKGROUND AND PURPOSE: The goal of this study was to evaluate the utility of perfusion-weighted CT (PWCT) in predicting final infarct volume and clinical outcome in patients with acute middle cerebral artery (MCA) stroke. METHODS: Twenty-two consecutive patients with MCA stem occlusion who underwent intra-arterial thrombolysis within 6 hours of stroke onset had noncontrast CT and CT angiography with whole-brain PWCT imaging before treatment. Infarct volumes were computed from the initial PWCT and follow-up scans; clinical outcome was measured with the modified Rankin scale. RESULTS: Initial PWCT lesion volumes correlated significantly with final infarct volume (P=0.0002) and clinical outcome (P=0.01). For the 10 patients with complete recanalization, the relationship between initial and final lesion volume was especially strong (R(2)=0.94, P<0.0001, slope of regression line=0.92). For those without complete recanalization, there was progression of lesion volume on follow-up imaging (R(2)=0.50, P=0.01, slope of regression line=1.61). All patients with either initial PWCT lesion volumes >100 mL or no recanalization had poor outcomes (Rankin scores, 4 to 6). Mean admission NIH Stroke Scale scores and mean lesion volumes in the poor outcome group were significantly different compared with the good or fair outcome (Rankin scores, 0 to 3) group (21+/-4 versus 17+/-5, P=0.05, and 106+/-79 versus 29+/-37 mL, P=0.01). Patients with initial volumes <100 mL and partial or complete recanalization all had good (Rankin scores, 0 to 2) or fair (Rankin score, 3) outcomes. CONCLUSIONS: Lesion volumes on admission PWCT images approximate final infarct volume for patients with early complete recanalization of MCA stem occlusion. For those without complete recanalization, there is subsequent enlargement of lesion volume on follow-up. Initial PWCT lesion volumes also have predictive value; volumes >100 mL are associated with a poor clinical outcome. In these highly selected patients, initial PWCT lesion volume was a stronger predictor of clinical outcome than was initial NIH Stroke Scale score.

Effects of fluoxetine on regional cerebral blood flow in obsessive-compulsive patients.

Six drug-free obsessive-compulsive patients were given single photon emission computerized tomography scans before and during treatment with fluoxetine. The treatment significantly reduced the patients' "hyperfrontality," as determined by the ratio between medial-frontal and whole cerebral cortex blood flow, and significantly lowered ratings of obsessive-compulsive and anxiety symptoms.

Elevated medial-frontal cerebral blood flow in obsessive-compulsive patients: a SPECT study.

Regional cerebral blood flow was measured with single photon emission computed tomography in 10 obsessive-compulsive patients and eight comparison subjects. The patients had a significantly higher ratio of medial-frontal to whole cortex blood flow; this was unrelated to symptom severity but was correlated negatively with anxiety. No differences in orbital-frontal blood flow were found.

Basal ganglia volumes and white matter hyperintensities in patients with bipolar disorder.

OBJECTIVE: Accumulating evidence suggests an association between abnormalities of the basal ganglia and affective disorders. The authors hypothesized that patients with bipolar disorder would demonstrate smaller basal ganglia volumes and a greater number of hyperintensities on magnetic resonance imaging than comparison subjects who were matched on age, race, sex, and education. METHOD: Volumes of the caudate, putamen, and globus pallidus were measured in 30 patients with bipolar disorder and 30 matched normal comparison subjects. The presence, number, and location of hyperintensities were also assessed. RESULTS: Male patients with bipolar disorder demonstrated larger caudate volumes than male comparison subjects. Older, but not younger, patients with bipolar disorder demonstrated more hyperintensities than comparison subjects, primarily in frontal lobe white matter. CONCLUSIONS: These results are not consistent with those of previous studies showing reduced basal ganglia volume in subjects with affective disorders, but they are consistent with previous findings of increased white matter hyperintensities, especially in older patients with bipolar disorder. Considered together with results from other studies, the findings suggest that the nature of basal ganglia/subcortical white matter involvement may differ according to the type of depression (unipolar versus bipolar) and the age and sex of the patient.

Dynamic susceptibility contrast MRI of regional cerebral blood volume in Alzheimer's disease.

OBJECTIVE: The purpose of this study was to investigate the potential effectiveness of dynamic susceptibility contrast magnetic resonance imaging (MRI) to discriminate elderly patients with Alzheimer's disease from normal matched comparison subjects. METHOD: Images of regional cerebral blood volume (CBV) were generated from echo-planar MRI with the dynamic susceptibility contrast method in 13 Alzheimer's disease patients and 13 comparison subjects group-matched on age and gender. RESULTS: Temporoparietal cerebral blood volume, expressed as a percentage of the cerebellum value, was reduced 17% bilaterally in the patients with Alzheimer's disease. Blood volume in sensorimotor regions was reduced only 8.5% in the patients. Discriminant function analysis based on left and right temporoparietal measures correctly classified 88.5% of the subjects as patients or comparison subjects. Temporoparietal CBV was reduced even in mildly affected Alzheimer's disease patients (Mini-Mental State scores > 24). CONCLUSIONS: Dynamic susceptibility contrast MRI of regional CBV is promising as a nonradioactive, potentially lower-cost alternative to other functional neuroimaging methods for evaluating Alzheimer's disease.

Correlation of acute cocaine-induced changes in local cerebral blood flow with subjective effects.

The authors administered 48 mg of intravenous cocaine or placebo to eight abstinent cocaine users in a double-blind, crossover design and examined blood flow using single photon emission computed tomography. Cocaine produced significant decreases in frontal cortical and basal ganglia blood flow; these latter correlated negatively with increases in self-ratings of "rush" and "high." The authors conclude that these local effects are compatible with dopaminergic system involvement.

Decreased regional cortical gray matter volume in schizophrenia.

OBJECTIVE: The authors hypothesized that cortical gray matter volume reduction in schizophrenia is greatest in the heteromodal association cortex. This area comprises a highly integrated, reciprocally interconnected system that coordinates higher order cortical functions. METHOD: Total brain and regional gray matter volumes were calculated in 46 schizophrenic patients and 60 age and sex-matched comparison subjects by using magnetic resonance images. Disease specificity was examined by assessing 27 patients with bipolar disorder. Approximations to the dorsolateral prefrontal cortex, inferior parietal lobule, and superior temporal gyrus were selected as regions of interest for the heteromodal association cortex. Occipital and sensorimotor areas were used as comparison regions to test the hypothesis for regional specificity. RESULTS: Gray matter volume was reduced in schizophrenic patients in index regions even after covariance for overall brain volume, sex, and age. Bipolar disorder patients did not exhibit heteromodal gray matter reduction. Comparison regions did not differ among the three groups. Global gray matter volume was not different among groups after covariance for global brain volume. Comprehensive individual region post hoc analysis found no additional gray matter differences. CONCLUSIONS: These findings support the theory of disproportionate reduction of gray matter volume in the heteromodal association cortex specific to schizophrenia.

Magnetic resonance imaging measurement of gray matter volume reductions in HIV dementia.

OBJECTIVE: The authors recently reported smaller basal ganglia volumes for patients with HIV-associated dementia than for HIV-infected patients without dementia and a seronegative comparison group. The purpose of the current study was to determine whether HIV dementia is associated with volume reductions in other brain regions. METHOD: The authors measured volumes of CSF and gray and white tissue on cranial magnetic resonance images from homosexual men who were 1) infected with HIV with HIV-associated dementia complex, 2) infected with HIV without dementia, and 3) HIV seronegative. RESULTS: Results suggest that loss of white matter occurs with HIV infection and is more severe in HIV-positive patients with dementia than in those without dementia. There was some generalized volume reduction in gray matter in HIV-positive demented patients, although group differences did not reach significance when adjusted for age. Volume of posterior cortex, however, was significantly smaller among HIV-positive patients with dementia than in either remaining group. There were no significant differences between HIV-positive nondemented patients and HIV-negative subjects in these regions. CONCLUSIONS: In conjunction with findings from previous research, the authors conclude that HIV dementia is associated with specific gray matter volume reduction in basal ganglia and posterior cortex, as well as with generalized volume reduction of white matter.

Basal ganglia volume and proximity to onset in presymptomatic Huntington disease.

OBJECTIVE: To determine in presymptomatic individuals who carry the gene mutation for Huntington disease whether proximity to estimated age at onset is associated with volume of basal ganglia, as measured on magnetic resonance imaging scans. DESIGN: Survey study involving correlations between basal ganglia volume, measured blind to subject status, and estimation of subjects' age at onset. SETTING: Huntington's Disease Presymptomatic Testing Program at The Johns Hopkins University School of Medicine, Baltimore, Md. PATIENTS AND OTHER PARTICIPANTS: Subjects included 47 individuals at risk for Huntington disease (ie, off-spring of patients with Huntington disease). Twenty subjects tested positive for the gene mutation but were not symptomatic. Twenty-seven subjects tested negative. MAIN OUTCOME MEASURES: Estimated age at onset was calculated for each of 20 gene-positive individuals using an empirically derived formula based on the subject's trinucleotide repeat length and parental age at onset. Each subject's age at the time of the magnetic resonance imaging scan was subtracted from his or her estimated age at onset, yielding estimated years to onset. Volumes of caudate, putamen, and globus pallidus were measured on magnetic resonance imaging scans. RESULTS: After controlling for the subject's age at the time of the scan, significant correlations were found between volumes of all basal ganglia structures and years to onset. Gene-positive subjects who were far from onset had smaller basal ganglia volumes than gene-negative subjects for all structures except globus pallidus. Gene-positive subjects who were close to onset had smaller volumes than gene-negative subjects for all basal ganglia structures and had smaller volumes than subjects far from onset for all structures except caudate. CONCLUSIONS: The results suggest that atrophy of the basal ganglia occurs gradually, beginning years before symptom onset.

Single photon emission computed tomographic blood flow and magnetic resonance volume imaging of basal ganglia in Huntington's disease.

OBJECTIVE: To examine basal ganglia dysfunction and atrophy in patients with mild to moderate Huntington's disease, with correlation of imaging measures with clinical and neuropsychological measures. DESIGN: Survey study in patients with Huntington's disease and matched controls, with imaging measures being evaluated by investigators unaware of the diagnosis. SETTING: Baltimore Huntington's Disease Project, The Johns Hopkins Hospital, Baltimore, Md. PATIENTS AND OTHER PARTICIPANTS: Subjects included 10 patients with mild to moderate Huntington's disease and nine healthy age-matched control subjects. MAIN OUTCOME MEASURES: Imaging measures included single photon emission computed tomographic regional cerebral blood flow in caudate, putamen, and thalamus, and magnetic resonance imaging measures of caudate and putamen volumes and bicaudate ratios. Patients underwent neurologic and mental status examinations and neuropsychological tests. RESULTS: The measure with the greatest difference between patients and control subjects was mean putamen volume, reduced 54.3% in patients, with no overlap between groups (P<.001). Of the cerebral blood flow measures, caudate showed the greatest difference (21.5% decrease; P<.001). Quantitative neurologic indexes of disease severity correlated with both putamen measures (P<.03), while Mini-Mental State Examination scores correlated with caudate volume (P<.02). Bicaudate ratio correlated with both clinical measures and was the best index of neurologic deterioration (r=.95; P<.001), while global atrophy (measured by cerebrospinal fluid percentage) was the best correlate of several neuropsychological tests, such as the Trail Making Test (r=93; P<.001). CONCLUSIONS: Volumetric measurement of putamen best discriminated patients with Huntington's disease from healthy subjects. Measures of caudate atrophy or single photon emission computed tomographic measures performed less well. Neurologic decline correlated best with subcortical atrophy measured by the bicaudate ratio, but neuropsychological performance best corresponded to cerebrospinal fluid percentage, a measure of global atrophy.

Reduced basal ganglia volume associated with the gene for Huntington's disease in asymptomatic at-risk persons.

Previous investigations using linear CT measures found no evidence of caudate atrophy in asymptomatic persons who have the DNA haplotype linked to the Huntington's disease (HD) gene. We measured volumes of the caudate, putamen, and globus pallidus on MRIs of 10 gene marker-positive and 18 gene marker-negative asymptomatic at-risk persons. The volumes of all basal ganglia structures were significantly reduced in the marker-positive group, even after controlling for age, total brain volume, and minor neurologic signs. Discriminant function analysis using basal ganglia volumes and age as predictor variables correctly identified genetic status in 86% of subjects. These results indicate that basal ganglia volume is reduced before individuals become symptomatic with HD.

Reduced basal ganglia volume in HIV-1-associated dementia: results from quantitative neuroimaging.

Although brain atrophy is a common neuroradiologic and pathologic finding in patients with HIV-1 infection, especially those with HIV-1-associated dementia complex, it is not clear whether specific regions of the brain are differentially responsible for tissue loss. In this study, we measured volumes of basal ganglia structures on MRIs for three groups: HIV-1-infected homosexual men with HIV-1-associated dementia complex (HIV+ demented), HIV-1-infected homosexual men without HIV dementia (HIV+ nondemented), and noninfected homosexual men. All groups were comparable on age and years of education, and the HIV+ groups were comparable on level of immunosuppression. Total brain volume was smaller in the HIV+ nondemented patients in comparison with HIV- control subjects; the HIV+ demented patients demonstrated even smaller brain volumes than the HIV+ nondemented patients. Smaller basal ganglia volumes, after corrections for intracranial volume, distinguished HIV+ demented patients from the other two groups; there were no differences between the HIV+ nondemented and HIV- groups on basal ganglia volumes. This study suggests that HIV infection causes generalized brain atrophy, but that the clinical features of HIV dementia develop with selective basal ganglia atrophy, consistent with the characterization of HIV dementia as subcortical.