Biomedical subjects

Jitendra Sharma

Publications and source records attributed to Jitendra Sharma.

14 recordsLinked to original sources

PubMed2021

AAV capsid variants with brain-wide transgene expression and decreased liver targeting after intravenous delivery in mouse and marmoset.

Genetic intervention is increasingly being explored as a therapeutic option for debilitating disorders of the central nervous system. The safety and efficacy of gene therapies rely upon expressing a transgene in affected cells while minimizing off-target expression. Here we show organ-specific targeting of adeno-associated virus (AAV) capsids after intravenous delivery, which we achieved by employing a Cre-transgenic-based screening platform and sequential engineering of AAV-PHP.eB between the surface-exposed AA452 and AA460 of VP3. From this selection, we identified capsid variants that were enriched in the brain and targeted away from the liver in C57BL/6J mice. This tropism extends to marmoset (Callithrix jacchus), enabling robust, non-invasive gene delivery to the marmoset brain after intravenous administration. Notably, the capsids identified result in distinct transgene expression profiles within the brain, with one exhibiting high specificity to neurons. The ability to cross the blood-brain barrier with neuronal specificity in rodents and non-human primates enables new avenues for basic research and therapeutic possibilities unattainable with naturally occurring serotypes.

Administration, Intravenous↗

PubMed2006

Study of mitoxantrone for the treatment of recurrent neuromyelitis optica (Devic disease).

BACKGROUND: Neuromyelitis optica is a severe demyelinating disease that selectively involves the optic nerves and the spinal cord but usually spares the brain. It is considered to have a B-cell-induced pathogenesis. Mitoxantrone hydrochloride, a synthetic anthracenedione approved for worsening relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis, has been shown to primarily suppress the humoral response. OBJECTIVE: To evaluate the benefit of mitoxantrone treatment in patients with relapsing neuromyelitis optica. DESIGN: Prospective 2-year study. SETTING: Academic multiple sclerosis center. PATIENTS: Five patients (3 women and 2 men) with an age range of 20 to 51 years and an Expanded Disability Status Scale score of 2.5 to 6.5 (mean +/- SD, 4.40 +/- 1.88). INTERVENTIONS: Monthly intravenous infusions of mitoxantrone hydrochloride, 12 mg/m2, for 6 months followed by 3 additional treatments every 3 months. MAIN OUTCOME MEASURES: Expanded Disability Status Scale score measured every 3 months and during relapses; findings on orbital, brain, and spinal cord magnetic resonance images performed at baseline and at 3, 6, 12, 18, and 24 months; and visual evoked potentials and results of ophthalmologic evaluations performed at baseline and annually. RESULTS: During the 2 years of treatment, 2 patients each had a relapse once within the initial 5 months of treatment (1 severe and 1 moderate). Improvement was seen clinically and on magnetic resonance images in 4 patients. Patients generally tolerated the treatment well, although 1 patient had a reversible decrease in cardiac ejection fraction. CONCLUSION: Our results suggest a beneficial effect of mitoxantrone treatment for relapsing neuromyelitis optica.

Adult↗

PubMed2006

A magnetization transfer MRI study of deep gray matter involvement in multiple sclerosis.

BACKGROUND/PURPOSE: Gray matter involvement in multiple sclerosis (MS) is of growing interest with respect to disease pathogenesis. Magnetization transfer imaging (MTI), an advanced MRI technique, is sensitive to disease in normal appearing white matter (NAWM) in patients with MS. DESIGN/METHODS: We tested if MTI detected subcortical (deep) gray matter abnormalities in patients with MS (n= 60) vs. age-matched normal controls (NL, n= 20). Magnetization transfer ratio (MTR) maps were produced from axial proton density, conventional spin-echo, 5 mm gapless slices covering the whole brain. Region-of-interest-derived MTR histograms for the caudate, putamen, globus pallidus, thalamus, and NAWM were obtained. Whole brain MTR was also measured. RESULTS: Mean whole brain MTR and the peak position of the NAWM MTR histogram were lower in patients with MS than NL (P < .001) and mean whole brain MTR was lower in secondary progressive (SP, n= 10) than relapsing-remitting (RR, n= 50, P < .001) patients. However, none of the subcortical gray matter nuclei showed MTR differences in MS vs. NL, RR vs. SP, or SP vs. NL. CONCLUSIONS: The MTI technique used in this cohort was relatively insensitive to disease in the deep gray matter nuclei despite showing sensitivity for whole brain disease in MS. It remains to be determined if other MRI techniques are more sensitive than MTI for detecting pathology in these areas.

Adult↗

PubMed2005

The relationship between whole brain volume and disability in multiple sclerosis: a comparison of normalized gray vs. white matter with misclassification correction.

We used SPM99 to obtain normalized whole brain volumes of gray matter, white matter, and total parenchyma in patients with multiple sclerosis (MS) (n = 41) and age-/sex-matched normal controls (n = 18). As SPM99's automated gray/white matter volumes were significantly influenced by tissue compartment misclassification due to the effect of MS-related brain lesions, we corrected these automated volumes for misclassification before performing our primary analyses. For MS patients (disease duration = 9.5 +/- 6.3 years; EDSS score = 3.2 +/- 1.8; 25FTW = 6.6 +/- 3.1 s), we also measured lesion load (total T1 hypointense [T1LV] and FLAIR hyperintense lesion volume [FLLV]), central brain atrophy (third ventricular width [TVW] and bicaudate ratio [BCR]), and clinical status (Expanded Disability Status Scale [EDSS] and 25-ft timed walk [25FTW]). Patients with MS had lower gray matter (707 +/- 33 cm(3) [-3.9%], P = 0.003) and total parenchymal volume (1088 +/- 48 cm(3) [-3.8%], P = 0.003), but only a trend for lower white matter volume (381 +/- 25 cm(3) [-3.7%], P = 0.052) relative to normal controls (gray matter: 736 +/- 33 cm(3); total parenchyma: 1132 +/- 49 cm(3); white matter: 396 +/- 26 cm(3)). Gray matter atrophy was related to clinical status (EDSS, 25FTW, and disease duration), lesion load (T1LV and FLLV), and central brain atrophy (TVW and BCR), whereas white matter atrophy was related to only central brain atrophy. These findings suggest that gray matter loss is related to other aspects of brain pathology and has more clinical relevance than white matter atrophy in MS.

Adult↗

PubMed2005

Bottom-up and top-down dynamics in visual cortex.

A key emergent property of the primary visual cortex (V1) is the orientation selectivity of its neurons. Recent experiments demonstrate remarkable bottom-up and top-down plasticity in orientation networks of the adult cortex. The basis for such dynamics is the mechanism by which orientation tuning is created and maintained, by integration of thalamocortical and intracortical inputs. Intracellular measurements of excitatory and inhibitory synaptic conductances reveal that excitation and inhibition balance each other at all locations in the cortex. This balance is particularly critical at pinwheel centers of the orientation map, where neurons receive intracortical input from a wide diversity of local orientations. The orientation tuning of neurons in adult V1 changes systematically after short-term exposure to one stimulus orientation. Such reversible physiological shifts in tuning parallel the orientation tilt aftereffect observed psychophysically. Neurons at or near pinwheel centers show pronounced changes in orientation preference after adaptation with an oriented stimulus, while neurons in iso-orientation domains show minimal changes. Neurons in V1 of alert, behaving monkeys also exhibit short-term orientation plasticity after very brief adaptation with an oriented stimulus, on the time scale of visual fixation. Adaptation with stimuli that are orthogonal to a neuron's preferred orientation does not alter the preferred orientation but sharpens orientation tuning. Thus, successive fixation on dissimilar image patches, as happens during natural vision, combined with mechanisms of rapid cortical plasticity, actually improves orientation discrimination. Finally, natural vision involves judgements about where to look next, based on an internal model of the visual world. Experiments in behaving monkeys in which information about future stimulus locations can be acquired in one set of trials but not in another demonstrate that V1 neurons signal the acquisition of internal representations. Such Bayesian updating of responses based on statistical learning is fundamental for higher level vision, for deriving inferences about the structure of the visual world, and for the regulation of eye movements.

Adaptation, Psychological↗

PubMed2005

Reproducibility and accuracy of quantitative magnetic resonance imaging techniques of whole-brain atrophy measurement in multiple sclerosis.

BACKGROUND AND PURPOSE: Whole-brain atrophy is of growing interest as an outcome measure in multiple sclerosis (MS) clinical trials. The authors compared the reproducibility and accuracy of 3 quantitative techniques of measurement in patients with MS. METHODS: Thirty-four patients with relapsing-remitting MS (median Expanded Disability Status Scale disability score = 1.5) were studied. Brain parenchymal fraction (BPF) was quantified on spin-echo 2-dimensional T1-weighted axial 5-mm slice thickness sequences by semiautomated (Buffalo, Trieste) or automated (SIENAX) algorithms. RESULTS: Mean +/- SD BPFs were 0.830 +/- 0.04 with Buffalo, 0.824 +/- 0.04 with Trieste, and 0.826 +/- 0.04 with SIENAX methods (P = nonsignificant [NS]). Mean BPF scan-rescan coefficient of variation (COV) was 0.41% for Buffalo, 0.44% for Trieste, and 0.32% for SIENAX (P =NS).The semiautomated methods showed higher accuracy than the automated method in brain extraction (masking; P = .001). The errors of skull stripping included scalp, skull bone marrow, inferior parts of temporal lobes anterior to the brain stem, face structures, sagittal sinuses, eyes, and optic nerves. Buffalo (r = -0.37, P = .034) and Trieste (r = -.36, P = .039) BPFs showed stronger cor relation with disability than SIENAX (r = -0.16, P = .219). These differences were statistically significant (P = .0031 for Buffalo and P = .0037 for Trieste BPF). CONCLUSIONS: This study showed a high reproducibility of both semiautomated and automated methods for brain atrophy measurement. The semiautomated methods showed higher accuracy than the automated SIENAX method did in the evaluation of brain extraction, especially in infratentorial and cortical regions, where operator interaction during the masking processes was essential.

Adult↗

PubMed2005

Regional lobar atrophy predicts memory impairment in multiple sclerosis.

BACKGROUND AND PURPOSE: In recent studies, measures of whole brain atrophy were strongly correlated with neuropsychological testing, explaining more variance than measures of lesion burden in patients with multiple sclerosis. The relationship between regional lobar atrophy and cognitive impairment is yet to be examined. We endeavored to assess the clinical significance of regional lobar atrophy in multiple sclerosis. METHODS: In a cross-sectional study, we evaluated 31 patients with multiple sclerosis with brain MR imaging and neuropsychological testing. Impairment was determined by comparison with demographically matched healthy controls. MR imaging generated measures of lesion burden (fluid-attenuated inversion recovery hyperintense volume), general atrophy (brain parenchymal fraction), central atrophy (lateral ventricle volume), and lobar atrophy (regional brain parenchymal fraction of frontal, temporal, parietal, and occipital lobes in each hemisphere). Neuropsychological testing emphasized measures of processing speed and memory, because these are commonly affected in multiple sclerosis. RESULTS: Patients with multiple sclerosis showed significant atrophy and impairment on all neuropsychological tests. Regional atrophy accounted for the most variance in all regression models predicting memory performance. Left temporal atrophy was the primary predictor of auditory/verbal memory (partial r's = 0.55-0.61), and both left and right temporal atrophy predicted visual/spatial memory performance (partial r's = 0.51-0.67). Models predicting learning consistency retained frontal lobe atrophy measures (partial r's = 0.44-0.68). Central and general atrophy measures were the primary predictors in modeling processing speed (partial r's = 0.42-0.64). CONCLUSION: Regional atrophy accounts for more variance than lesion burden, whole brain atrophy, or lateral ventricle volume in predicting multiple sclerosis-associated memory dysfunction.

Adult↗

PubMed2004

Prediction of neuropsychological impairment in multiple sclerosis: comparison of conventional magnetic resonance imaging measures of atrophy and lesion burden.

BACKGROUND: Cognition and magnetic resonance imaging correlations are well established in patients with multiple sclerosis (MS), but it is unclear whether lesion burden or atrophy accounts for most of the predictive variance. These indices have been directly compared in only a few studies. No such study included measurement of the third ventricle, which was strongly predictive of neuropsychological competence in the early literature. Furthermore, few studies accounted for the influence of age, premorbid intelligence, or depression. OBJECTIVE: To determine if conventional measures of lesion burden or atrophy predict cognitive dysfunction in MS while accounting for age, premorbid intelligence, and depression. METHODS: We studied 37 patients with MS and 27 controls matched according to demographic variables. Correlations between neuropsychological tests and the following magnetic resonance imaging indices were considered: T1 hypointense lesion volume, fluid-attenuated inversion recovery hyperintense lesion volume, third ventricle width, bicaudate ratio, and brain parenchymal fraction. Regression models predicting neuropsychological performance controlled for the effects of age, premorbid intelligence, and depression. We included only those tests discriminating patients with MS from controls. RESULTS: In each regression model, third ventricle width was the sole magnetic resonance imaging measure retained. When this variable was removed from consideration, brain parenchymal fraction was retained in all analyses. CONCLUSIONS: Brain atrophy accounts for more variance than lesion burden in predicting cognitive impairment in MS, and central atrophy in particular is strongly associated with neuropsychological morbidity. This finding may be explained in part by atrophy of the thalamus, a deep gray matter structure that mediates cognitive function via cortical and subcortical pathways. Enthusiasm for the clinical utility of third ventricle width is tempered by modest intraobserver and interobserver reliability.

Adult↗

PubMed2004

Central venous catheter-related blood stream infections: incidence, risk factors, outcome, and associated pathogens.

OBJECTIVE: To determine the incidence, risk factors, outcome, and pathogens of central venous catheter-related bloodstream infections (CVC-BSIs). DESIGN: Prospective study. SETTING: Escorts Heart Institute and Research Centre, New Delhi, India. PARTICIPANTS: One thousand three hundred fourteen consecutive patients undergoing cardiac operations who were admitted to the intensive care unit with CVC. INTERVENTIONS: All patients were assigned into CVC-BSI (n = 35) and non-CVC-BSI (n = 1,279) groups. MEASUREMENT AND MAIN RESULTS: Of the 1,314 patients in the study, 35 (2.6%) had CVC-BSI. On univariate analysis, significant risk factors were use of multilumen catheters, coexistent infections, intra-aortic balloon counterpulsation (IABC), total ventilation hours, emergency surgery, acute physiology, age, chronic health evaluation score (APACHE II), and steroids. On multivariate analysis, duration of catheterization (24.5 +/- 10.9 v 6.1 +/- 3.2; p < 0.001), coexistent infections (57.11% v 2.61%; p < 0.001), IABC (77.1% v 4.1%; p = 0.005), and temperature (38.2 +/- 0.6 v 37.4 +/- 0.3; p < 0.001) were independent predictors of CVC-BSI. Pathogens isolated were Escherichia coli (47%), Acinetobacter species (11.7%), Enterobacter species (5.8%), Proteus species (5.8%), methicillin-resistant Staphylococcus species (11.7%), coagulase-negative Staphylococcus species (5.8%), and Candida (11.7%). The mortality rate in CVC-BSI was 22.9% as compared with 0.2% in non-CVC-BSI cases (p < 0.001). CONCLUSION: By univariate analysis, the risk factors for CVC-BSI were use of multilumen catheters, duration of catheterization, total ventilation hours, IABC, emergency surgery, APACHE II score, coexistent infections, and steroids. On multivariate analysis, duration of catheterization, IABC, coexistent infections, and temperature were independent predictors of CVC-BSI. The mortality was increased with CVC-BSI.

Bacteremia↗

PubMed2003

V1 neurons signal acquisition of an internal representation of stimulus location.

A fundamental aspect of visuomotor behavior is deciding where to look or move next. Under certain conditions, the brain constructs an internal representation of stimulus location on the basis of previous knowledge and uses it to move the eyes or to make other movements. Neuronal responses in primary visual cortex were modulated when such an internal representation was acquired: Responses to a stimulus were affected progressively by sequential presentation of the stimulus at one location but not when the location was varied randomly. Responses of individual neurons were spatially tuned for gaze direction and tracked the Bayesian probability of stimulus appearance. We propose that the representation arises in a distributed cortical network and is associated with systematic changes in response selectivity and dynamics at the earliest stages of cortical visual processing.

Analysis of Variance↗

PubMed2003

A semiautomated measure of whole-brain atrophy in multiple sclerosis.

Brain atrophy is a proposed MRI marker of irreversible pathologic damage in multiple sclerosis (MS). The brain parenchymal fraction (BPF) is the ratio of brain parenchymal volume to the total volume within the surface contour. We developed a semiautomated measure of BPF using commercially available edge-finding and thresholding software (30-min analysis time per patient). We measured BPF in 78 patients with MS and 17 healthy controls. BPF was lower in a cohort of patients with MS (n=50) (0.843+/-0.042, range 0.743-0.906) age-matched to controls (0.877+/-0.020, range 0.835-0.901) (p<0.001). BPF correlated inversely with third ventricular width (r=-0.785, p<0.001), and total T1 hypointense lesion volume (r=-0.347, p=0.011), but not with total T2 hyperintense lesion volume (r=-0.213, p=0.13). BPF correlated negatively with expanded disability status scale (EDSS) score (r=-0.391, p=0.0006) and disease duration (r=-0.281, p=0.01). Stepwise regression compared the relative abilities of MRI variables to predict clinical data. By regression of age, BPF, third ventricular width, T2 lesions, and T1 lesions, BPF was the best predictor of disability score (R(2)=0.204, p<0.001). Third ventricular width was the best predictor of disease duration (R(2)=0.316, p<0.001). None of the MRI variables differed between relapsing-remitting (RR) (n=60) and secondary progressive (SP) (n=18) disease course (p>0.05). The intrarater, interrater, and scan-rescan BPF variability (COV) was 0.31%, 0.34%, and 0.41% and the accuracy against a phantom was 99.1%. We conclude that whole-brain atrophy in MS can be reliably and readily quantified by a semiautomated approach. Longitudinal studies are warranted to determine if this method provides a sensitive biologic marker of the MS disease process.

Adult↗

PubMed2003

Thalamic involvement in multiple sclerosis: a diffusion-weighted magnetic resonance imaging study.

BACKGROUND AND PURPOSE: Injury to deep gray matter structures in multiple sclerosis (MS) has been suggested by recent neuro-imaging and neuropathology studies. Diffusion-weighted magnetic resonance imaging (MRI) can assess tissue damage with greater sensitivity than conventional MRI. The authors' objective was to assess thalamic gray matter damage by diffusion-weighted imaging in MS patients. METHODS: This was a retrospective study performed at a tertiary care, university-affiliated comprehensive MS center of 82 MS patients and 43 controls. The main outcome measures were thalamic apparent diffusion coefficients (ADCs), whole-brain atrophy (brain parenchymal fraction), fluid-attenuated inversion recovery (FLAIR) hypertense lesion volume, and clinical course. RESULTS: ADCs in the left thalamus were higher in MS patients (0.741 +/- 0.044 x 10(-3) mm2/s) than controls (0.723 +/- 0.036 x 10(-3) mm2/s) (P = .027) and higher in secondary progressive MS patients (0.761 +/- 0.044 x 10(-3) mm2/s) than relapsing-remitting MS patients (0.735 +/- 0.032 x 10(-3) mm2/s) (P = .029). ADCs in the right thalamus were higher in secondary progressive MS patients (0.784 +/- 0.069 x 10(-3) mm2/s) than controls (0.757 +/- 0.038 x 10(-3) mm2/s) (P = .033). In the MS group, left thalamus ADCs correlated negatively with brain parenchymal fraction (r = -0.30, P = .008), total left hemispheric FLAIR lesion volume correlated with ADCs in the left (r = 0.35, P = .001) and right (r = 0.39, P < .001) thalami, and total right hemispheric FLAIR lesion volume correlated with ADCs in the left (r = 0.31, P = .006) and right thalami (r = 0.22, P = .048). CONCLUSION: MS patients have increased water diffusion in the thalamus that is partly associated with clinical course, lesion load, and whole-brain atrophy. Both indirect and direct mechanisms of gray matter injury may play a role in the pathophysiology of MS.

Adult↗

PubMed2002

Dynamics of neuronal sensitivity in visual cortex and local feature discrimination.

A striking aspect of natural scenes is that image features such as line orientation are strongly correlated at neighboring spatial locations but not at distant locations. Thus, during the viewing of a scene, eye movements are often accompanied by a change in the orientation structure of the image. How does this behavior influence the discrimination of local features and their encoding by visual cortical neurons? Here we examined the perceived changes in orientation induced by brief exposure to oriented image patterns in monkeys and humans, and then used reverse correlation to investigate dynamic changes in neuronal sensitivity in the primary visual cortex (V1) of behaving monkeys. Whereas brief adaptation to an oriented grating impaired identification of nearby orientations by broadening orientation selectivity and changing the preferred orientation of individual V1 neurons, it actually enhanced the identification of orthogonal orientations by sharpening neuronal selectivity. Hence, successive exposure to image patches of dissimilar spatial structure enhances both the ability to discriminate local features and the encoding of these features by V1 neurons.

Action Potentials↗

PubMedDate not supplied

Whole-brain atrophy in multiple sclerosis measured by automated versus semiautomated MR imaging segmentation.

BACKGROUND AND PURPOSE: Semiautomated and automated methods are used to measure whole-brain atrophy in multiple sclerosis (MS), but their comparative reliability, sensitivity, and validity are unknown. METHODS: Brain parenchymal fraction (BPF) was measured in patients with MS (n = 52) and healthy control subjects (n = 17) by four methods: semiautomated or automated segmentation and 2D or 3D pulse sequences. Linear measures of atrophy, whole-brain lesion volumes, and clinical data were used to explore validity. RESULTS: The 2D automated method yielded unreliable segmentation and was discarded. The three other BPF methods produced data that were highly intercorrelated and indistinguishable by analysis of variance. In the MS group, semiautomated (2D: 0.84 +/- 0.04, P <.001; 3D: 0.84 +/- 0.05, P =.04) and automated 3D (0.83 +/- 0.05, P =.002) BPFs were lower than controls (semiautomated 2D: 0.88 +/- 0.02; 3D: 0.88 +/- 0.03; automated 3D: 0.88 +/- 0.03). In the MS group, the semiautomated (r = -.79 to -.82) and automated 3D (r = -.81) BPFs inversely correlated with third ventricular width and showed similarly robust correlations with the bicaudate ratio (all r = -.74). The semiautomated and automated BPFs showed similar, moderate correlations with T1 hypointense and FLAIR hyperintense lesion volume, physical disability (Expanded Disability Status Scale) score, and disease duration and similar differences between secondary progressive and relapsing-remitting patients. The intraobserver, interobserver, and test-retest reliability was somewhat higher for the automated than for the semiautomated methods. CONCLUSION: These automated and semiautomated measures of whole-brain atrophy provided similar and nearly interchangeable data regarding MS. They discriminated MS from healthy individuals and showed similar relationships to established disease variables.

Adult↗