Shahriar Salamat

Mitochondrial DNA–Deletion Mutations Accumulate Intracellularly to Detrimental Levels in Aged Human Skeletal Muscle Fibers

Skeletal muscle-mass loss with age has severe health consequences, yet the molecular basis of the loss remains obscure. Although mitochondrial DNA (mtDNA)-deletion mutations have been shown to accumulate with age, for these aberrant genomes to be physiologically relevant, they must accumulate to high levels intracellularly and be present in a significant number of cells. We examined mtDNA-deletion mutations in vastus lateralis (VL) muscle of human subjects aged 49-93 years, using both histologic and polymerase-chain-reaction (PCR) analyses, to determine the physiological and genomic integrity of mitochondria in aging human muscle. The number of VL muscle fibers exhibiting mitochondrial electron-transport-system (ETS) abnormalities increased from an estimated 6% at age 49 years to 31% at age 92 years. We analyzed the mitochondrial genotype of 48 single ETS-abnormal, cytochrome c oxidase-negative/succinate dehydrogenase-hyperreactive (COX-/SDH++) fibers from normal aging human subjects and identified mtDNA-deletion mutations in all abnormal fibers. Deletion mutations were clonal within a fiber and concomitant to the COX-/SDH++ region. Quantitative PCR analysis of wild-type and deletion-containing mtDNA genomes within ETS-abnormal regions of single fibers demonstrated that these deletion mutations accumulate to detrimental levels (>90% of the total mtDNA).

Anterior Cingulate Metabolism Correlates with Stroop Errors in Paranoid Schizophrenia Patients

Using [O-15]-H2O PET Carter et al. (1997) reported that medicated patients with schizophrenia performing computerized single trial Stroop (1935) showed a reduction in the anterior cingulate activation response to the more attention demanding, incongruent Stroop condition. In that study, both patients and controls also showed a direct correlation between anterior cingulate activation and errors committed during incongruent trials of the task. In this study we follow up with an examination of paranoid schizophrenia outpatients and controls with very high resolution positron emission tomography (PET) and the longer half-life tracer [F-18]-fluorinated deoxyglucose (FDG) (Valk et al. 1990). All subjects (10 controls and 9 paranoid schizophrenia patients) were studied with FDG-PET while performing a computerized trial-by-trial version of the Stroop task during the uptake phase of the tracer (Carter et al. 1992). Results: As in previous studies using the single trial Stroop, patients were able to perform the task but made more color-naming errors during incongruent trials than controls. The patients in the present study showed a trend towards increased metabolic activity in the right anterior cingulate cortex. In the patient group, but not in controls, the anterior cingulate glucose metabolic rate correlated positively with the total incongruent trial errors. Conclusion: These results are consistent with the hypothesis that the anterior cingulate plays a performance-monitoring role during human cognition. This study does not rule out a reduction in error sensitivity in this region of the brain in schizophrenia, as other studies have suggested, however the data show that in unmedicated patients with the paranoid subtype this function is preserved to some extent.

Atypical meningioma: Randomized trials are required to resolve contradictory retrospective results regarding the role of adjuvant radiotherapy

BACKGROUND The role of postoperative radiation (RT) in atypical meningioma remains controversial. MATERIALS AND METHODS We report a retrospective review of outcomes and prognostic factor analysis in 158 patients treated between 2000 and 2010, and extensively review the literature. RESULTS Following resection, 23 patients received immediate RT, whereas 135 did not. Median progression-free survival (PFS) with and without RT was 59 (range 43-86) and 88 (range 64-123) months. For Simpson grade (G) 1-3 resection, with and without RT, median PFS was 48 (2-80) versus 96 (88-123) months and for Simpson G4, it was 59 (6-86) versus 47 (15-104) months (P = 0.4). The rate of 5-year overall survival (OS) with and without RT was 89% and 83%, respectively. On univariate analysis, Simpson G4 (HR 3.2, P = 0.0006) and brain invasion (HR 2.2, P = 0.03) were significantly associated with progression, whereas age >60 years (HR 9.7, P = 0.002), mitoses >5 per 10 high-power field (0.2, P = 0.0056), and Simpson G4 (HR 2.4, P = 0.07) were associated with higher risk of death. We summarized 22 additional reports, which provide very divergent results regarding the benefit of RT. CONCLUSIONS In our series, adjuvant RT is surprisingly associated with worse PFS and OS, and this is more likely to be due to selection bias of referring tumors with more aggressive characteristics such as elevated Ki-67 and brain invasion for adjuvant RT, rather than a direct causal effect of adjuvant RT. Although there is a trend toward improved PFS with adjuvant RT after subtotal resection, no improvement was noted in OS. Multivariate analysis did not yield statistical significance for any of the factors including Simpson grades of resection, adjuvant RT, or six pathological defining features. The relatively divergent results in the literature are most likely explained by patient selection variability; therefore, randomized trials to adequately address this question are clearly necessary.

A case series of primary central nervous system posttransplantation lymphoproliferative disorder: imaging and clinical characteristics.

BACKGROUND Primary central nervous system posttransplantation lymphoproliferative disorder (PCNS-PTLD) is a rare complication after solid organ transplantation (SOT). With increasing rates of SOT, PCNS-PTLD incidence is increasing. OBJECTIVE To describe the characteristics of PCNS-PTLD patients requiring neurosurgical intervention. METHODS From 2000 to 2011, 10 patients with prior SOT underwent biopsy for evaluation of brain lesions and were diagnosed with PCNS-PTLD. Data collected included imaging characteristics, pathology, treatments administered, and survival outcomes. RESULTS All patients had kidney transplantation, and 3 had concurrent pancreas transplantation. Median age at diagnosis was 49 years, with a median of 4.5 years from SOT to diagnosis (range, 1.8-11.4 years). Presenting symptoms most often included focal neurological deficits (n = 6), although several patients had nonspecific symptoms of headache and altered mental status. Brain lesions were generally multiple (n = 7), supratentorial (n = 8), and lobar or periventricular in distribution with ring enhancement. Diagnosis was established by stereotactic (n = 4) and open surgical (n = 6) biopsy. Treatments most frequently administered included reduction of immunosuppression (n = 10), dexamethasone (n = 10), rituximab (n = 8), high-dose methotrexate (n = 3), and whole-brain radiotherapy (n = 6). Six patients remain alive without PCNS-PTLD relapse, including 4 patients who have sustained remissions beyond 2 years from diagnosis of PCNS-PTLD. Of 4 observed deaths, 1 was related to progressive PCNS-PTLD. CONCLUSION PCNS-PTLD must be considered in the differential diagnosis of any patient with prior SOT presenting with an intracranial lesion. Histological diagnosis with brain biopsy is imperative, given the risk for opportunistic infections that may have similar imaging findings and presentation. Prognosis is variable, although long-term survival has been reported.

Organ weight changes associated with body mass index determined from a medical autopsy population.

ContextExisting organ weight charts used by pathologists for patients undergoing medical autopsy do not illustrate the effect of obesity and age on organ weights among a general population of older individuals with multiple comorbidities. MethodsWe retrospectively reviewed 300 medical autopsy reports to extract data to analyze the effect of obesity and age on organ weights. ResultsIn both men and women, there were statistically significant increases in organ weights with body mass index (BMI) but decreases with age for liver, spleen, and kidneys. In men, increased age was associated with increased left ventricular wall thickness, whereas increased BMI was associated with increased heart weight. In women, only BMI was associated with changes in all 3 anatomic cardiac parameters (heart weight and thickness of the right and left ventricular walls). Age effects were not observed for heart parameters in women. Thyroid weight increased with BMI in men but not in women. ConclusionsThe findings demonstrate changes in organ weights/sizes with obesity and age in a population of patients with multiple comorbidities. The differential effects of age and BMI on the heart between men and women raise the possibility that increased BMI in women may have a greater impact on cardiovascular causes of death than that in men.

Convection enhanced delivery to the Brain: preparing for gene therapy and protein delivery to the Brain for functional and restorative Neurosurgery by understanding low-flow neurocatheter infusions using the Alaris® system infusion pump

Background Convection enhanced delivery (CED) is an emerging form of direct brain infusion therapy employed in human functional and restorative neurosurgery clinical trials delivering protein, viral vectors for gene therapy, and siRNA. Purpose Pressure monitoring has become a vital tool in ensuring infusion safety and success. We report details of this benchmark first trial of the use of a leading syringe infusion pump system capable of low-flow infusions. Methods Low-flow infusion performance of the FDA approved Alaris® System syringe pump, commonly used at our institution, was assessed during in vitro and ex vivo CED infusions. In vitro infusion cloud morphology and line pressure were analyzed utilizing a neuroinfusion catheter and delivering volumes and flow rates proposed for a human gene therapy protocol for Parkinson’s disease. Results Pressure monitoring results correlated with previously published in-line pressure monitoring results however the time to peak with catheter occlusion was extended due to the method of pressure monitoring with this device. Conclusion MRI compatible infusion pumps used for brain delivery injectables, pressure monitoring is set to be a guiding instrument for the health care professional employing this emerging form of infusion-to-brain delivery. Further development of infusion pump technology is warranted to allow for infuse/withdraw mode, infusion pressure graphical and numerical display, and pressure monitoring without the need for an inflatable reservoir pressure device. MRI safe infusion systems will need to be available and nursing staff educated to prepare infusions within the high-field environment.

Intracranial blastomycosis presenting as an enhancing cerebellopontine mass.

Isolated Blastomyces dermatitidis infection of the central nervous system is an uncommonly encountered entity. If left untreated it can be fatal; thus accurate diagnosis in a timely manner is critical. A 37-year-old white male presented with a severe headache. An MRI scan revealed a right-sided enhancing cerebellopontine angle mass with extension into the internal acoustic canal and diffuse basilar enhancement. After thorough assessment of the patient, an open surgical biopsy of the lesion was performed for pathological evaluation. The biopsy demonstrated broad-based budding yeasts. The cerebrospinal fluid antigen enzyme immunoassay (EIA) (MVista®) for Blastomyces dermatitidis was also positive with a level of 4.28 EIA units.

Microsurgical anatomy of the posterior median septum of the human spinal cord

The aim of this study was to analyze the topographical anatomy of the dorsal spinal cord (SC) in relation to the posterior median septum (PMS). This included the course and variations in the PMS, and its relationship to and distance from other dorsal spinal landmarks. Microsurgical anatomy of the PMS was examined in 12 formalin‐fixed adult cadaveric SCs. Surface landmarks such as the dorsal root entry zone (DREZ), the denticulate ligament, the architecture of the leptomeninges and pial vascular distribution were noted. The PMS was examined histologically in all spinal segments. The PMS extended most deeply at spinal segments C7 and S4. This was statistically significant for all spinal segments except C5. The PMS was shallowest at segments T4 and T6, where it was statistically significantly thinner than at any other segment. In 80% of the SCs, small blood vessels were identified that traveled in a rostrocaudal direction in the PMS. The longest distance between the PMS and the DREZ was at the C1–C4 vertebral levels and the shortest distance was at the S5 level. Prevention of deficits following a dorsal midline neurosurgical approach to deep‐seated SC lesions requires careful identification of the midline of the cord. The PMS and septum define the midline on the dorsum of the SC and their accurate identification is essential for a safe midline surgical approach. In this anatomical study, we describe the surface anatomy of the dorsal SC and its relationship with the PMS, which can be used to determine a safe entry zone into the SC. Clin. Anat. 28:45–51, 2015.

The subparietal and parietooccipital sulci: An anatomical study

The subparietal and parietooccipital sulci are both located on the medial surface of the brain. Both of these sulci reveal significant variability in pattern and complexity. Both subparietal and parietooccipital sulci play an important role as surgical landmarks using posterior interhemispheric parietooccipital approach to lesions located adjacent to the ventricular trigon deep to the cingulate gyrus. The aim of this study is to analyze variations in the patterns of the subparietal and parietooccipital sulci and to emphasize their surgical importance. Fifty‐six formalin‐fixed cadaveric cerebral hemispheres from 28 adult humans are examined. Subparietal and parietal sulci patterns, variations and their relationship with the cingulate sulcus are studied according to the terminology introduced by Ono et al. The H‐pattern was observed in 50% (n = 28) of all hemispheres, being the most common pattern of the subparietal sulcus. The Straight pattern was observed in the 30.4% (n = 17) of all hemispheres, being the most common pattern of the parietooccipital sulcus. Furthermore, more detailed results among the patterns, connections, side branches and the relationship with the adjacent sulci are given. Our study further confirms the complexities in the patterns of the subparietal and parietooccipital sulci and demonstrates that these sulci fall within an expected range of variations. Better knowledge of these variations will further help neurosurgeons to navigate easily during approaches involving the medial surface of the parietal lobe. Clin. Anat. 26:667–674, 2013.

356 Microsurgical Anatomy of the Brainstem Safe Entry Zones: A Cadaveric Study With High-Resolution Magnetic Resonance Imaging and Fiber Tracking.

Abstract Operative management of intrinsic brainstem lesions remains challenging despite advances in electrophysiological monitoring and neuroimaging. Surgical intervention in this region requires detailed knowledge of adjacent, critical white matter tracts and cranial nerve nuclei. Our aim was to systematically verify internal anatomy associated with each brainstem safety zone entry zone (BSEZ) using a cadaveric model supplemented with neuroimaging modalities commonly used in preoperatively planning, namely high-resolution magnetic resonance imaging (MRI) and fiber tracking. Twelve BSEZs were simulated in 8 formalin-fixed, cadaveric heads. Specimens then underwent radiological investigation including T2-weighted imaging and fiber tracking using 4.7 T MRI. The distance between simulated BSEZs and predefined, adjacent, critical structures was systemically recorded. Entry points and anatomic limits on the surface of the brainstem are described for each BSEZ, along with description of neurological sequelae if such limits are violated. With high-resolution imaging, we verified maximal depth and optimal angle of entry for each BSEZ. The relationship between BSEZs and adjacent, critical structures was quantified. Orbitozygomatic, suboccipital, retrosigmoid, retrolabyrinthine, and petrosectomy approaches were used to simulate BSEZs in the ventral, dorsal, and lateral brainstem. Critical structures most at risk for injury during BSEZ approach included the oculomotor nerve, trochlear nerve, red nucleus, medial lemniscus, medial longitudinal fasciculus, corticospinal tract, and hypoglossal nucleus. Once thought to be universally inoperable, select lesions of the brainstem may now be treated by experienced surgeons with adjunct instrumentation, imaging, neuromonitoring, and intricate knowledge of BSEZs. All approaches adhered to the 2-point rule while minimizing neural and vascular damage. In combination with cadaveric dissection, high-resolution MRI and fiber tracking allow the surgical team to develop a better understanding of the internal architecture of the brainstem, particularly as related to BSEZs. The careful study of such imaging may lead to more accurate and safe surgery through use of optimal surgical corridors.INTRODUCTION Operative management of intrinsic brainstem lesions remains challenging despite advances in electrophysiological monitoring and neuroimaging. Surgical intervention in this region requires detailed knowledge of adjacent, critical white matter tracts and cranial nerve nuclei. Our aim was to systematically verify internal anatomy associated with each brainstem safety zone entry zone (BSEZ) using a cadaveric model supplemented with neuroimaging modalities commonly used in preoperatively planning, namely high-resolution magnetic resonance imaging (MRI) and fiber tracking. METHODS Twelve BSEZs were simulated in 8 formalin-fixed, cadaveric heads. Specimens then underwent radiological investigation including T2-weighted imaging and fiber tracking using 4.7 T MRI. The distance between simulated BSEZs and predefined, adjacent, critical structures was systemically recorded. RESULTS Entry points and anatomic limits on the surface of the brainstem are described for each BSEZ, along with description of neurological sequelae if such limits are violated. With high-resolution imaging, we verified maximal depth and optimal angle of entry for each BSEZ. The relationship between BSEZs and adjacent, critical structures was quantified. Orbitozygomatic, suboccipital, retrosigmoid, retrolabyrinthine, and petrosectomy approaches were used to simulate BSEZs in the ventral, dorsal, and lateral brainstem. Critical structures most at risk for injury during BSEZ approach included the oculomotor nerve, trochlear nerve, red nucleus, medial lemniscus, medial longitudinal fasciculus, corticospinal tract, and hypoglossal nucleus. CONCLUSION Once thought to be universally inoperable, select lesions of the brainstem may now be treated by experienced surgeons with adjunct instrumentation, imaging, neuromonitoring, and intricate knowledge of BSEZs. All approaches adhered to the 2-point rule while minimizing neural and vascular damage. In combination with cadaveric dissection, high-resolution MRI and fiber tracking allow the surgical team to develop a better understanding of the internal architecture of the brainstem, particularly as related to BSEZs. The careful study of such imaging may lead to more accurate and safe surgery through use of optimal surgical corridors.