Recruited macrophages that colonize the post-inflammatory peritoneal niche convert into functionally divergent resident cells.

Inflammation generally leads to recruitment of monocyte-derived macrophages. What regulates the fate of these cells and to what extent they can assume the identity and function of resident macrophages is unclear. Here, we show that macrophages elicited into the peritoneal cavity during mild inflammation persist long-term but are retained in an immature transitory state of differentiation due to the presence of enduring resident macrophages. By contrast, severe inflammation results in ablation of resident macrophages and a protracted phase wherein the cavity is incapable of sustaining a resident phenotype, yet ultimately elicited cells acquire a mature resident identity. These macrophages also have transcriptionally and functionally divergent features that result from inflammation-driven alterations to the peritoneal cavity micro-environment and, to a lesser extent, effects of origin and time-of-residency. Hence, rather than being predetermined, the fate of inflammation-elicited peritoneal macrophages seems to be regulated by the environment.

From the Historical Examples of Drs. Osler, Cushing, and Van Wagenen: Lessons on the Importance of Mentorship in Contemporary Neurosurgery.

Although the historical relationships between William Osler, Harvey Williams Cushing, and William Perine Van Wagenen are well known in the neurosurgical world, the nature of the mentor-mentee relationships that existed between these historical giants is not widely appreciated. In this historical vignette, we describe and exemplify such relationships, while at the same time extract important and applicable principles from them. We reviewed relevant primary and secondary sources that documented the interactions between Cushing, Osler, and Van Wagenen. In founding the field of neurological surgery, the brilliant yet volatile Dr. Harvey Cushing received guidance from his mentor, Dr. William Osler. Through our review, it is undeniable that Dr. Osler's personal and professional guidance was vital to young Dr. Cushing's success as the founder of modern neurosurgery. Likewise, Cushing's tutelage of Van Wagenen enabled Van Wagenen to become a leader of a second generation of neurosurgeons, thereby perpetuating the existence of Cushing's high neurosurgical standards. These historical mentor-mentee relationships were built on 4 primary components: accurate recognition of talent, guidance, arrangement of opportunity, and sustenance of mentorship-actions that are commonly implicated in effective mentorship in contemporary studies. Proper mentorship remains indispensable for the success of neurosurgical trainees.

Reorganized language network connectivity after left arcuate fasciculus resection: A case study.

Understanding the neural mechanisms that support spontaneous recovery of cognitive abilities can place important constraints on mechanistic theories of brain organization and function, and holds potential to inform clinical interventions. Connectivity-based MRI measures have emerged as a way to study how recovery from brain injury is modulated by changes in intra- and inter-hemispheric connectivity. Here we report a detailed and multi-modal case study of a 26 year-old male who presented with a left inferior parietal glioma infiltrating the left arcuate fasciculus. The patient underwent pre- and post-operative functional MRI and Diffusion Tensor Imaging, as well as behavioral assessments of language, motor, vision and praxis. The surgery for removal of the tumor was carried out with the patient awake, and direct electrical stimulation mapping was used to evaluate cortical language centers. The patient developed a specific difficulty with repeating sentences toward the end of the surgery, after resection of the tumor and partial transection of the arcuate fasciculus. The patient recovered from the sentence repetition impairments over several months after the operation. Coincident with the patient's cognitive recovery, we document a pattern whereby intra-hemispheric functional connectivity was reduced in the left hemisphere, while inter-hemispheric connectivity increased between classic left hemisphere language regions and their right hemisphere homologues. These findings suggest that increased synchrony between the two hemispheres, in the setting of focal transection of the left arcuate fasciculus, can facilitate functional recovery.

Direct electrical stimulation mapping of cognitive functions in the human brain.

Direct electrical stimulation (DES) is a well-established clinical tool for mapping cognitive functions while patients are undergoing awake neurosurgery or invasive long-term monitoring to identify epileptogenic tissue. Despite the proliferation of a range of invasive and noninvasive methods for mapping sensory, motor and cognitive processes in the human brain, DES remains the clinical gold standard for establishing the margins of brain tissue that can be safely removed while avoiding long-term neurological deficits. In parallel, and principally over the last two decades, DES has emerged as a powerful scientific tool for testing hypotheses of brain organization and mechanistic hypotheses of cognitive function. DES can cause transient "lesions" and thus can support causal inferences about the necessity of stimulated brain regions for specific functions, as well as the separability of sensory, motor and cognitive processes. This Special Issue of Cognitive Neuropsychology emphasizes the use of DES as a research tool to advance understanding of normal brain organization and function.

Translational Brain Mapping at the University of Rochester Medical Center: Preserving the Mind Through Personalized Brain Mapping.

The Translational Brain Mapping Program at the University of Rochester is an interdisciplinary effort that integrates cognitive science, neurophysiology, neuroanesthesia, and neurosurgery. Patients who have tumors or epileptogenic tissue in eloquent brain areas are studied preoperatively with functional and structural MRI, and intraoperatively with direct electrical stimulation mapping. Post-operative neural and cognitive outcome measures fuel basic science studies about the factors that mediate good versus poor outcome after surgery, and how brain mapping can be further optimized to ensure the best outcome for future patients. In this article, we describe the interdisciplinary workflow that allows our team to meet the synergistic goals of optimizing patient outcome and advancing scientific understanding of the human brain.

Direct electrical stimulation of the left frontal aslant tract disrupts sentence planning without affecting articulation.

Sentence production involves mapping from deep structures that specify meaning and thematic roles to surface structures that specify the order and sequencing of production ready elements. We propose that the frontal aslant tract is a key pathway for sequencing complex actions with deep hierarchical structure. In the domain of language, and primarily with respect to the left FAT, we refer to this as the 'Syntagmatic Constraints On Positional Elements' (SCOPE) hypothesis. One prediction made by the SCOPE hypothesis is that disruption of the frontal aslant tract should disrupt sentence production at grammatical phrase boundaries, with no disruption of articulatory processes.  We test this prediction in a patient undergoing direct electrical stimulation mapping of the frontal aslant tract during an awake craniotomy to remove a left frontal brain tumor. We found that stimulation of the left FAT prolonged inter-word durations at the start of grammatical phrases, while inter-word durations internal to noun phrases were unaffected, and there was no effect on intra-word articulatory duration. These results provide initial support for the SCOPE hypothesis, and motivate novel directions for future research to explore the functions of this recently discovered component of the language system.

A Role for the Frontal Aslant Tract in Speech Planning: A Neurosurgical Case Study.

Frontal and temporal white matter pathways play key roles in language processing, but the specific computations supported by different tracts remain a matter of study. A role in speech planning has been proposed for a recently described pathway, the frontal aslant tract (FAT), which connects the posterior inferior frontal gyrus to the pre-SMA. Here, we use longitudinal functional and structural MRI and behavioral testing to evaluate the behavioral consequences of a lesion to the left FAT that was incurred during surgical resection of a frontal glioma in a 60-year-old woman, Patient AF. The pattern of performance in AF is compared, using the same measures, with that in a 37-year-old individual who underwent a left anterior temporal resection and hippocampectomy (Patient AG). AF and AG were both cognitively intact preoperatively but exhibited specific and doubly dissociable behavioral deficits postoperatively: AF had dysfluent speech but no word finding difficulty, whereas AG had word finding difficulty but otherwise fluent speech. Probabilistic tractography showed that the left FAT was lesioned postoperatively in AF (but not AG) whereas the inferior longitudinal fasciculus was lesioned in AG (but not AF). Those structural changes were supported by corresponding changes in functional connectivity to the posterior inferior frontal gyrus: decreased functional connectivity postoperatively between the posterior inferior frontal gyrus and pre-SMA in AF (but not AG) and decreased functional connectivity between the posterior inferior frontal gyrus and the middle temporal gyrus in AG (but not AF). We suggest from these findings that the left FAT serves as a key communicative link between sentence planning and lexical access processes.

Direct Electrical Stimulation in the Human Brain Disrupts Melody Processing.

Prior research using functional magnetic resonance imaging (fMRI) [1-4] and behavioral studies of patients with acquired or congenital amusia [5-8] suggest that the right posterior superior temporal gyrus (STG) in the human brain is specialized for aspects of music processing (for review, see [9-12]). Intracranial electrical brain stimulation in awake neurosurgery patients is a powerful means to determine the computations supported by specific brain regions and networks [13-21] because it provides reversible causal evidence with high spatial resolution (for review, see [22, 23]). Prior intracranial stimulation or cortical cooling studies have investigated musical abilities related to reading music scores [13, 14] and singing familiar songs [24, 25]. However, individuals with amusia (congenitally, or from a brain injury) have difficulty humming melodies but can be spared for singing familiar songs with familiar lyrics [26]. Here we report a detailed study of a musician with a low-grade tumor in the right temporal lobe. Functional MRI was used pre-operatively to localize music processing to the right STG, and the patient subsequently underwent awake intraoperative mapping using direct electrical stimulation during a melody repetition task. Stimulation of the right STG induced "music arrest" and errors in pitch but did not affect language processing. These findings provide causal evidence for the functional segregation of music and language processing in the human brain and confirm a specific role of the right STG in melody processing. VIDEO ABSTRACT.

William P. Van Wagenen (1897-1961): pupil, mentor, and neurosurgical pioneer.

William Perrine ("Van") Van Wagenen (1897-1961) was the first Chief of Neurosurgery at the University of Rochester Medical Center (URMC), serving from 1928 to 1954, and was a leading figure in 20th-century neurosurgery. He was a devoted pupil of Dr. Harvey Cushing and helped to found the Harvey Cushing Society (now the AANS) in honor of his mentor and was elected as its first President in 1932. He served as the 27th President of the Society of Neurological Surgeons in 1952. Upon his death in 1961 he bequeathed an endowment for the Van Wagenen Fellowship, which has advanced the education of many leaders in American neurosurgery. His legacy of operative skill, his commitment to resident education and research in neurological disease, his inspiration for the foundation of the Cushing Brain Tumor registry, and his contributions to organized neurosurgery form the foundation of the legacy of neurosurgery at URMC.

Stereotactic radiosurgery for glioblastoma: retrospective analysis.

PURPOSE: This retrospective study was done to better understand the conditions for which stereotactic radiosurgery (SRS) for glioblastoma may be efficacious. METHODS: Between 2000 and 2007, 33 patients with a pathological diagnosis of glioblastoma received SRS with the Novalis Shaped Beam Radiosurgery system. Eighteen patients (54%) underwent salvage SRS for recurrence while 15 (45%) patients received upfront SRS following standard fractionated RT for newly diagnosed glioblastoma. RESULTS: There were no RTOG grade >2 acute side effects. The median survival after SRS was 6.7 months (range 1.4 - 74.7). There was no significant difference in overall survival (from the time of initial diagnosis) with respect to the timing of SRS (p = 0.2). There was significantly better progression free survival in patients treated with SRS as consolidation versus at the time of recurrence (p = 0.04). The majority of patients failed within or at the margin of the SRS treatment volume (21/26 evaluable for recurrence). CONCLUSION: SRS is well tolerated in the treatment of glioblastoma. As there was no difference in survival whether SRS is delivered upfront or at recurrence, the treatment for each patient should be individualized. Future studies are needed to identify patients most likely to respond to SRS.

Characterization of circulating monocytes expressing HLA-DR or CD71 and related soluble factors for 2 weeks after severe, non-thermal injury.

BACKGROUND: Severe injury is associated with changes in monocytes that may contribute to poor outcomes. Longitudinal characterization of monocyte response patterns after trauma may provide added insight into these immunological alterations. METHODS: Venous blood obtained seven times during post-injury days 1 through 13 from 61 patients with an injury severity score >20 was assessed by flow cytometry for monocytes (CD14+) expressing HLA-DR or CD71 (transferrin receptor) and for circulating levels of interleukin (IL) 1alpha, IL-1beta, IL-6, soluble CD14 (sCD14), tumor necrosis factor-alpha (TNF-alpha), prostaglandin E(2) (PGE(2)), thromboxane B(2) (TXB(2)), and endotoxin. Urine neopterin was measured by high-pressure liquid chromatography, expressed as a neopterin-creatinine ratio. RESULTS: Trauma patients had leucocytosis days 1 through 13, monocytosis days 5 through 13, reduced proportions of CD14+HLA-DR+ cells days 2 through 5, and elevated proportions of CD14+CD71+ cells days 1 through 13. Neopterin was elevated all days, peaking on day 10. sCD14 was elevated days 2 through 13, and there were sporadic elevations of IL-1alpha, IL-1beta, IL-6, TNF-alpha, PGE(2), TXB(2), and endotoxin. Sepsis syndrome patients (n = 6) had larger and more prolonged reductions in CD14+HLA-DR+ cells and higher neopterin values, in comparison with uneventful patient outcomes. CONCLUSIONS: Altered proportions of monocytes expressing HLA-DR and CD71 and elevated sCD14 and urine neopterin levels, for up to 2 weeks after severe injury, underscores an extended period of profound immunological effects. Additional studies to more fully assess temporal monocyte response patterns after severe injury, including activation, may be warranted.

Axial loading during MR imaging can influence treatment decision for symptomatic spinal stenosis.

BACKGROUND AND PURPOSE: Previous studies have shown that axial loading can narrow the spinal canal. However, the clinical significance is unclear. The purpose of this study was to determine whether the narrowing of the spinal canal with axial loading during MR imaging could influence treatment decision for spinal stenosis. METHODS: Two hundred patients with clinical symptoms of spinal stenosis underwent routine MR imaging and then immediately underwent axially loaded MR imaging. We selected 20 of these patients because they had narrowing of the spinal canal shown on the axially loaded images. Three experienced neurosurgeons evaluated these 20 patients based on clinical information and routine MR images. The same neurosurgeons were then asked for second treatment decisions based on the same clinical information but with axially loaded MR images. RESULTS: Axial loading during MR imaging of the lumbar spine can influence neurosurgeons in their treatment decisions for symptomatic spinal stenosis. For this selected group of patients, all three neurosurgeons changed their treatment decision from conservative management to decompressive surgery for five patients when shown the axially loaded MR images. For two other patients, two neurosurgeons changed their treatment decisions, and for three additional patients, one neurosurgeon changed his treatment decision, all based on the axially loaded MR images. Treatment was not changed from surgical to medical management for any of the patients when shown the axially loaded images. CONCLUSION: In selected patients with spinal stenosis and apparent narrowing of the spinal canal shown by axially loaded MR imaging, the additional information gained from this technique can influence experienced neurosurgeons in their treatment decisions.

Determination of laboratory reference ranges for lymphocyte immunophenotype subsets in healthy adult Japanese using flow cytometry.

This study represents a comprehensive evaluation of normative values for lymphocyte immunophenotype subsets using flow cytometry techniques in a Japanese population. Lymphocyte reference ranges were determined for percentage and absolute count of T, B, and NK cells in healthy adult Japanese using an extensive two-color immunophenotyping panel and consistently applied quality control methodology. Reference values were also determined for activation markers on CD3+ lymphocytes CD3+/CD25+, CD3+/CD38+ and CD3+/HLA-DR+. Differences in age and gender were observed for specific lymphocyte subsets. Comparison of the Japanese study with a Thai multi-center study that used similar methodology also demonstrated ethnic differences in lymphocyte reference ranges. The results in this study strongly suggest that reference values derived from studies in one population may not be applied to another population even when similar protocols for reagents, instruments and procedures are used although such studies do appear useful for epidemiological comparisons.

Micro-flowcell conductometric sweat analysis for cystic fibrosis diagnosis.

This paper describes a device specifically designed to facilitate neonatal sweat testing. The components are sized appropriately for attachment to the limbs of newborns. Iontophoretic electrodes, with pilocarpine gel inserts, are latched into small holders attached by straps to the limb. The holder at the anodic site remains in place to receive and align the sensor cell, which uses a conical collecting surface to channel the sweat directly and anaerobically from the sweat ducts to the continuous flow-through conductivity cell within its body. A crib-side analysis unit incorporates an iontophoretic power supply and displays a continuous readout of sweat electrical conductivity. The average conductivity during a specific time interval and the initial sweating rate are automatically displayed. The method, which simplifies sweat tests, is currently being assessed in three neonatal clinical trials to test its ability to reduce test failures in the newborn due to insufficient sweat.

Lymphocyte activation after non-thermal trauma.

BACKGROUND: Severe injury causes immunological changes that may contribute to a poor outcome. Longitudinal characterization of lymphocyte response patterns may provide further insight into the basis of these immunological alterations. METHODS: Venous blood obtained seven times over 2 weeks from 61 patients with injury severity scores above 20 was assessed for lymphocyte phenotypic and activation markers together with serum levels of interleukin (IL) 2, IL-4, soluble IL-2 receptor (sIL-2R), soluble CD4 (sCD4), soluble CD8 (sCD8) and interferon gamma. RESULTS: Severe injury was associated with profound changes in the phenotypic and activation profile of circulating lymphocytes. Activation was indicated by increased numbers of T cells expressing CD25, CD69 and CD71, and raised serum levels of IL-2, sIL-2R, sCD4 and sCD8. Relatively higher levels of sIL-2R and sCD4 were found in patients with sepsis syndrome. CONCLUSION: Polytrauma is associated with dramatic alterations in the phenotypic and activation profile of circulating lymphocytes which are generally independent of clinical course. In contrast, several lymphocyte soluble factors, including sCD4 and sIL-2R, paralleled the clinical course. These data provide new insight into lymphocyte responses after injury and suggest that further assessment of soluble factors as clinical correlates, including those related to lymphocyte activation or generalized inflammation, may be warranted.

Scar formation after skin injury to the human foetus in utero or the premature neonate.

A macroscopically visible scar was present at birth in three infants with a history of injury during amniocentesis at 16-20 weeks' gestation. In several neonates born between 21 and 31 weeks' gestation, chemical injury to the skin caused by extravasation of calcium gluconate healed by formation of a large scar. In the infant born at 21 weeks, biopsy of the injured area showed infiltration by large numbers of neutrophils and macrophages. It appears that a very immature neonate can mount a prominent inflammatory reaction and that both a midtrimester foetus and a very immature neonate heal injuries to the skin by scar formation and not by scarless healing.

Chronic relapsing experimental autoimmune encephalomyelitis: effects of insulin-like growth factor-I treatment on clinical deficits, lesion severity, glial responses, and blood brain barrier defects.

Chronic relapsing experimental autoimmune encephalomyelitis (crEAE), a model for multiple sclerosis, was used to test 2 regimens of insulin-like growth factor-I (IGF-I) treatment. We induced crEAE by injecting 3x10(7) myelin basic protein-(MBP) sensitized lymph node cells into adult female SJL/J mice. Fifty-one mice, divided randomly into 4 groups, were used in the first trial. Two groups received IGF-I (a gift of Cephalon, Inc.) 0.6 mg/kg/d subcutaneously from day 7 to day 16 and the other two groups received placebo injections. IGF-I treatment reduced clinical deficits during the first attack and during 2 subsequent relapses. Image analysis of immunostained and histological sections showed that IGF-I treatment reduced BBB defects and both the numbers and sizes of inflammatory, demyelinating, and demyelinated lesions. Twelve mice that had recovered from their first attack were used in our second trial to evaluate possible adverse effects of prolonged treatment with a higher dose of IGF-I. Six received 1.2 mg/kg/d for 6 weeks (days 19-63). No adverse effects of IGF-I treatment were identified. The eyes, hearts, livers, and kidneys of IGF-I-treated mice were normal histologically and their spleens also appeared normal except for mild to moderate microscopic increases in lymphopoesis. Our results suggest that prolonged IGF-I treatment is well tolerated and that the anti-inflammatory effects of IGF-I have a major role in reducing clinical deficits and lesion severity in crEAE. These effects, if present in multiple sclerosis, may benefit patients with this disease.

Prefabrication of mucosa-lined flaps: a preliminary study in the pig model.

There is a need in reconstructive surgery for flaps lined by nonkeratizing stratified squamous epithelium or mucous membrane. Applications could be found in nasal, oral, genital, and esophageal reconstruction and even in reconstruction of hollow intra-abdominal tubes. Prefabrication of lined flaps has so far been limited to a pretransfer grafting of split-thickness skin. However, in certain situations this does not satisfy the primary requirement of replacing "like with like." Also, the availability of donor sites for harvesting mucosa is limited. The present study involves prefabrication of mucosa-lined flaps without causing donor site morbidity. The study was carried out on six mini-Hartford pigs. Buccal mucosa was harvested from the cheeks; the sheet was divided into several smaller graft pieces of 1 to 2 cm2 area. These graft pieces were then applied to the deep fascia at a distance of 5 to 15 mm from one another, also to galea, and to the undersurface of skin flaps. The grafted area was isolated from the opposing surface with a silicone sheet or Marlex mesh. The grafts were allowed to take and, it was hoped, merge together to form a sheet graft of dimensions greater than those of the original. Two to 7 weeks after the initial grafting, the skin flap was elevated; the mucosal grafts were observed macroscopically for take and surface area and microscopically to confirm that the lining was indeed mucosa. The mucosa took well on both the fascia and galea and also on the undersurface of the skin; it enlarged in size, and the small pieces became confluent to form a single sheet. The increase in surface area varied from 33 percent at 11 days postgrafting to a maximum of 238 percent after 7 weeks. All pigs had positive cultures from the mucosa before implantation but only one developed gross infection leading to partial graft loss.