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Brain stem auditory, visual and somatosensory evoked potentials in leukodystrophies.

Brain stem auditory (BAERs), visual (VEPs) and somatosensory evoked responses (SEPs) were recorded in 12 patients with Pelizaeus-Merzbacher leukodystrophy (PMD), three with adrenoleukodystrophy (ALD) and three with metachromatic leukodystrophy (MLD). All the 3 evoked responses were abnormal in all patients except normal VEPs and SEPs in a patient with early ALD. In most patients wave I with and without wave II were the only components of the BAERs that remained, subsequent components (waves III-VII) were absent. VEPs were severely altered; either no identifiable response to flash or pattern reversal stimuli could be recorded or the major components were significantly delayed in latency. Short latency SEPs following median nerve stimulation usually showed a normally recorded Erb's potential (N10), but an absence or marked attenuation of cervical (N14) and early scalp components (N19 and P22) or the occurrence of the scalp components with a significant delay. Multimodality evoked responses provide more information regarding the functional integrity of several afferent systems in patients with white matter disorders.

Acoustic Stimulation↗

A prospective short-term study of chronic low back pain patients utilizing novel objective functional measurement.

The present study utilized recently developed diagnostic tests that permit recognition of functional deficits in spine mobility, trunk strength, endurance, coordination, and dynamic lifting capacity. Changes in these tests were compared to changes in psychological functioning (e.g., self-report of pain) as well as to outcome criteria such as return-to-work and resolution of litigation. The study utilized these tests repeatedly during a new treatment approach to feed back objective information of the patient's functional capacity, not amenable to simple visual inspection, to both the patient and the surgeon. The program itself integrated a low back physical rehabilitation program with a multimodal pain management program and was guided by repeated functional capacity measurements. A total of 66 patients were evaluated. Results demonstrated significant improvement in physical function in these patients, which was also accompanied by changes in self-report of pain complaints. Moreover, an 82% return-to-work rate was achieved in this sample which was initially 92% unemployed. These results indicate that the physician dealing with chronic low back dysfunction can employ objective measures of functional capacity as an alternative to the sole reliance on pain patient self-report or structured tests, such as radiographic imaging, which merely document a universal, progressive degenerative process.

Adult↗

Magnetic resonance spectroscopy guided brain tumor resection: differentiation between recurrent glioma and radiation change in two diagnostically difficult cases.

BACKGROUND: It is often difficult to differentiate a recurrent glioma from the effects of post-operative radiotherapy by means of conventional neurodiagnostic imaging. Proton magnetic resonance spectroscopic imaging (1H-MRSI), that allows in vivo measurements of the concentration of brain metabolites such as choline-containing phospholipids (Cho), may provide in vivo biochemical information helpful in distinguishing areas of tumor recurrence from areas of radiation effect. PATIENTS AND METHODS: Two patients who had undergone resection and post-operative radiotherapy for a cerebral glioma became newly symptomatic. Computed tomographic (CT) and magnetic resonance imaging (MRI) performed after the intravenous infusion of contrast material, and in one case, [18F]fluorodeoxyglucose positron emission tomography (PET), could not differentiate between the possibilities of recurrent glioma and radiation effect. The patients underwent 1H-MRSI prior to reoperation and the 1H-MRSI results were compared to histological findings originating from the same locations. RESULTS: A high Cho signal measured by 1H-MRSI was seen in areas of histologically-proven dense tumor recurrence, while low Cho signal was present where radiation changes predominated. CONCLUSIONS: The differentiation between the recurrence of a cerebral glioma and the effects of post-operative irradiation was achieved using 1H-MRSI in these two patients whose conventional neurodiagnostic imaging was equivocal for such a distinction. Where these two conditions are present, metabolite images from 1H-MRSI, such as that based on Cho, can be co-registered with other imaging modalities such as MRI and may also be integrated with functional MRI or functional PET within a multimodal imaging-guided surgical navigation system to assure maximal resection of recurrent tumor while minimizing the risk of added neurological damage.

Adult↗

Heat shock protein 70: role in antigen presentation and immune stimulation.

Heat shock proteins (HSP) when released into the extracellular milieu can act simultaneously as a source of antigen due to their ability to chaperone peptides and as a maturation signal for dendritic cells, thereby inducing DCs to cross-present antigens to CD8+ T-cells. HSP can also act independently from associated peptides, stimulating the innate immune system. Previous results regarding the activation of NK cells by HSP70 cell surface expression on tumour cells and soluble HSP70 will be further covered elsewhere within this issue. For cross-presentation, HSP70-peptide complexes (HSP70-PC) were used from two human melanoma cell lines that differ in the expression of the tumour-associated antigen tyrosinase. Purified HSP70-PC consists of both the constitutively expressed HSC70 and the inducible HSP70. HSP70-peptide complexes purified from tyrosinase positive (HSP70-PC/tyr+) human melanoma cells, incubated with immature DCs, results in the activation of HLA-*A0201-restricted tyrosinase peptide-specific T-cells. Receptor-mediated uptake of HSP70-PC by DCs and intracellular transport are required for efficient MHC class I restricted cross-presentation of chaperoned peptides. Demonstration of HSP70-PC mediated cross-presentation of such non-mutated naturally expressed tumour antigens is of special clinical interest with regard to hyperthermia. Tumour regression and improved local control have been shown within clinical phase II/III trials integrating regional hyperthermia combined with radiation and/or chemotherapy in multimodal treatment strategies. According to the proposed concept, local necrosis induced by hyperthermic treatment induces the release of HSPs, followed by uptake, processing and presentation of associated peptides by DCs. By acting as chaperone and a signal for DC maturation, HSP70-PC might efficiently prime circulating T-cells. Therefore, upregulating HSP70 and causing local necrosis in tumour tissue by hyperthermia offers great potential as a new approach to directly activate the immune system.

Animals↗

The development, validity and reliability of a multimodality objective structured clinical examination in psychiatry.

OBJECTIVES: To evaluate the development, validity and reliability of a multimodality objective structured clinical examination (OSCE) in undergraduate psychiatry, integrating interactive face-to-face and telephone history taking and communication skills stations, videotape mental state examinations and problem-oriented written stations. METHODS: The development of the OSCE on a restricted budget is described. This study evaluates the validity and reliability of 4 15-18-station OSCEs for 128 students over 1 year. Face and content validity were assessed by a panel of clinicians and from feedback from OSCE participants. Correlations with consultant clinical 'firm grades' were performed. Interrater reliability and internal consistency (interstation reliability) were assessed using generalisability theory. RESULTS: The OSCE was feasible to conduct and had a high level of high perceived face and content validity. Consultant firm grades correlated moderately with scores on interactive stations and poorly with written and video stations. Overall reliability was moderate to good, with G-coefficients in the range 0.55-0.68 for the 4 OSCEs. CONCLUSIONS: Integrating a range of modalities into an OSCE in psychiatry appears to represent a feasible, generally valid and reliable method of examination on a restricted budget. Different types of stations appear to have different advantages and disadvantages, supporting the integration of both interactive and written components into the OSCE format.

Clinical Competence↗

Functional, structural, and metabolic abnormalities of the hippocampal formation in Williams syndrome.

Williams syndrome (WS), caused by microdeletion of some 21 genes on chromosome 7q11.23, is characterized by dysmorphic features, mental retardation or learning difficulties, elastin arteriopathy, and striking neurocognitive and social-behavioral abnormalities. Recent studies of murine knockouts of key genes in the microdeleted region, LIM kinase 1 (LIMK1) and cytoplasmatic linker protein 2 (CYLN2), demonstrated significant functional and metabolic abnormalities, but grossly normal structure, in the hippocampal formation (HF). Furthermore, deficits in spatial navigation and long-term memory, major cognitive domains dependent on hippocampal function, have been described in WS. We used multimodal neuroimaging to characterize hippocampal structure, function, and metabolic integrity in 12 participants with WS and 12 age-, sex-, and IQ-matched healthy controls. PET and functional MRI studies showed profound reduction in resting blood flow and absent differential response to visual stimuli in the anterior HF in WS. Spectroscopic measures of N-acetyl aspartate, considered a marker of synaptic activity, were reduced. Hippocampal size was preserved, but subtle alterations in shape were present. These data demonstrate abnormalities in HF in WS in agreement with murine models, implicate LIMK1 and CYLN2 in human hippocampal function, and suggest that hippocampal dysfunction may contribute to neurocognitive abnormalities in WS.

Adult↗

[Oncologic surgery--scope and status in surgery].

The primary goal of oncological surgery still consists of an operation which eradicates the tumor and results in an R0-resection. Comparing the various subspecialties in the different operative fields, oncological surgery unfolds its major activity in the area of visceral and thoracic surgery which is very similar in the related operative fields of gynecology and urology. Intraoperative radiation therapy is now established as an integral part of the treatment, as part of the multimodal chemotherapy currently used. Intraoperative radiation therapy offers a logical therapeutic concept in advanced tumor cases. The development of further improved prognostic factors and the addition of new molecular methods for diagnostics and therapy are probably the key future tasks in surgical oncology.

Chemotherapy, Adjuvant↗

Multimodality monitoring and telemonitoring in neurocritical care: from microdialysis to robotic telepresence.

PURPOSE OF REVIEW: This review will highlight the state-of-the-art in brain monitoring in neurointensive care and define methods of integrating this technology into patient care using telemedicine methods. RECENT FINDINGS: Several new methods of brain monitoring have been established over the last several years including continuous EEG monitoring, brain tissue oxygenation, jugular venous oxygenation, and cerebral microdialysis. Observational research using these monitors has documented that the brain metabolism, blood flow and function are dynamic after a primary insult. The dynamic nature of the brain can predispose the brain to secondary insults that can occur in the setting of intensive care. Several variables of brain metabolism and function can be monitored and directly impact treatment decisions as well as provide diagnostic and prognostic information. General treatment guidelines for brain injury and brain hemorrhage were developed, in part, prior to implementation of use of these monitors, and there is a trend away from adoption of a one-size-fits-all approach and a trend towards monitor-guided therapy. Dealing with the data provided by multimodality monitoring can be overwhelming. Efficient use of such information requires methods to integrate diverse sets of information, and methods to access the online monitoring information remotely and at any time, day or night. Such remote access integration methods will be reviewed. SUMMARY: Multimodality and telemedicine techniques have advanced the state of knowledge about brain function in critically ill patients, and are presently being implemented to direct therapy. Increasing complexity of care will become commonplace, but will be facilitated by computer-enhanced tools that permit the intensivist to integrate this information into an improved treatment regimen.

Brain Injuries↗

Hydrodynamic contributions to multimodal guidance of prey capture behavior in fish.

Water movements, of both abiotic and biotic origin, provide a wealth of information of direct relevance to the guidance of prey capture behavior. To gather hydrodynamic information, fish have sensors of two basic types: those scattered over the surface of the body known as superficial neuromasts and similar sensors embedded in subdermal lateral line canals. Recently, the anatomical dichotomy between superficial and canal neuromasts has been matched by demonstrations of a corresponding functional dichotomy. Prey detection and localization are evidently mediated by canal neuromasts, whereas superficial neuromasts are more sensitive to water flows over the surface of the fish and participate in the orientation to water currents, a behavior known as rheotaxis. However, rheotaxis in combination with chemosensory inputs can also guide fish to their prey. Thus there is evidence that both lateral line sub-modalities either alone or in concert with other senses play a role in prey capture. Are there circumstances where prey capture requires integration of information from both lateral line sub- modalities? Recent evidence shows that fish are capable of tracking other fish on the basis of the hydrodynamic trails left behind by their swimming motion. Pharmacological and physical ablation of lateral line end organs shows that indeed integration of information from both sub-modalities is required for the complex hydrodynamic task of natural prey capture in the dark. Furthermore, these experiments provide an excellent demonstration of the integration of hydrodynamic, chemosensory, tactile and visual information for the multimodal guidance of prey capture behavior.

Animals↗

Integrating care for chronic pain patients.

Problems in the treatment of the chronic pain patient in a staff model HMO often lead to ineffective and expensive care. The authors support a multimodal approach, which includes medical, psychosocial, and behavioral elements. This treatment is offered in an individualized, integrated, and episodic fashion, which is particularly relevant to the multiple and extended needs of the chronic pain patient. Two cases are presented to illustrate the approach.

Adult↗

Iterative, multimodal, and scalable single-cell profiling for discovery and characterization of signaling regulators.

Cell signaling plays a critical role in regulating cellular state, yet uncovering regulators of signaling pathways and understanding their molecular consequences remains challenging. Here, we present an iterative experimental and computational framework to identify and characterize regulators of signaling proteins, using the mTOR marker phosphorylated RPS6 (pRPS6) as a case study. We present a customized workflow that uses the 10x Flex assay to jointly profile intracellular protein levels, transcriptomes, and CRISPR perturbations in single cells. We use this to generate a "glossary" dataset of paired protein-RNA measurements across targeted perturbations, which we leverage to train a predictive model of pRPS6 levels based solely on transcriptomic data. Applying this model to a genome-wide Perturb-seq dataset enables in silico screening for pRPS6 and nominates novel regulators of mTOR signaling. Experimental validation confirms these predictions and reveals mechanistic diversity among hits, including changes in signaling output driven by anabolic activity, cellular proliferation and multiple stress pathways. Our work demonstrates how integrated experimental and computational approaches provide a scalable framework for multimodal phenotyping and discovery.

Journal Article↗

[Quality control in multimodal postoperative therapy].

Effects of anaesthesia and analgesia on postoperative morbidity and mortality remain controversial. Numerous studies have demonstrated that epidural anaesthesia and pain relief by epidural analgesia reduces perioperative stress responses and thus may reduce postoperative morbidity and mortality. In patients undergoing vascular surgery, epidural anaesthesia diminished postoperative hypercoagulability. These patients may benefit from less thromboembolic complications as well as a reduced risk of a re-operation. However, regional anaesthesia does not affect cardiopulmonary morbidity or overall mortality significantly in most clinical studies. One reason for this disappointing finding may be the missing integration of improved postoperative pain relief into general surgical care. A multimodal therapeutic approach, which consists of preoperative patient information, sufficient analgesia, early mobilisation and enteral feeding, may solve this discrepancy. Therefore, prospective controlled studies are needed to assess the influence of this perioperative approach on outcome.

Clinical Trials as Topic↗

Trends and perspectives in multimodality therapy of locoregionally advanced non-small cell lung cancer.

In recent years progress has been made in the therapy of patients with stage III non-small cell lung cancer. Induction chemotherapy and concomitant chemoradiotherapy have been proven to be superior to radiation therapy alone for unresectable stage disease. In direct comparisons of induction and concomitant chemoradiotherapy, the latter has been found to lead to higher median survival times, albeit at the cost of increased toxicity within the irradiated field. Additional trials have explored the administration of both induction chemotherapy and concomitant chemoradiotherapy in sequence and the integration of the taxanes, gemcitabine and vinorelbine and irinotecan into the multimodality therapy setting. These and other novel concepts are discussed.

Antineoplastic Agents↗

Periodic, multimodal distribution of granule volumes in mast cells.

The areas of 2327 mast cell granules in transmission electron micrographs of sections of peritoneal mast cells from adult rats were measured by digitized planimetry. A histogram constructed using equivalent volumes calculated from the measured areas assuming approximation of the granules to spheres showed a periodic multimodal distribution in which the modes fell at volumes that were successively larger integral multiples of the volume at the first mode. Application of a moving-bin technique to the data confirmed the presence of the modes. We propose a mechanism of fusion of unit sized granules to account for the multimodal distribution. The presence of pear- and dumbbell-shaped granules in mast cells is consistent with this mechanism.

Animals↗

Bone scintigraphy and multimodality imaging in bone neoplasia: strategies for imaging in the new health care climate.

The integration of multiple imaging modalities in the assessment of musculoskeletal neoplasia is complex. Although no two instances are identical, certain guidelines can be gleaned from our experience as well as that reported in the literature. Assessment of most soft tissue masses is best carried forth with a combination of conventional radiography and magnetic resonance imaging (MRI). Screening skeletal scintigraphy without localizing symptomatology that includes axial and appendicular skeleton is best carried out initially with bone scintigraphy. Screening the axial skeleton in the presence of clinical symptomatology or a strong suspicion of axial skeletal metastases or pathology is best implemented as a total spine screening examination with MRI and specialized pulsing sequences. Computed tomography is reserved primarily for assessment of cortical and juxtacortical lesions, fracture fragment positioning and/or configuration, and characterization of lesion matrix calcification or ossification when conventional radiographs are indeterminate. Although physical examination and conventional radiography still remain the initial medical algorithms used to evaluate possible musculoskeletal neoplasia, primary skeletal tumors may require multimodality imaging to segregate aggressive and nonaggressive processes. In this multimodality scenario, bone scintigraphy has a critical role in assisting with differentiation between malignant and benign neoplasms.

Bone Neoplasms↗

Superior temporal sulcus anatomical abnormalities in childhood autism: a voxel-based morphometry MRI study.

The underlying neurobiology of autism, a severe pervasive developmental disorder, remains unknown. Few neocortical brain MRI abnormalities have been reported. Using rest functional brain imaging, two independent studies have described localized bilateral temporal hypoperfusion in children with primary autism. In order to search for convergent evidence of anatomical abnormalities in autistic children, we performed an anatomical MRI study using optimized whole-brain voxel-based morphometry (VBM). High-resolution 3-D T1-weighted MRI data sets were acquired in 21 children with primary autism (mean age 9.3 +/- 2.2 years) and 12 healthy control children (mean age 10.8 +/- 2.7 years). By comparing autistic children to normal children, we found bilaterally significant decreases of grey matter concentration located in superior temporal sulcus (STS) (P < 0.05 corrected, after small volume correction; SVC). Children with autism were also found to have a decrease of white matter concentration located in the right temporal pole and in cerebellum (P < 0.05, corrected) compared to normal children. These results suggest that autism is associated with bilateral anatomical abnormalities localized in the STS and are remarkably consistent with functional hypoperfusion previously reported in children with autism. The multimodal STS areas are involved in highest level of cortical integration of both sensory and limbic information. Moreover, the STS is now recognized as a key cortical area of the "social brain" and is implicated in social perceptual skills that are characteristically impaired in autism. Therefore, the convergent anatomical and functional temporal abnormalities observed in autism may be important in the understanding of brain behavior relationships in this severe developmental disorder.

Adolescent↗

Multimodal quantal release at individual hippocampal synapses: evidence for no lateral inhibition.

Most CNS synapses investigated thus far contain a large number of vesicles docked at the active zone, possibly forming individual release sites. At the present time, it is unclear whether these vesicles can be discharged independently of one another. To investigate this problem, we recorded miniature excitatory currents by whole-cell and single-synapse recordings from CA3-CA1 hippocampal neurons and analyzed their stochastic properties. In addition, spontaneous release was investigated by ultrastructural analysis of quickly frozen synapses, revealing vesicle intermediates in docking and spontaneous fusion states. In these experiments, no signs of inhibitory interactions between quanta could be detected up to 1 msec from the previous discharge. This suggests that exocytosis at one site does not per se inhibit vesicular fusion at neighboring sites. At longer intervals, the output of quanta diverged from a random memoryless Poisson process because of the presence of a bursting component. The latter, which could not be accounted for by random coincidences, was independent of Ca2+ elevations in the cytosol, whether from Ca2+ flux through the plasma membrane or release from internal stores. Results of these experiments, together with the observation of spontaneous pairs of omega profiles at the active zone, suggest that multimodal release is produced by an enduring activation of an integrated cluster of release sites.

Animals↗

Back to the Future for Clinical Oncology.

Dear Colleague: I remember, but just barely, what it was like to practice medicine in the first half of this century. My Dad was a general practitioner in a very small farming community in central Illinois, with a hospital of six beds and a trusting clientele. His patients thought he knew how to do everything: deliver babies, set broken bones and take out an appendix. He was an advocate for his patients, not for an HMO or an insurance company. He derived great satisfaction from his practice and was comfortable in this role, up to a point, but knew that he frequently needed the help of specialists from Decatur, St. Louis, and the Mayo Clinic. As his experience and practice evolved, and as medicine itself changed, referrals became a sign of good practice and not an indication of weakness or inadequacy. Some doctors in our town continued to do more than they should have and resisted the trend, and their patients, many with blind faith in their doctor, suffered for it. Clearly, there were economic as well as emotional factors that contributed to this reluctance to ask for help. Clinical oncology is facing much the same situation today. Scientific and economic forces are revolutionizing medicine, but not always in compatible directions. Practice and research have evolved to the point where old patterns of practice are no longer optimal. Few cancer patients can be managed without the input, advice, and even direct involvement of specialists from sister disciplines. Thus, multimodality management of cancer patients is now the norm rather than the exception. At the same time, strong economic forces are dictating a movement in the opposite direction, undermining the strength of traditional academic centers and limiting choices, streamlining patient evaluation, and creating "pathways" to standardize patient management. Who should be setting the course for the cancer patient? We agree that it should not be a clerk at the other end of the phone at the HMO, a computerized practice manual, or even the gatekeeper, who watches his or her capitated bottom line with great nervousness. It should be the physician(s) best able to evaluate the alternatives and communicate these choices to the patient and family. Often it is not possible for a solo physician to make these choices in isolation, particularly when the decisions involve multiple specialties and multimodality therapies. At presentation, many primary cancers now require an integration of the opinion of more than one specialist, and increasingly this integration occurs before surgery. Breast, lung, and prostate cancer, three of our most common diseases, illustrate this point with growing clarity. While less convenient for the doctor, and perhaps less efficient than the "old style" of practice, multimodatity disease center clinics offer significant advantages both to the patient and to the research effort, and are here to stay. Certainly for the payer it is faster and cheaper to have one doctor do it all, but I doubt that the results will be as good. Obviously not all patients need this cooperative approach. It would waste good physicians' time to require that all patients be seen by a radiotherapist, surgeon, and medical oncologist or pediatric oncologist. The specific circumstances may clearly dictate a simple approach and an uncomplicated decision, particularly in dealing with metastatic solid tumors, or at the other extreme, in managing easily resectable, low-risk tumors. However, even here, optimal management of local disease or of potentially resectable metastases may require consideration of an expanded series of options. Thus, all cancer specialists need to be aware of the potential of their colleagues to contribute to disease management. ellipsisWhich brings us to the reason for this journal. The editorial board members of The Oncologist hold the belief that the various subspecialists in oncology should share the same information base and read from the same journal. We believe that cancer specialists should resist the trend to capitulate our responsibilities in disease management to payers, gatekeepers, and hospital administrators. It is up to us to defend the patient's turf and to assure that the patient has an advocate. In order to do so, we will have to be united and fully informed. In this journal, we hope to put the best and latest information on cancer management before our readership, to prepare them for the future, and to do their best as a team for every patient. To this end, we hope to challenge the reader to understand what is new and better, and to let you glimpse the future, not only in terms of research, but also in terms of new team approaches to disease management. We hope to explore how cancer medicine could be and will be practiced as we pass through the economic revolution and return to the future.

Journal Article↗