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PubMed2003

Orthopaedic surgery in the elderly.

The orthopaedic surgeon brings to the operating room some of the greatest challenges for the anaesthesiologist. Various factors, such as age, health status, disease process, type and extent of operative procedure, provide differing circumstances, which an anaesthesiologist is obliged to cope with. This contrasts to other surgical specialities in which patient factors and operative procedures are much more predictable. The number of older patients in orthopaedics is steadily growing, and the anaesthesiologist has to take all measures to permit an early and efficient rehabilitation, a concept which is now widely recognized for improving the success of orthopaedic surgical procedures. Factors which may hinder this concept are post-operative pain, central nervous system dysfunction, fatigue, deep sedation, delayed enteral feeding and absorption. There is no evidence that regional anaesthesia without the use of the continuous regional analgesic technique decreases morbidity and mortality as compared to general anaesthesia, in this context. However, the advantages of continuous analgesia through a perineural spinal or epidural catheter are promising and deserve further investigation. The concept of the optimal post-operative multimodal regimen needs to be defined. The application of NSAID and paracetamol is an integral part of this concept, and the dose of opioids should be titrated to the lowest efficient dose needed. Thus, this chapter discusses the different controversies and future trends of anaesthesia with regard to the elderly in orthopaedic surgery.

Aged↗

PubMedDate not supplied

Multimodal assessment of the primary healthcare system of Serbia: a model for evaluating post-conflict health systems.

INTRODUCTION: Conflicts, social unrest, and disasters can significantly affect the ability of a healthcare system to provide for the needs of its citizens. The collapse of the primary healthcare system in Serbia is a model of the effects that civil unrest can have on the health of a population. However, with improving social and political conditions, focus now can be turned towards the greatly needed development and reorganization of the primary healthcare system in Serbia. Due to the complexity of health-system reform in the post-conflict/post-disaster setting, attempts to restructure health services are fraught with pitfalls that often are unanticipated because of inadequate preliminary assessments. A multimodal assessment involving quantitative and qualitative methodologies may provide a more robust mechanism to identify key programmatic priorities and critical barriers for appropriate and sustainable health-system interventions. The purpose of this study is to describe a multimodal assessment using primary healthcare in post-conflict Serbia as a model. METHODS: Integrated quantitative and qualitative methodologies--system characterization and observation, focus group discussions, free-response questionnaires, and Q-methodology--were used to identify needs, problems, and potential barriers to primary healthcare development in Serbia. Participants included primary healthcare providers and administrators from 13 institutions throughout Belgrade. RESULTS: Demographic data indicate a well-established infrastructure of primary health centers and stations. However, focus group discussions and free-response questionnaires reveal significant impediments to delivery of care: (1) Inadequate equipment, supplies, and medications; (2) Poor financial investment; (3) Discouraging worker salaries; (4) Few opportunities for professional development; and (5) Little emphasis on or respect for primary healthcare. Q-methodology of provider perceptions and opinions supports these concerns, shows remarkable consensus among participants, and provides further insights toward system development by grouping respondents into distinctive types. CONCLUSIONS: This study identified the critical needs and barriers to development of primary healthcare in Serbia. This combined methodology may serve as a model for future health system assessments in the post-conflict and post-disaster settings.

Delivery of Health Care↗

PubMed2000

Involuntary orienting to sound improves visual perception.

To perceive real-world objects and events, we need to integrate several stimulus features belonging to different sensory modalities. Although the neural mechanisms and behavioural consequences of intersensory integration have been extensively studied, the processes that enable us to pay attention to multimodal objects are still poorly understood. An important question is whether a stimulus in one sensory modality automatically attracts attention to spatially coincident stimuli that appear subsequently in other modalities, thereby enhancing their perceptual salience. The occurrence of an irrelevant sound does facilitate motor responses to a subsequent light appearing nearby. However, because participants in previous studies made speeded responses rather than psychophysical judgements, it remains unclear whether involuntary auditory attention actually affects the perceptibility of visual stimuli as opposed to postperceptual decision and response processes. Here we provide psychophysical evidence that a sudden sound improves the detectability of a subsequent flash appearing at the same location. These data show that the involuntary orienting of attention to sound enhances early perceptual processing of visual stimuli.

Adult↗

PubMed2025

Integrating Imaging-Derived Clinical Endotypes with Plasma Proteomics and External Polygenic Risk Scores Enhances Coronary Microvascular Disease Risk Prediction.

Coronary microvascular disease (CMVD) is an underdiagnosed but significant contributor to the burden of ischemic heart disease, characterized by angina and myocardial infarction. The development of risk prediction models such as polygenic risk scores (PRS) for CMVD has been limited by a lack of large-scale genome-wide association studies (GWAS). However, there is significant overlap between CMVD and enrollment criteria for coronary artery disease (CAD) GWAS. In this study, we developed CMVD PRS models by selecting variants identified in a CMVD GWAS and applying weights from an external CAD GWAS, using CMVD-associated loci as proxies for the genetic risk. We integrated plasma proteomics, clinical measures from perfusion PET imaging, and PRS to evaluate their contributions to CMVD risk prediction in comprehensive machine and deep learning models. We then developed a novel unsupervised endotyping framework for CMVD from perfusion PET-derived myocardial blood flow data, revealing distinct patient subgroups beyond traditional case-control definitions. This imaging-based stratification substantially improved classification performance alongside plasma proteomics and PRS, achieving AUROCs between 0.65 and 0.73 per class, significantly outperforming binary classifiers and existing clinical models, highlighting the potential of this stratification approach to enable more precise and personalized diagnosis by capturing the underlying heterogeneity of CMVD. This work represents the first application of imaging-based endotyping and the integration of genetic and proteomic data for CMVD risk prediction, establishing a framework for multimodal modeling in complex diseases.

Cardiovascular Disease↗

PubMed2025

Ferroptosis in Oral Cancer: Mechanistic Insights and Clinical Prospects.

Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, has emerged as a pivotal vulnerability in oral squamous cell carcinoma (OSCC). This review provides an overview of ferroptosis mechanisms and their implications for OSCC pathobiology and therapy. OSCC cells exhibit heightened reliance on anti-ferroptotic defenses such as GPX4, SLC7A11, FSP1, and Nrf2, and disrupting these pathways suppresses tumor growth and restores sensitivity to chemotherapy, radiotherapy, and immunotherapy. Genetic and epigenetic regulators, including p53, PER1, circ_0000140, and STARD4-AS1, critically modulate ferroptotic sensitivity, while metabolic enzymes such as ACSL4, LPCAT3, and TPI1 link ferroptosis to cellular plasticity and resistance. Preclinical studies highlight the promise of small-molecule inhibitors, repurposed agents (e.g., sorafenib, artesunate, trifluoperazine), natural compounds (e.g., piperlongumine, Evodia lepta, quercetin), and nanomedicine platforms for targeted ferroptosis induction. We further address ferroptosis within the tumor microenvironment, highlighting its immunogenic and context-dependent dual roles, and summarize genomic and transcriptomic evidence linking ferroptosis-related genes to patient prognosis. Beyond cancer, ferroptosis also contributes to non-malignant oral diseases, including pulpitis, periodontitis, and infection-associated inflammation, where inhibitors may protect tissues. Despite these advances, clinical translation is constrained by the lack of safe ferroptosis inducers and validated biomarkers. Future research should focus on developing pharmacologically viable GPX4 inhibitors, refining biomarker-driven patient stratification, and designing multimodal regimens that combine ferroptosis induction with standard therapies while preserving immune and tissue integrity. Ferroptosis therefore represents both a mechanistic framework and a translational opportunity to reshape oral oncology and broader oral disease management.

Humans↗

PubMed2000

[Vulvar Paget's disease. Clinico-pathologic review of the literature].

In 1986 the International Society For the Study of Vulvar Disease classified vulvar Paget's disease (VPD) as a non-squamous intraepithelial lesion of the vulva. The clinical multiform aspect of VPD, similar to other dermatological lesions, often delays the execution of a biopsy. Paget's cells could be instead easily identified at histological examination and with histochemical reactions. Underlying adenocarcinomas or stromal invasion are present in about 10% of intraepithelial VPD. Patients with VPD are at risk for a second synchronous or metachronous neoplasia: colo-rectal adenocarcinoma (more frequent in perianal localization of VPD), cervical adenocarcinoma, carcinoma of the transitional epithelium from the renal pelvis to urethra and mammary carcinoma. A wide spectrum of frequency of these associations is reported in the literature (0-45%). Therapy for intraepithelial VPD is wide and deep surgical resection comprising all the skin appendages. However VPD has a high frequency of recurrences (15-62%), often irrespective for radicality of surgical excision. When association with underlying invasive adenocarcinoma or stromal invasion is histologically confirmed, vulvar surgical approach must be integrated with inguino-femoral lymphadenectomy. The role of chemotherapy and radiotherapy in the multimodal approach to extensive or recurring VPD is still controversial. Recurrences or progression of intraepithelal VPD are reported more than 10 years from first surgical resection so that long term follow-up is mandatory.

Female↗

PubMed2006

Performance test of an LSO-APD detector in a 7-T MRI scanner for simultaneous PET/MRI.

UNLABELLED: PET combined with CT has proven to be a valuable multimodality imaging device revealing both functional and anatomic information. Although PET/CT has become completely integrated into routine clinical application and also has been used in small-animal imaging, CT provides only limited soft-tissue contrast and, in preclinical studies, exposes the animal to a relatively high radiation dose. Unlike CT, MRI provides good soft-tissue contrast even without application of contrast agents and, furthermore, does not require ionizing radiation. METHODS: This project focused on combining a high-resolution PET scanner with a 7-T MRI system for animal research. Because classic PET detectors based on photomultiplier tubes cannot be used in high magnetic fields, we used a detector technology based on 10 x 10 lutetium oxyorthosilicate crystal arrays and 3 x 3 avalanche photodiode arrays. A ring of such PET detectors will ultimately be used as an insert for the 119-mm-diameter MRI bore. RESULTS: Initial measurements with 1 PET detector module in the 7-T field during application of MRI sequences were encouraging. Position profiles from the PET detectors and a first MR image of a mouse could be acquired simultaneously. CONCLUSION: Further work will concentrate on the construction of a full PET detector ring with compact, integrated electronics.

Animals↗

PubMed1987

Defective cytoplasmic granule formation. I. Abnormalities affecting tissue mast cells and pancreatic acinar cells of beige mice.

Beige mice (C57BL/6-bgJ/bgJ) express the Chediak-Higashi syndrome, a genetically determined constellation of morphologic and functional abnormalities affecting cells that synthesize cytoplasmic granules; a similar disorder also occurs in humans and several other mammalian species. We used a computer-assisted morphometric approach to identify and quantitate the effect of the beige mutation on the structure of mast cell or pancreatic acinar cell cytoplasmic granules. Beige and control mouse mast cell or pancreatic acinar cell granules exhibited periodic, multimodal distributions of equivalent volumes in which the modes fell at volumes that were integral multiples of the volume of the "unit granule," whose volume (the "unit volume" or v1) was defined by the first mode in the granule equivalent volume distribution. But the modal frequency of the C57BL/6-bgJ/bgJ mast cell granule equivalent volume distribution fell at v1, a pattern consistent with a haphazard pattern of "unit granule" fusion, whereas the corresponding modal frequency for the control mast cell granules fell at v3, a pattern consistent with a "unit addition" model of granule fusion. In addition, the unit volume of beige mouse mast cell granules was 18 times that of control mouse mast cell granules. By contrast, the unit volume of beige mouse pancreatic acinar cell granules was only slightly (23%) greater than that of control cells. C57BL/6-bgJ/bgJ and control cells did not differ significantly in total cell or nuclear volume, or in the aggregate volume of their cytoplasmic granules. However, C57BL/6-bgJ/bgJ mast cells or pancreatic acinar cells contained significantly fewer granules than did their normal counterparts. These findings are consistent with the hypothesis that the beige mutation affects the formation of unit granules and also alters the pattern of aggregation and fusion of unit granules. The data also identify quantitative differences in the expression of the beige mutation in mast cells and pancreatic acinar cells.

Animals↗

PubMed1999

Interactive processing of sensory input and motor output in the human hippocampus.

Recent studies of visuomotor integration suggest that the motor system may be intimately involved in the detection of salient features of the sensory scene. The final stages of sensory processing occur in hippocampal structures. We measured human neuromagnetic responses during motor reaction to an auditory cue embedded in high-speed multimodal stimulation. Our results demonstrate that large-scale cognitive networks may recruit additional resources from the hippocampus during sensorimotor integration. Hippocampal activity from 300 msec before to 200 msec after cued movements was enhanced significantly over that observed during self-paced movements. The dominant hippocampal activity appeared equally synchronized to both sensory input and motor output, consistent with timing by an intrinsic mechanism, possibly provided by ongoing theta oscillations

Acoustic Stimulation↗

PubMed2025

Vasoactive Agent Therapy in Septic Shock: From Monotherapy Battles to Tailored Hemodynamic Optimization.

Hemodynamic stabilization and preservation of organ perfusion are central elements in the management of septic shock. This is achieved by fluid resuscitation and by administration of vasoactive agents to secure a time window for definitive cause-directed therapy. Guided by the Surviving Sepsis Campaign, the optimization of vasoactive agent strategies, namely protective hemodynamic management, has become a central focus. Tracing key research over the past 25 years reveals a paradigm shift in vasopressor therapy, from empiricism to goal-directed strategy. This evolution has deepened our understanding of the benefit-risk profile of vasoactive agents and fostered a new conceptual framework regarding organ perfusion and protection. Under this framework, management strategies have advanced from the mere pursuit of hemodynamic parameters to care bundles that integrate the monitoring of organ perfusion, microcirculation, and oxygen metabolism. These advances have optimized agent selection, established safe dosing ranges, and ultimately promoted the widespread adoption of combined and multimodal therapy concepts. This review delineates this transformative journey, synthesizing evidence on the reappraisal of traditional agents and exploring "de-catecholaminization" strategies, thereby aiming to broaden the therapeutic landscape. The integration of artificial intelligence and genomic medicine is expected to further advance personalized management strategies for septic shock.

Humans↗

PubMed2001

Multimodality neuroimaging: research and clinical applications.

This manuscript reviews the current stance and the pertinent problems of transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) as brain mapping methodologies. The missing structure-function relation limits the use of TMS, whereas the uncertainty about the functional significance of activated cortical regions might render interpretation of fMRI studies difficult. Advances in image processing, however, allowed for 3- dimensional real-time visual guidance of TMS and integration with fMRI data. We describe the method used to coregister TMS and fMRI and present examples where a multimodality neuroimaging approach might add to our understanding of normal and pathological brain function.

Brain Mapping↗

PubMed2006

A new combination treatment for premature ejaculation: a sex therapist's perspective.

This article describes the diagnosis and treatment of premature ejaculation (PE) from a sex therapist's perspective and proposes that combination therapy integrating sex therapy and sexual pharmaceuticals is frequently the best treatment approach. Failure to appreciate the multimodal etiology and pathophysiology of PE makes the condition more difficult to diagnose and treat. Many physicians have tried pharmacologic approaches, but are limited to providing topical anesthetics or suggesting off-label uses of antidepressant and erectile dysfunction medications, because no medication is currently indicated specifically for PE. Furthermore, patients frequently relapse after discontinuation of the pharmaceutical. Sex therapists appreciate the multidimensional nature of PE for the patient and partner, but few patients seek out this approach, which is labor-intensive and often lacking long-term follow-up success. Most men with PE are not receiving treatment, secondary to their embarrassment about discussing their condition and a lack of clinician inquiry about sexual dysfunction. Even for those who do engage in discussion, diagnoses may be inconsistent, because a universally accepted definition of the condition and diagnostic criteria are nonexistent. Men with PE experience anxiety and lack sexual self-confidence; subsequently, their sexual and overall relationship frequently suffer. Because PE involves psychosocial and physiologic factors, treatment that addresses both should yield the best balance of function. There is interest in new agents designed specifically for PE to provide an improved pharmacotherapeutic opportunity. Yet, a combination treatment integrating pharmaceuticals and sex therapy would provide an optimized approach. Besides increasing coital latency directly, sexual pharmaceuticals could be used to provide greater opportunity for men to recognize their premonitory sensations to ejaculation more readily, facilitating a "choice point", which is key to facilitating behavioral change and learning. Such a combination approach would result in prolonged ejaculatory latency, improved treatment satisfaction, and superior long-term outcome.

Clinical Competence↗

PubMed1998

Visual and song nuclei correlate with courtship skills in brown-headed cowbirds.

We assessed courtship success in 14 adult male brown-headed cowbirds, Molothrus ater. Volumes of song control nuclei and visual nuclei were measured in Nissl stained tissue. Variation in courtship success was found to be related to variation in two areas of the avian brain: the song control nucleus, area X, and the thalamic visual area, nucleus rotundus. Volume of area X was negatively correlated with song potency, as assessed by female playback, and with rate of vocalizing. Volume of nucleus rotundus was positively correlated with song potency, vocalizing to females and courtship persistence. These data are the first to implicate a visual nucleus in the use of song. The data also complement previous findings with cowbirds suggesting that song learning involves visual attention to females. Taken as a whole, these results suggest that use of song depends on integration of auditory, vocal and visual information. In that female songbirds in many species assess multimodal performance of song, these findings with cowbirds suggest that future studies of brain and behaviour include a broader view of possible behavioural and neural correlates. Copyright 1998 The Association for the Study of Animal Behaviour.

Journal Article↗

PubMed1994

Contemplating the plasmalemmal control center model.

An abundant epidermal mechanosensory calcium-selective ion channel appears able not only to detect mechanical stimuli such as those that initiate gravitropism but also to detect thermal, electrical, and various chemical stimuli. Because it responds to multimodal input with a second messenger output, this channel system seems likely to be an integrator that can engage in feedbacks with many other systems of the cell--and feedback is the hallmark of regulation. In general, the mechanical tension required for channel activation is likely transmitted from the relatively rigid cell wall to the plasma membrane system via linkage or adhesion sites that display antigenicities recognized by antibodies to animal beta-1 integrin, vitronectin, and fibronectin and which have mechanical connections to the cytoskeleton. Thus, functionally, leverage exerted against any given adhesion site will tend to control channels within a surrounding domain. Reactions initiated by passage of calcium ions through the channels could presumably be more effectively regulated if channels within the domains were somewhat clustered and if appropriate receptors, kinases, porters, pumps, and some key cytoskeletal anchoring sites were in turn clustered about them. Accumulating evidence suggests not only that activity of clusters of channels may contribute to control of cytoskeletal architecture and of regulatory protein function within their domain, but also that both a variety of regulatory proteins and components of the cortical cytoskeleton may contribute to control of channel activity. The emerging capabilities of electronic optical microscopy are well suited for resolving the spatial distributions of many of these cytoskeletal and regulatory molecules in living cells, and for following some of their behaviors as channels are stimulated to open and cytosolic calcium builds in their vicinity. Such microscopy, coupled with biochemical and physiological probing, should help to establish the nature of the feedback loops putatively controlled by the linkage sites and their channel domains.

Calcium Channels↗

PubMed1999

Soft tissue sarcoma in adults.

Soft tissue sarcomas are a heterogeneous group of tumors, consisting of numerous histiotypes that all share a putative common mesenchymal origin. Although prognosis of these tumors is determined by clinical parameters (size, location, and resection margin status) and pathologic features (mitotic activity and necrosis), the histologic subtype has never been shown to be a consistent independent prognostic factor. Some relevant differences among these histiotypes are emerging, in specific biological parameters such as proliferation indices, in integrin expression profiles, and with regard to drug sensitivity. Several biological factors are considered to be prognostically important. Most attention is directed to regulators of cell-cycle progression. The significance of p53 dysregulation is confirmed by the inhibition of cellular proliferation, both in in-vitro and in in-vivo sarcoma models, after reintroduction of wild type p53. A multidisciplinary approach is essential for the optimal treatment of soft tissue sarcomas. Multimodality treatment has led to a patient-tailored approach with limb-sparing resections integrated with external and/or interstitial irradiation. The value of chemotherapy both in the neoadjuvant and the adjuvant setting, although of critical value in other sarcomas such as Ewing's sarcoma and osteosarcoma, remains to be established for soft tissue sarcomas.

Adult↗

PubMed1999

[The hyperkinetic child in ambulatory care. Therapeutic strategies for long-term care].

Children with a hyperkinetic disorder (attention deficit, hyperactivity, impulsiveness) should be diagnosed early in order to avoid difficulties in the family and with friends, and, in particular at school, and thus to positively influence the child's development. The present article discusses the definition, course, accompanying disorders and appropriate forms of treatment. Most important for outpatient treatment is the multimodal approach, in which various forms of therapy for the children and their families are integrated. Adequate outpatient treatment facilities must be made available in order to induce the children and their families to undergo long-term treatment.

Adolescent↗

PubMed1991

Crossmodal integration in the identification of consonant segments.

Although speechreading can be facilitated by auditory or tactile supplements, the process that integrates cues across modalities is not well understood. This paper describes two "optimal processing" models for the types of integration that can be used in speechreading consonant segments and compares their predictions with those of the Fuzzy Logical Model of Perception (FLMP, Massaro, 1987). In "pre-labelling" integration, continuous sensory data is combined across modalities before response labels are assigned. In "post-labelling" integration, the responses that would be made under unimodal conditions are combined, and a joint response is derived from the pair. To describe pre-labelling integration, confusion matrices are characterized by a multidimensional decision model that allows performance to be described by a subject's sensitivity and bias in using continuous-valued cues. The cue space is characterized by the locations of stimulus and response centres. The distance between a pair of stimulus centres determines how well two stimuli can be distinguished in a given experiment. In the multimodal case, the cue space is assumed to be the product space of the cue spaces corresponding to the stimulation modes. Measurements of multimodal accuracy in five modern studies of consonant identification are more consistent with the predictions of the pre-labelling integration model than the FLMP or the post-labelling model.

Attention↗

PubMed2001

Spatial attention and crossmodal interactions between vision and touch.

In the present paper, we review several functional imaging studies investigating crossmodal interactions between vision and touch relating to spatial attention. We asked how the spatial unity of a multimodal event in the external world might be represented in the brain, where signals from different modalities are initially processed in distinct brain regions. The results highlight several links between visual and tactile spatial representations. First, we found that activity in the anterior part of the intraparietal sulcus was influenced by stimulus position independently of the modality of the stimulation. This is consistent with crossmodal interactions via sensory convergence from early modality-specific spatial maps to higher-order multimodal regions. Second, we found that stimulation in, or attention to, one modality could affect activity in areas dedicated to a different modality, in a spatially-specific manner. These spatial crossmodal effects in unimodal regions demonstrate congruous activity in anatomically distant brain areas that represent similar external locations, implicating a distributed network of spatial representations in crossmodal integration. Finally, the results suggest that the temporo-parietal junction may be involved in aspects of controlling spatial attention, for both vision and touch. A multimodal attentional system may influence activity in distinct brain areas representing common regions of space for different modalities, thus suggesting a link between spatial attention and crossmodal integration.

Attention↗