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PubMed1994

A CMOS integrated circuit for multichannel multiple-subject biotelemetry using bidirectional optical transmissions.

A CMOS integrated circuit for a noninvasive biological-signal telemetry system specified for use in medical and physiological studies of the influence of weightlessness in space is presented. The system can monitor multichannel (4 channels maximum) biological signals from multiple subjects (4 subjects maximum) in real time by using time multiplexing. A key technique, so-called synchronized multiple-subject telemetry, to achieve multiple-subject telemetry has been proposed. This technique utilizes bidirectional optical transmissions with direct and scattered infrared lights between an observer and each of the subjects. An experimental CMOS IC to give a small light-weight low-power, and smart telemetry instrument for use on animals has been developed. This IC is for evaluating circuit blocks of the implantable monolithic telemetry instrument. The major circuit blocks include CMOS digital circuits for synchronization, subject selection and time multiplexing, analog circuits for pulse interval modulation (PIM), and other blocks such as a CMOS optical pulse receiver and an LED driver. A preliminary experimental multichannel telemetry from two subjects has been performed with the implemented IC chips, and the principal operation of the multiple-subject optical biotelemetry has been demonstrated.

Aerospace Medicine↗

PubMed2000

Hypothalamic resetting at puberty and the sexual dimorphism of migraine.

It is well known that migraine is far more represented in females than in males. However, this gender-related difference is present only during reproductive life since in prepubertal children, migraine prevalence figures are independent of sex. Thus, transition to puberty accounts for changes which render females more susceptible to migraine attacks. In females, the main driver of the hormonal events allowing sexual maturation is the pulsatile secretion of hypothalamic LHRH modulated by opioid activity. Clinical reports suggest that migraine attacks could be prevented by the abolition of this neurohormonal secretion. On the other hand, several clinical and experimental observations have focused on neuroendocrine systems (opiatergic, serotonergic, adrenergic) as participating in the constitution of the so-called "migraine trait", the biological predisposition in patients that would explain their sensitivity to migraine triggers. Such neuroendocrine secretions are mainly dependent upon hypothalamic activity where a sexual dimorphic nucleus has been discovered in the preoptic area. We suggest that the sexual dimorphism of migraine should be sought in hypothalamic networks related to LHRH secretion.

Adolescent↗

PubMed2001

Lateral interactions between targets and flankers in low-level vision depend on attention to the flankers.

Detection of an oriented visual target can be facilitated by collinear visual flankers. Such lateral interactions are thought to reflect integrative processes in low-level vision. In past studies, the flankers were task-irrelevant, and were typically assumed to be unattended. Here we manipulated attention to the flankers directly, by requiring observers to judge the relative alignment of two flankers while ignoring a second flanker-pair. Under identical stimulus conditions, attended flankers produced typical lateral interactions, but ignored flankers did not. These data show that lateral interactions can depend on attention to the flanking context, revealing the functional consequences of attentional modulation in low-level vision.

Humans↗

PubMed2025

Cardiac hypertrophy at the crossroads: Mechanistic insights and emerging multimodal therapeutic strategies.

Cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide, accounting for approximately 17.9 million deaths annually. Among their diverse manifestations, cardiac hypertrophy is a clinically significant condition that predisposes patients to heart failure, arrhythmias, and and sudden cardiac death. Clinically, hypertrophy can be classified into three forms: physiological (adaptive) hypertrophy, which supports cardiac performance and is reversible, pathological hypertrophy most often secondary to hypertension, valvular disease, hemodynamic stress, or sustained neurohumoral activation; and hypertrophic cardiomyopathy (HCM) represents a primary genetic disorder, most often caused by mutations in sarcomeric proteins. These distinct etiologies have important therapeutic implications, as they determine how efficiently pharmacological agents can target underlying mechanisms. Conventional pharmacological treatments are widely used in clinical practice, yet they provide limited reversal of established remodeling. This therapeutic gap has driven the development of innovative modalities such as RNA-based therapeutics, exosome-mediated interventions, stem cell-derived therapies, and genome-editing technologies, which aim to modulate maladaptive signaling and restore myocardial integrity. This review integrates clinical perspectives with mechanistic insights, delineating the drivers of pathological hypertrophy while evaluating both established therapies and emerging strategies that hold promise for precision cardiology and improved patient outcomes.

Humans↗

PubMed2004

Pharmacological and genetic modulation of Wnt-targeted Cre-Lox-mediated gene expression in colorectal cancer cells.

Wnt-targeted gene therapy has been proposed as a treatment for human colorectal cancer (CRC). The Cre-Lox system consists of methodology for enhancing targeted expression from tissue-specific or cancer-specific promoters. We analyzed the efficiency of Wnt-specific promoters as drivers of the Cre-mediated activity of a luciferase reporter gene or cell death effector gene in CRC cell lines in the presence and absence of two modulators of Wnt activity, sodium butyrate and lithium chloride. Butyrate is present in the colonic lumen after digestion of fiber-rich foods, whereas the colonic lumen is readily accessible to lithium chloride. In both SW620 and HCT-116 CRC cells, a physiologically relevant concentration of butyrate upregulated reporter and effector activity and altered the Wnt-specific expression pattern. Lithium chloride markedly enhanced Cre-Lox-mediated Wnt-specific reporter expression only in APC wild-type CRC cells. Possibilities for genetic modulation of the proposed CRC therapy included Wnt-specific expression of a floxed Lef1-VP16 fusion that enhanced Wnt-specific cell death and of a floxed dominant-negative Tcf4 that specifically downregulated endogenous Wnt activity. These findings demonstrated that the Cre-Lox system, in combination with pharmacological and genetic modulators, represents effective methodology for enhancing Wnt-targeted gene therapy.

Apoptosis↗

PubMed2005

Gaze direction modulates auditory spatial deficits in stroke patients with neglect.

We investigated the effects of eye position on auditory spatial deficits in four patients with left neglect and right-hemisphere damage, using three blocked gaze directions (35 degrees to the right, central, or 35 degrees to the left), while preventing any head-movement to ensure that initial auditory inputs remained constant regardless of eye-in-orbit position. The auditory task required speeded discrimination of sound elevation, with patients moving a central lever up or down according to the vertical position of a peripheral target sound, regardless of its side (left or right). Replicating previous auditory research, the patients' vertical discrimination performance was worse for auditory targets on the contralesional (left) versus the ipsilesional side, indicating neglect-related auditory deficits on this task. Critically, while this worse performance for left than right auditory targets was present (for both reaction times and errors) when gaze was directed centrally or rightwards, it was considerably reduced when gaze was directed leftwards. These results demonstrate that lateral gaze-direction can modulate neglect-related auditory spatial deficits, even though eye-position did not alter the initial auditory inputs. This outcome may relate to audio-visual links in spatial orienting and potentially some retinocentric influences on perceived sound location, although the latter alone could not explain all our results. Such findings might involve multisensory brain structures in which responses to sounds are modulated by eye-in-orbit position.

Attention↗

PubMed1989

Ciliogenesis and ciliation of the respiratory epithelium in the human fetal cartilaginous trachea.

Ciliogenesis of the respiratory epithelium in the human cartilaginous trachea start during the 12th week of gestation. Ciliary shafts are first seen under the scanning electron microscope during the 13th week. Unlike its membranous counterpart, ciliary shafts appear all over the epithelial surface at almost the same time. Epithelial cells destined to become ciliated cells first develop numerous long and thin microvilli. A process of individual cell extrusion and proliferation of neuroepithelial bodies around the carinal angle precede ciliation in the respiratory epithelium of the cartilaginous trachea. Epithelial cell differentiation patterns in both the cartilaginous and membranous trachea are different. The mechanisms involved in modulating cell differentiation are currently under investigation.

Cartilage↗

PubMed2001

Effects of attention and emotion on face processing in the human brain: an event-related fMRI study.

We used event-related fMRI to assess whether brain responses to fearful versus neutral faces are modulated by spatial attention. Subjects performed a demanding matching task for pairs of stimuli at prespecified locations, in the presence of task-irrelevant stimuli at other locations. Faces or houses unpredictably appeared at the relevant or irrelevant locations, while the faces had either fearful or neutral expressions. Activation of fusiform gyri by faces was strongly affected by attentional condition, but the left amygdala response to fearful faces was not. Right fusiform activity was greater for fearful than neutral faces, independently of the attention effect on this region. These results reveal differential influences on face processing from attention and emotion, with the amygdala response to threat-related expressions unaffected by a manipulation of attention that strongly modulates the fusiform response to faces.

Adult↗

PubMed1995

A strategy for database interoperation.

To realize the full potential of biological databases (DBs) requires more than the interactive, hypertext flavor of database interoperation that is now so popular in the bioinformatics community. Interoperation based on declarative queries to multiple network-accessible databases will support analyses and investigations that are orders of magnitude faster and more powerful than what can be accomplished through interactive navigation. I present a vision of the capabilities that a query-based interoperation infrastructure should provide, and identify assumptions underlying, and requirements of, this vision. I then propose an architecture for query-based interoperation that includes a number of novel components of an information infrastructure for molecular biology. These components include a knowledge base that describes relationships among the conceptualizations used in different biological databases, a module that can determine the DBs that are relevant to a particular query, a module that can translate a query and its results from one conceptualization to another, a collection of DB drivers that provide uniform physical access to different database management systems, a suite of translators that can interconvert among different database schema languages, and a database that describes the network location and access methods for biological databases. A number of the components are translators that bridge the heterogeneities that exist between biological DBs at several different levels, including the conceptual level, the data model, the query language, and data formats.

Artificial Intelligence↗

PubMed2025

Comparative Phylogenetics Reveal Clade-specific Drivers of Recombination Rate Evolution Across Vertebrates.

Meiotic recombination is an integral cellular process, required for the production of viable gametes. Recombination rate is a fundamental genomic parameter, modulating genomic responses to selection. Our increasingly detailed understanding of its molecular underpinnings raises the prospect that we can gain insight into trait divergence by examining the molecular evolution of recombination genes from a pathway perspective, as in mammals, where protein-coding changes in later stages of the recombination pathway are connected to divergence in intra-clade recombination rate. Here, we leverage increased availability of avian and teleost genomes to reconstruct the evolution of the recombination pathway across two additional vertebrate clades: birds, which have higher and more variable rates of recombination and similar divergence times to mammals, and teleost fish, which have much deeper divergence times. Rates of molecular evolution of recombination genes are highly correlated between vertebrate clades and significantly elevated compared to control panels, suggesting that they experience similar selective pressures. Avian recombination genes are significantly more likely to exhibit signatures of positive selection than other clades, unrestricted to later stages of the pathway. Signatures of positive selection in genes linked to recombination rate variation in mammalian populations and those with signatures of positive selection across the avian phylogeny are highly correlated. In contrast, teleost fish recombination genes have significantly less evidence of positive selection despite high intra-clade recombination rate variability. Gaining clade-specific understanding of patterns of variation in recombination genes can elucidate drivers of recombination rate and thus, factors influencing genetic diversity, selection efficacy, and species divergence.

Animals↗

PubMed2026

Newly identified invasion drivers define the tumor front in oral squamous cell carcinoma.

Cells at the invasive front of oral squamous cell carcinoma (OSCC) occupy a partial epithelial-to-mesenchymal transition (p-EMT) state that drives invasion and therapeutic resistance yet remains poorly understood. To define the regulators of this metastable state, we developed an isogenic OSCC model that captures stable epithelial and p-EMT phenotypes and used it to perform a genome-wide CRISPR invasion screen. This unbiased strategy identified 17 modulators of invasion, most previously unrecognized in cancer and virtually unexplored in OSCC, that converge on cytoskeletal remodeling, adhesion, and epigenetic regulation. Within this network, EDIL3 emerged as a central driver of EMT, invasion, and chemoresistance in head and neck cancer, extending prior reports in other tumor types. Importantly, the invasion signature derived from our screen localized with striking specificity to the tumor invasive front of human OSCC, providing direct clinical validation. Together, these findings reveal a novel, targetable network of transient invasion drivers defining the OSCC tumor front.

Journal Article↗

PubMed2004

Tetracycline-regulated transactivators driven by the involucrin promoter to achieve epidermal conditional gene expression.

To achieve conditional gene expression in the differentiated layers of the epidermis, we generated transgenic mice with the tetracycline-regulated transactivator proteins, tTA (tetracycline transactivator) and rtTA (reverse tetracycline transactivator), expressed from the human involucrin promoter. Interaction with tetracycline turns off or turns on the tTA and rtTA molecules, respectively, allowing for regulation of downstream target genes during development and postnatally. These transactivator lines were crossed with reporter mice driving LacZ expression from a tetracycline response element to analyze the specificity and levels of target gene expression. Quantitative beta-galactosidase experiments demonstrate a 30-fold induction, specific to epithelial tissues. Immunohistochemistry results illustrate that the beta-galactosidase staining follows that of endogenous involucrin expression. Induction initiates at embryonic day 14.5 with expression over the entire epidermal surface by E16.5. Together with other driver lines, expressing tetracycline transactivators in the mitotically active layers of the epidermis, these mice will allow investigators to specifically modulate expression of target genes to specific stages of epidermal differentiation.

Animals↗

PubMed2001

Role of lateral acceleration in curve driving: driver model and experiments on a real vehicle and a driving simulator.

Experimental studies show that automobile drivers adjust their speed in curves so that maximum vehicle lateral accelerations decrease at high speeds. This pattern of lateral accelerations is described by a new driver model, assuming drivers control a variable safety margin of perceived lateral acceleration according to their anticipated steering deviations. Compared with a minimum time-to-lane-crossing (H. Godthelp, 1986) speed modulation strategy, this model, based on nonvisual cues, predicts that extreme values of lateral acceleration in curves decrease quadratically with speed, in accordance with experimental data obtained in a vehicle driven on a test track and in a motion-based driving simulator. Variations of model parameters can characterize "normal" or "fast" driving styles on the test track. On the simulator, it was found that the upper limits of lateral acceleration decreased less steeply when the motion cuing system was deactivated, although drivers maintained a consistent driving style. This is interpreted per the model as an underestimation of curvilinear speed due to the lack of inertial stimuli. Actual or potential applications of this research include a method to assess driving simulators as well as to identify driving styles for on-board driver aid systems.

Acceleration↗

PubMed2005

Design and testing of low intensity laser biostimulator.

BACKGROUND: The non-invasive nature of laser biostimulation has made lasers an attractive alternative in Medical Acupuncture at the last 25 years. However, there is still an uncertainty as to whether they work or their effect is just placebo. Although a plethora of scientific papers published about the topic showing positive clinical results, there is still a lack of objective scientific proofs about the biostimulation effect of lasers in Medical Acupuncture. The objective of this work was to design and build a low cost portable laser device for stimulation of acupuncture points, considered here as small localized biosources (SLB), without stimulating any sensory nerves via shock or heat and to find out a suitable method for objectively evaluating its stimulating effect. The design is aimed for studying SLB potentials provoked by laser stimulus, in search for objective proofs of the biostimulation effect of lasers used in Medical Acupuncture. METHODS: The proposed biostimulator features two operational modes: program mode and stimulation mode and two output polarization modes: linearly and circularly polarized laser emission. In program mode, different user-defined stimulation protocols can be created and memorized. The laser output can be either continuous or pulse modulated. Each stimulation session consists of a pre-defined number of successive continuous or square pulse modulated sequences of laser emission. The variable parameters of the laser output are: average output power, pulse width, pulse period, and continuous or pulsed sequence duration and repetition period. In stimulation mode the stimulus is automatically applied according to the pre-programmed protocol. The laser source is 30 mW AlGaInP laser diode with an emission wavelength of 685 nm, driven by a highly integrated driver. The optical system designed for beam collimation and polarization change uses single collimating lens with large numerical aperture, linear polarizer and a quarter-wave retardation plate. The proposed method for testing the device efficiency employs a biofeedback from the subject by recording the biopotentials evoked by the laser stimulus at related distant SLB sites. Therefore measuring of SLB biopotentials caused by the stimulus would indicate that a biopotential has been evoked at the irradiated site and has propagated to the measurement sites, rather than being caused by local changes of the electrical skin conductivity. RESULTS: A prototype device was built according to the proposed design using relatively inexpensive and commercially available components. The laser output can be pulse modulated from 0.1 to 1000 Hz with a duty factor from 10 to 90%. The average output power density can be adjusted in the range 24-480 mW/cm2, where the total irradiation is limited to 2 Joule per stimulation session. The device is controlled by an 8-bit RISC Flash microcontroller with internal RAM and EEPROM memory, which allows for a wide range of different stimulation protocols to be implemented and memorized. The integrated laser diode driver with its onboard light power control loop provides safe and consistent laser modulation. The prototype was tested on the right Tri-Heater (TH) acupuncture meridian according to the proposed method. Laser evoked potentials were recorded from most of the easily accessible SLB along the meridian under study. They appear like periodical spikes with a repetition rate from 0.05 to 10 Hz and amplitude range 0.1-1 mV. CONCLUSION: The prototype's specifications were found to be better or comparable to those of other existing devices. It features low component count, small size and low power consumption. Because of the low power levels used the possibility of sensory nerve stimulation via the phenomenon of shock or heat is excluded. Thus senseless optical stimulation is achieved. The optical system presented offers simple and cost effective way for beam collimation and polarization change. The novel method proposed for testing the device efficiency allows for objectively recording of SLB potentials evoked by laser stimulus. Based on the biopotential records obtained with this method, a scientifically based conclusion can be drawn about the effectiveness of the commercially available devices for low-level laser therapy used in Medical Acupuncture. The prototype tests showed that with the biostimulator presented, SLB could be effectively stimulated at low power levels. However more studies are needed to derive a general conclusion about the SLB biostimulation mechanism of lasers and their most effective power and optical settings.

Acupuncture Points↗

PubMed2006

Occupational exposure to diesel exhausts and risk for lung cancer in a population-based case-control study in Italy.

BACKGROUND: We studied the effect of exposure to diesel exhausts on lung cancer risk in a population-based case-control study in the city of Turin, Italy. PATIENTS AND METHODS: Information on occupational histories of 595 incident lung cancer cases diagnosed in 1991-1992 and 845 population controls was obtained. During the interviews, diesel job-specific modules (D-JSMs) were administered whenever subjects had worked in occupations included in the following nine categories: railroad workers, miners, professional drivers and transport conductors, heavy-machine operators, mechanics and testers, filling station attendants, motor-vehicle park attendants, transport equipment operators, and occupations carried out in/near urban roads. All D-JSMs were evaluated for probability, intensity and frequency of exposure. RESULTS: The odds ratio for ever exposure to diesel exhausts was 1.04 (95% confidence interval 0.79-1.37), after adjusting for age, sex, smoking and having worked in occupations entailing exposure to known lung carcinogens. No association was found with intensity, probability and duration of exposure. CONCLUSIONS: Although misclassification of the exposure may have contributed to the negative results, we did not find an association between occupational exposure to diesel exhausts and lung cancer risk.

Case-Control Studies↗

PubMed2005

Does a pre-hospital emergency pathway improve early diagnosis and referral in suspected stroke patients?--Study protocol of a cluster randomised trial [ISRCTN41456865].

BACKGROUND: Early interventions proved to be able to improve prognosis in acute stroke patients. Prompt identification of symptoms, organised timely and efficient transportation towards appropriate facilities, become essential part of effective treatment. The implementation of an evidence based pre-hospital stroke care pathway may be a method for achieving the organizational standards required to grant appropriate care. We performed a systematic search for studies evaluating the effect of pre-hospital and emergency interventions for suspected stroke patients and we found that there seems to be only a few studies on the emergency field and none about implementation of clinical pathways. We will test the hypothesis that the adoption of emergency clinical pathway improves early diagnosis and referral in suspected stroke patients. We designed a cluster randomised controlled trial (C-RCT), the most powerful study design to assess the impact of complex interventions. The study was registered in the Current Controlled Trials Register: ISRCTN41456865--implementation of pre-hospital emergency pathway for stroke--a cluster randomised trial. METHODS/DESIGN: Two-arm cluster-randomised trial (C-RCT). 16 emergency services and 14 emergency rooms were randomised either to arm 1 (comprising a training module and administration of the guideline), or to arm 2 (no intervention, current practice). Arm 1 participants (152 physicians, 280 nurses, 50 drivers) attended an interactive two sessions course with continuous medical education CME credits on the contents of the clinical pathway. We estimated that around 750 patients will be met by the services in the 6 months of observation. This duration allows recruiting a sample of patients sufficient to observe a 30% improvement in the proportion of appropriate diagnoses. Data collection will be performed using current information systems. Process outcomes will be measured at the cluster level six months after the intervention. We will assess the guideline recommendations for emergency and pre-hospital stroke management relative to: 1) promptness of interventions for hyperacute ischaemic stroke; 2) promptness of interventions for hyperacute haemorrhagic stroke 3) appropriate diagnosis. Outcomes will be expressed as proportions of patients with a positive CT for ischaemic stroke and symptoms onset < or = 6 hour admitted to the stroke unit. DISCUSSION: The fields in which this trial will play are usually neglected by randomised controlled trial (RCT). We have chosen the cluster-randomised controlled trial (C-RCT) to address the issues of contamination, adherence to real practice, and community dimension of the intervention, with a complex definition of clusters and an extensive use of routine data to collect the outcomes.

Brain Ischemia↗

PubMedDate not supplied

Alcohol and the driver. Council on Scientific Affairs.

Scientific investigations have produced 50 years of accumulated evidence showing a direct relationship between increasing blood alcohol concentration (BAC) in drivers and increasing risk of a motor vehicle crash. There is scientific consensus that alcohol causes deterioration of driving skills beginning at 0.05% BAC or even lower, and progressively serious impairment at higher BACs. Drivers aged 16 to 24 years have the highest representation of all age groups in alcohol-related road crashes; young drivers involved in alcohol-related fatal crashes have lower average BACs than older drivers. Alcohol impairs driving skills by its effects on the central nervous system, acting like a general anesthetic. It renders slower and less efficient both information acquisition and information processing, making divided-attention tasks such as steering and braking more difficult to carry out without error. The influence of alcohol on emotions and attitudes may be a crash risk factor related to driving style in addition to driving skill. Biologic variability among humans produces substantial differences in alcohol influence and alcohol tolerance, making virtually useless any attempts to fix a "safe" drinking level for drivers. The American Medical Association supports a policy recommending (1) public education urging drivers not to drink, (2) adoption by all states of 0.05% BAC as per se evidence of alcohol-impaired driving, (3) 21 years as the legal drinking age in all states, (4) adoption by all states of administrative driver's license suspension in driving-under-the-influence cases, and (5) encouragement for the automobile industry to develop a safety module that thwarts operation of a motor vehicle by an intoxicated person.

Accidents, Traffic↗

PubMed2004

Influence of gaze direction on crossmodal modulation of visual ERPS by endogenous tactile spatial attention.

Recent evidence indicates that the spatial direction of endogenous covert spatial attention in one sensory modality can crossmodally influence early processing of stimuli in a different modality. However, spatial locations are initially coded according to different frames of reference for different modalities (e.g., body-centered for touch versus retinocentric vision) and postural changes (e.g., gaze shifts) will realign these. Here, we used event-related potentials (ERPs) to investigate how the direction of endogenous tactile attention affects sensory-specific visual ERP components. Critically, by manipulating direction of gaze, we were able to test whether any crossmodal effects depend on visual and tactile projections to a common hemisphere, on common locations in external space, or on some combination of the two. We found that both P1 and N1 visual components were modulated according to the direction of endogenous tactile attention. While the P1 crossmodal effect followed purely hemispheric constraints, the attentional modulation of N1 appeared to combine both anatomical and external spatial constraints.

Adult↗