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PubMed1990

The impact of technology on the quality of health care.

Laser technology, developments in three-dimensional imaging, genetic engineering, and biosynthetic materials, and other technologies can promote quality care if they are used appropriately and correctly, are accessible to physicians and patients, and are shown to lead to successful outcomes. Formal organizational linkages and networks will enable providers to specialize in different technology and equipment yet still assure access for their patients to a full continuum of health care services. Advances in technology should have a significant, positive impact on the quality of care, yet with continued escalations in cost. Technology-based cost increases can be minimized with a renewed focus on early detection of diseases and on preventive strategies, efforts to ensure appropriate and cost-effective use of technology, greater selectivity in the use of "halfway" technologies, and increased incentives for healthy life-styles.

Cost-Benefit Analysis↗

PubMed2005

Psychiatric disease in the genomic era: rational approach.

Although the introduction of explicit diagnostic criteria and rule-based classifications, such as Research Diagnostic Criteria, Diagnostic and Statistical Manual Ed 3 and Ed 4, has dramatically influenced teaching and research psychiatric practice, it has significant limitations. As new knowledge is developed with genetic, imaging and metabolomic technologies, a method to incorporate this research in a systematic manner with current classification systems is needed. The current approach, which is essentially nominalist in character, has to be developed where new data and new concepts of disease can be integrated and tested. Examples of how this could happen is shown in the context of Alzheimer's disease and subcortical ischemic disease. It is likely that a standardized approach that can develop and modify classification systems in a timely manner, based on science and free of societal and political influence, can enhance research, teaching and clinical practice.

Alzheimer Disease↗

PubMed2002

Biomedical technology revolution: opportunities and challenges for oral and maxillofacial surgeons.

During this 45-minute presentation, I have tried to describe my vision of the exciting future that awaits us. I have tried to impart my enthusiasm for the opportunities provided to us as surgeons by the advances in molecular biology and genetics, imaging, surgical technology and bioinformatics. Most of all, I hope I have transmitted my optimism for the future to our younger members. I think the following statement or observation by the great educator Margaret Mead accurately summarizes our current situation regarding the application of all this new knowledge that will become available to us as surgeons: 'We are now at the point where we must educate people (surgeons) in what nobody knew yesterday, and prepare in our schools (training programs) for what no one knows yet but what some people must know tomorrow.'

Adult↗

PubMed2006

Translocation of molecules into cells by pH-dependent insertion of a transmembrane helix.

We have previously observed the spontaneous, pH-dependent insertion of a water-soluble peptide to form a helix across lipid bilayers [Hunt, J. F., Rath, P., Rothschild, K. J. & Engelman, D. M. (1997) Biochemistry 36, 15177-15192]. We now use a related peptide, pH (low) insertion peptide, to translocate cargo molecules attached to its C terminus across the plasma membranes of living cells. Translocation is selective for low pH, and various types of cargo molecules attached by disulfides can be released by reduction in the cytoplasm, including peptide nucleic acids, a cyclic peptide (phalloidin), and organic compounds. Because a high extracellular acidity is characteristic of a variety of pathological conditions (such as tumors, infarcts, stroke-afflicted tissue, atherosclerotic lesions, sites of inflammation or infection, or damaged tissue resulting from trauma) or might be created artificially, pH (low) insertion peptide may prove a useful tool for selective delivery of agents for drug therapy, diagnostic imaging, genetic control, or cell regulation.

Amino Acid Sequence↗

PubMed1993

Psychopharmacologic treatment of schizophrenia.

Antipsychotic (neuroleptic) medications continue to be a critical component in the treatment of schizophrenia. Despite numerous advances in brain imaging, genetics, and neurochemistry, the pharmacologic agents routinely used to treat schizophrenia have not changed markedly over the last 30 years. The introduction of clozapine, however, represents an important step in drug development and has stimulated renewed activity in this area. In addition, its novel effects have had a heuristic value in efforts to better understand neuropharmacologic mechanisms. While we await further advances in treatment development, we are benefiting from clinical research focusing on improving our ability to use available pharmacotherapy in the most effective and least toxic manner. Recent studies reemphasize the potential value of using the minimum effective dosage for acute treatment (e.g., 10-15 mg/day of oral haloperidol) and provide needed data on the benefits and risks of long-term dosage reduction strategies (i.e., continuous low-dose or targeted/intermittent treatment).

Antipsychotic Agents↗

PubMed2002

Attention deficit/hyperactivity disorder across the lifespan.

Attention deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder presenting for treatment in youth. ADHD is often chronic with prominent symptoms and impairment spanning into adulthood. ADHD is often associated with co-occurring anxiety, mood, and disruptive disorders, as well as substance abuse. The diagnosis of ADHD by careful review of symptoms and impairment is both reliable and valid. Recent genetic, imaging, neurochemistry, and neuropsychological data support the biological underpinning of the disorder. All aspects of an individual's life must be considered in the diagnosis and treatment of ADHD. Pharmacotherapy, including stimulants, antidepressants, and antihypertensives, plays a fundamental role in the management of ADHD across the lifespan.

Adolescent↗

PubMedDate not supplied

Obsessive-compulsive symptom dimensions as predictors of compliance with and response to behaviour therapy: results from a controlled trial.

BACKGROUND: Recent factor-analytic studies in obsessive-compulsive disorder (OCD) identified consistent symptom dimensions. Support for the validity of these dimensions comes from studies of psychiatric comorbidity, functional brain imaging, genetic transmission, and treatment response to medications. This study examined whether previously identified OCD symptom dimensions are associated with treatment compliance and response to behaviour therapy (BT) for OCD. METHODS: One hundred and fifty-three OCD outpatients who participated in a multi-centre randomised controlled trial of computer- versus clinician-guided BT for OCD were included in the study. Logistic and multiple regression models tested for significant predictors of compliance with and response to BT and relaxation. RESULTS: The patients studied were phenomenologically comparable (including the presence of 'pure' obsessions and mental rituals) to those in previous serotonin reuptake inhibitor (SRI) trials and those in clinical epidemiology studies. High scorers on the 'hoarding' dimension were more likely to drop out prematurely from the study and tended to improve less. For those completing treatment, the strongest predictor of outcome was pre-treatment severity. Initial depression scores were unrelated to outcome. After controlling for symptom severity, higher scores on the 'sexual/religious obsessions' factor predicted poorer outcome with BT, especially when computer-guided. CONCLUSIONS: BT is especially indicated for OCD patients with aggressive/checking, contamination/cleaning and symmetry/ordering symptoms. Previous accounts of unsuccessful BT in patients with hoarding symptoms may be due in part to their propensity to drop out earlier from treatment. Patients with sexual/religious obsessions, but not those with mental rituals, might respond less well to traditional BT techniques. Existing treatments need to be refined and/or new treatments developed to improve these patients' adherence and response to treatment.

Adult↗

PubMed2001

Pharmacological treatment of childhood obsessive-compulsive disorder: from theory to practice.

Discusses pharmacological treatment of childhood obsessive-compulsive disorder (OCD), chronic and underrecognized psychiatric condition that affects up to 2% to 3% of children and adolescents. Research in OCD in children, including neuropharmacology, brain imaging, genetics, and clinical phenomenology, informs current views of OCD pathophysiology. Contemporary research supports the notion of a dysregulation in serotonin subsystems in the central nervous system, with target areas of dysfunction including basal ganglia and orbitofrontal cortex. Pharmacotherapy, along with cognitive-behavioral approaches, constitutes the indicated treatment for childhood OCD. Pharmacological treatment is best guided by a phenomenological understanding of the type of obsessions and compulsions, the intensity and frequency of their presentation with attention to behavioral reinforcements, and psychosocial factors that affect the course of the disease. Serotonin-enhancing agents, such as fluoxetine, fluvoxamine, paroxetine, and sertraline and citalopram (SSRIs) are first-line pharmacological agents, whereas refractory symptoms can be treated by augmentation with neuroleptics or other agents. Clomipramine is as effective as the SSRIs but its use may be accompanied by increased side effects. Genetic factors probably influence susceptibility to OCD as well as response to treatment, and the elucidation of these and other risk factors will be important elements in the future understanding and treatment of this disorder.

Antipsychotic Agents↗

PubMedDate not supplied

R831X mutation of the androgen receptor gene in an adolescent with complete androgen insensitivity syndrome and bilateral testicular hamartomata.

An 18-year old, phenotypically female individual was examined for primary amenorrhea. Three months before her referral, the patient underwent surgery and a pelvic mass was removed. The physical examination revealed normal female external genitalia, normal breast development, sparse pubic hair and absence of axillary hair. The gynecological examination revealed a short blind vagina pouch and absence of cervix and uterus. Serum testosterone and dihydrotestosterone levels were very high. Karyotype was that of a normal male (46,XY). The transabdominal ultrasound, computed tomography (CT) and Magnetic resonance imaging (MRI) showed absence of uterus and fallopian tubes and revealed testis-like gonads located at the internal opening of the inguinal canal bilaterally. Bilateral gonadectomy was subsequently performed. The pathology report was that of "hamartomatous testes" and associated paratesticular leiomyoma. The clinical, laboratory, imaging, genetic and histological findings confirmed the diagnosis of complete androgen insensitivity syndrome. DNA analysis revealed a R831X mutation in exon 7 of the androgen receptor gene. A Sertoli-cell dynamic test showed elevated basal serum inhibin-B and anti-Müllerian hormone levels without further rise following FSH stimulation. The patient was started on hormone replacement therapy with conjugated estrogens. Complete androgen insensitivity syndrome must be considered in any case of primary amenorrhea. Gonadectomy must be planned to eliminate the risk of gonadal malignancy.

Adolescent↗

PubMed2026

Spindle Assembly Checkpoint Competency Determines Sensitivity to KIF18A Inhibition in Small-Cell Lung Cancer.

BACKGROUND: Small-cell lung cancer (SCLC) is characterized by pervasive chromosomal instability (CIN) and remains largely refractory to targeted therapies. KIF18A, a motor protein that regulates chromosome alignment during mitosis, has emerged as a selective dependency in CIN-high tumors. Whether this dependency extends to SCLC, a prototypical CIN-high cancer, has not been established, and biomarkers predicting response to KIF18A inhibition, currently in clinical trials, are lacking. METHODS: We integrated analyses of patient tumor datasets, neuroendocrine (NE) and non- NE SCLC cell lines, and functional perturbation models to define the determinants of response to KIF18A inhibition. Chromosomal instability metrics, transcriptional programs, mitotic dynamics, and spindle assembly checkpoint (SAC) function were assessed using genomic profiling, live-cell imaging, genetic perturbation, and pharmacologic inhibition. RESULTS: KIF18A expression was elevated in SCLC tumors and correlated with CIN-associated transcriptional programs, proliferative markers, and NE status; however, these features did not predict sensitivity to KIF18A inhibition. Instead, response was determined by the functional integrity of the SAC. SAC-proficient SCLC cells underwent sustained mitotic arrest followed by apoptotic cell death upon KIF18A inhibition, whereas SAC-defective cells failed to maintain checkpoint activation and survived. Mechanistically, resistant cells exhibited impaired kinetochore recruitment of core SAC components, including MAD1 and BUBR1. Importantly, transient induction of acute CIN through MPS1 inhibition partially restored sensitivity to KIF18A inhibition in resistant models. CONCLUSIONS: This study provides the first mechanistic characterization of KIF18A dependency in SCLC, identifying SAC competency as the primary determinant of response. These findings establish a biologically informed framework for patient stratification and rational combination strategies. TRANSLATIONAL RELEVANCE: Small-cell lung cancer (SCLC) is an aggressive malignancy with few effective targeted therapies and marked chromosomal instability. KIF18A has emerged as a potential therapeutic target in genomically unstable cancers, but biomarkers predicting response to KIF18A inhibition are lacking. We demonstrate that sensitivity to KIF18A inhibition in SCLC is determined not by KIF18A expression, neuroendocrine subtype, or baseline chromosomal instability, but by the functional integrity of the spindle assembly checkpoint (SAC). SCLC cells with intact SAC signaling undergo sustained mitotic arrest and apoptosis upon KIF18A inhibition, whereas SAC-defective cells bypass checkpoint activation and survive aberrant mitosis. Notably, transient induction of acute chromosomal instability through MPS1 inhibition partially restores sensitivity in resistant models. Together, these findings identify mitotic checkpoint competency as a mechanistic determinant and candidate predictive biomarker for KIF18A-targeted therapies, providing a biologically informed framework for patient stratification and rational combination strategies relevant to ongoing KIF18A inhibitor clinical trials.

Journal Article↗

PubMed1994

[Craniocervical dystonia. Pragmatic general concept or nosologic entity?].

The focal dystonias of cranial-nerve innervated muscles are described. They include the ocular dystonia, blepharospasmus and other facial dystonias, mandibular dystonia, pharyngeal dystonia, spasmodic dysphonia, external laryngeal dystonia, spasmodic torticollis and lingual dystonia. They share similar clinical aspects such as the inadequate co-contraction of antagonistic muscles, dystonic overflow of muscle activity to muscles not normally involved, similar facilitating and inhibitory activities and various "antagonistic gestures". Genetic, imaging, neuroanatomic, physiologic and pharmacologic findings suggest common pathogenetic mechanisms for these diseases. Similar therapeutic approaches are established. The frequent and variable combinations of these focal dystonias and their similar pathogenetic background favour their common classification as craniocervial dystonias.

Cranial Nerve Diseases↗

PubMed1996

The Value of Aortic Valve and Aortic Arch Imaging in the Identification of Genetic Syndromes.

Echocardiographers imaging the aortic valve, root, and arch may observe coincidental extracardiac malformations, unusual facial features or body habitus, and/or mental or growth retardation. The pattern of anomalies may indicate a previously unrecognized genetic malformation syndrome. Echocardiographers also encounter genetic syndromes when clinicians specifically refer patients with certain syndromes for prospective detection of cardiac anomalies. Although aortic valve, root, and arch anomalies occur in a large number of syndromes, this article will focus on the most distinctive associations. In addition to discussing structural congenital cardiovascular malformations, aortic root dilation occurring in inherited disorders of connective tissue will be included. (ECHOCARDIOGRAPHY, Volume 13, July 1996)

Journal Article↗

PubMed2006

Genetic, clinical, and imaging characterization of one patient with late-onset, slowly progressive, pantothenate kinase-associated neurodegeneration.

We report on a patient with late-onset, pantothenate kinase-associated neurodegeneration (PKAN) who revealed two new heterozygous mutations at gene testing and showed asymmetric moderately reduced striatal dopamine transporter binding with single photon emission computed tomography, possibly due to prolonged neuroleptic treatment. These findings expand the genetic and imaging spectrum of this rare disorder.

Age Factors↗

PubMed1991

Quantification of vascular graft seeding by use of computer-assisted image analysis and genetically modified endothelial cells.

Current methods for the evaluation of retention of endothelial cells seeded on vascular grafts are limited by the inability to specifically identify and quantitate seeded cells on a long-term basis. To address this problem we developed a method of quantification of graft surface coverage using genetic labeling of endothelial cells combined with computer-assisted image analysis. Rabbit aortic endothelial cells were transduced with a marker gene (lac-Z) and seeded on polytetrafluoroethylene grafts. After histochemical staining in which the genetically labeled cells turn blue, computer-assisted image analysis was used to measure the percentage of graft surface covered by the seeded cells. The utility of the method was evaluated by using it to assess the effect on graft coverage of seeded cell density and by precoating with fibronectin. Quantification of surface area coverage was automated and reproducible both between scans and between observers. Use of this method allowed the determination of a linear correlation between cell density in the seeding suspension and graft coverage (r2 = 0.93, p less than 0.0001). The method also permitted confirmation of the positive contribution of fibronectin coating to graft coverage by seeded cells: 73% coverage coated versus 8% coverage uncoated (p less than 0.0001). The ability of this method to specifically identify genetically marked endothelial cells and their progeny makes it attractive for use in studies targeted at optimization of graft coverage in vivo.

Animals↗

PubMed1998

Edge detection in medical images using a genetic algorithm.

An algorithm is developed that detects well-localized, unfragmented, thin edges in medical images based on optimization of edge configurations using a genetic algorithm (GA). Several enhancements were added to improve the performance of the algorithm over a traditional GA. The edge map is split into connected subregions to reduce the solution space and simplify the problem. The edge-map is then optimized in parallel using incorporated genetic operators that perform transforms on edge structures. Adaptation is used to control operator probabilities based on their participation. The GA was compared to the simulated annealing (SA) approach using ideal and actual medical images from different modalities including magnetic resonance imaging (MRI), computed tomography (CT), and ultrasound. Quantitative comparisons were provided based on the Pratt figure of merit and on the cost-function minimization. The detected edges were thin, continuous, and well localized. Most of the basic edge features were detected. Results for different medical image modalities are promising and encourage further investigation to improve the accuracy and experiment with different cost functions and genetic operators.

Algorithms↗

PubMed2002

Volumetric segmentation of brain images using parallel genetic algorithms.

Active model-based segmentation has frequently been used in medical image processing with considerable success. Although the active model-based method was initially viewed as an optimization problem, most researchers implement it as a partial differential equation solution. The advantages and disadvantages of the active model-based method are distinct: speed and stability. To improve its performance, a parallel genetic algorithm-based active model method is proposed and applied to segment the lateral ventricles from magnetic resonance brain images. First, an objective function is defined. Then one instance surface was extracted using the finite-difference method-based active model and used to initialize the first generation of a parallel genetic algorithm. Finally, the parallel genetic algorithm is employed to refine the result. We demonstrate that the method successfully overcomes numerical instability and is capable of generating an accurate and robust anatomic descriptor for complex objects in the human brain, such as the lateral ventricles.

Algorithms↗

PubMed1998

Spectral imaging in preconception/preimplantation genetic diagnosis of aneuploidy: multicolor, multichromosome screening of single cells.

PURPOSE: Our purpose was to evaluate the utility of spectral imaging for multicolor, multichromosome enumeration in human interphase cell nuclei. METHODS: Chromosome-specific probes labeled with different fluorochromes or nonfluorescent haptens were obtained commercially or prepared in-house. Metaphase spreads, interphase lymphocytes, or blastomeres cells were hybridized with either 7 or 11 distinctly different probes. Following 46 hr of hybridization, slides were washed and detected using either a filter-based quantitative image processing system (QUIPS) developed in-house or a commercial spectral imaging system. RESULTS: The filter-based fluorescence microscope system is preferred for simultaneous detection of up to seven chromosome targets because of its high sensitivity and speed. However, this approach may not be applicable to interphase cells when 11 or more targets need to be discriminated. Interferometer-based spectral imaging with a spectral resolution of approximately 10 nm allows labeling of chromosome-specific DNA probes with fluorochromes having greatly overlapping emission spectra. This leads to increases in the number of fluorochromes or fluorochrome combinations available to score unambiguously chromosomes in interphase nuclei. CONCLUSIONS: Spectral imaging provides a significant improvement over conventional filter-based microscope systems for enumeration of multiple chromosomes in interphase nuclei, although further technical development is necessary in its application to embryonic blastomeres. When applied to preconception/preimplantation genetic diagnosis, presently available probes for spectral imaging are expected to detect abnormalities responsible for 70-80% of spontaneous abortions caused by chromosomal trisomies.

Aneuploidy↗

PubMed2006

Genetic and DAT imaging studies of familial parkinsonism in a Taiwanese cohort.

We here summarize the results of genetic investigations on a series of 82 parkinsonian patients from 60 families in Taiwan. We found 13 parkin patients in 7 families (12%), 2 PINK1 sibs from 1 family, and 1 LRRK2 patient from 1 family with I2012T mutation. We also identified SCA2 in 8 patients from 5 families (8%) and SCA3 in 3 patients from 1 family, all presenting with parkinsonian phenotype. In the available patients with parkin, PINK1, SCA2 and SCA3, the dopamine transporter (DAT) scan revealed that the reduction of uptake was primarily observed in the bilateral putamen, basically sharing a similar pattern with that in idiopathic Parkinson's disease. We concluded that the genetic causes contributed to about 25% of our series of familial parkinsonism. The parkin mutations and SCA2 were the most frequent genetic causes in our series with Chinese ethnicity. The results of DAT scan indicated that bilateral putamen was essentially involved in various genetically-caused familial parkinsonism.

Adult↗