The initial presentation of multifactor dimensionality reduction (MDR) featured cross-validation to mitigate over-fitting, computationally efficient searches of the epistatic model space, and variable construction with constructive induction to alleviate the curse of dimensionality. However, the method was unable to differentiate association signals arising from true interactions from those due to independent main effects at individual loci. This issue leads to problems in inference and interpretability for the results from MDR and the family-based compliment the MDR-pedigree disequilibrium test (PDT). A suggestion from previous work was to fit regression models post hoc to specifically evaluate the null hypothesis of no interaction for MDR or MDR-PDT models. We demonstrate with simulation that fitting a regression model on the same data as that analyzed by MDR or MDR-PDT is not a valid test of interaction. This is likely to be true for any other procedure that searches for models, and then performs an uncorrected test for interaction. We also show with simulation that when strong main effects are present and the null hypothesis of no interaction is true, that MDR and MDR-PDT reject at far greater than the nominal rate. We also provide a valid regression-based permutation test procedure that specifically tests the null hypothesis of no interaction, and does not reject the null when only main effects are present. The regression-based permutation test implemented here conducts a valid test of interaction after a search for multilocus models, and can be applied to any method that conducts a search to find a multilocus model representing an interaction.

A combination of cytomorphological features and cytochemical staining reactions in the diagnoses of the different types of acute leukemia removes much of the subjective difficulty of diagnosis. The number of cytochemical stains used may be limited, and in our experience the PAS, combined NCE and ANE reactions, and either SB or Px staining will yield as much diagnostic information as needed in most cases. With regard to the prognostic implications, it would appear at the present time that the amount of ANE staining in the cytoplasm of blasts is inversely proportional to the chances of remission induction and length of survival in cases of acute leukemia. However, further studies must be carried out to verify this finding before using the information to compliment other prognostic variables, such as age of patient, previous therapy, cytokinetics, etc.

The increasing diversity of the populations encountered and served by child welfare workers challenges cultural competence models. Current concerns focus on the unintentional over-emphasis on shared group characteristics, undervaluing unique differences of individuals served, and privileging worker expertise about the client's culture, thereby exacerbating the power imbalance between them. This article promotes cultural humility in child welfare service delivery as a compliment to cultural competence, to liberate workers from expectations of cultural expertise about others, and to actively engage the clients, inclusive of their cultural differences, in the service delivery process. Skills and practice principles are discussed.

Biosynthesis of estrogens from androgens is catalyzed by cytochrome P450 aromatase. Aromatase inhibition by the triazole compounds letrozole (LTZ) and anastrozole is a prevalent therapy for estrogen-dependent postmenopausal breast cancer. Azoles are widely used as agricultural fungicides and antimycotic drugs that target 14α-demethylase. Some were previously shown to inhibit aromatase, thereby raising the possibility of endocrine disruptive effects. However, mechanistic analysis of their inhibition has never been undertaken. We have evaluated the inhibitory effects of 3 common fungicides, bifonazole, imazalil, and flusilazole, in human aromatase purified from placenta and compared them with LTZ, the most potent inhibitor of aromatase. Bifonazole exhibits strong inhibitory effects with an IC50 of 270nM and Ki (Michaeles-Menten inhibition constant) of 68nM, compared with 10nM and 13nM, respectively, for LTZ. The IC50 and Ki are 1100nM and 278nM for imazilil and 3200nM and 547nM for flusilazole, respectively. Analyses of inhibition kinetics suggest that the modes of inhibition by azole fungicides are mixed or competitive, whereas LTZ inhibition could be noncompetitive or mixed. We interpret the inhibition mechanism in the context of the x-ray structure of aromatase-androstenedione complex. Structural data show that aromatase has 3 binding pockets in relation to the heme. The substrate-binding cavity at the heme-distal site closely compliments the structures of the natural substrate, androstenedione, and steroidal aromatase inhibitors. Because the structures of LTZ and the azole fungicides are entirely dissimilar to the androstenedione backbone, the azoles possibly inhibit by binding to a structurally rearranged active site, the 2 other catalytically important sites, or both, in agreement with the kinetics data.

BACKGROUND

Brucellosis is a major cause of infertility and reproductive failure in livestock. While cattle in the Eastern Indonesian archipelago suffers from reproductive problems information on bovine brucellosis in the region is fragmentary. The control of brucellosis requires a major and prolonged effort and confirmation of the infection by isolation with detailed knowledge of the spread of the infection is essential when planning a control program.

RESULTS

Serological investigation of Brucella infection in beef cattle tended under extensive farming conditions revealed a high seroprevalence (19.3%; 95% CI, 17-22) in the compliment fixation tests. The results of a rapid and simple field test correlated well with the Rose Bengal test (kappa, 0.917) and indicated an acceptable sensitivity (87.5%) and specificity (98.1%) compared with the complement fixation test. Reproductive failure was reported for 39.0% of the cows with a loss of calves due to abortion or early death amounting to 19.3%. Past reproductive failure did not, however, correlate with seropositivity in the complement fixation test (RP = 1.21; P = 0.847). B. abortus biovar 1 was freshly isolated from the hygromas of two cows and together with thirty banked isolates collected since 1990 from different parts of Sulawesi and Timor eight related genotypes could be distinguished with one genotype being identical to that of an isolate (BfR91) from Switzerland. The Indonesian genotypes formed together with BfR91 and one African and one North American isolate a distinct branch on the B. abortus biovar 1 dendogram.

CONCLUSIONS

Bovine brucellosis appears to be widespread in the Eastern Indonesian archipelago and calls for urgent intervention. The fresh isolation of the pathogen together with the observed high seroprevalence demonstrates the presence and frequent exposure of cattle in the area to the pathogen. The application of a rapid and simple field test for brucellosis could be very useful for the quick screening of cattle at the pen side.

Glucosinolates (GSLs), a group of compounds found in Brassica plants, are toxic to some soil-borne plant pathogens because of the toxicity of their hydrolysis products, isothiocyanates. Other phytochemicals found in Brassica plants, such as phenols and ascorbic acid, may compliment the activity of GSLs. A survey of Brassica accessions from the national germplasm repository was conducted to identify potential cover crops that could be soil-incorporated for use as biofumigants. Ten Brassica accessions that demonstrated relative cold tolerance, rapid maturity, and superior biomass production were selected. The selected accessions were grown under three climatic conditions (fall greenhouse, winter high tunnel, and spring field) to investigate whether growing conditions affect their GSL, phenol, and ascorbic acid content. The selected accessions included seven accessions of Brassica juncea (Indian mustard), one of Brassica napus (oil seed rape), one of Brassica campestris (field mustard), and one of Eruca sativa (arugula). Separation of GSLs from the selected Brassica accessions was achieved using ion-exchange sephadex in disposable pipette tips. Quantification of total GSLs was based on inactivation of the endogenous thioglucosidase and liberation of the glucose moiety from the GSL molecule by addition of standardized thioglucosidase (myrosinase) and colorimetry. GSL concentration of greenhouse, high tunnel, and field-grown shoots (leaves and stems) averaged 24, 40 and 76 micromoles g(-1) fresh weight, respectively. Accessions of B. juncea generally had the highest GSL content. A comparison of accessions revealed that Ames 8887 of B. juncea contained the greatest GSL concentration, but had the lowest biomass yield and ascorbic acid concentration, in part because phytochemical concentration tended to be negatively correlated with biomass yield. More promising was B. juncea accession 'Pacific Gold' which coupled high biomass yield with above-average GSL production, but had low phenol and ascorbic acid concentration. We concluded that environmental stress on growing plants can increase the concentration of GSLs, ascorbic acid, and total phenols in Brassica shoots, but does not increase yields of these phytochemicals per unit area.

Intravascular photoacoustic (IVPA) imaging has been developed in recent years as a viable imaging modality for the assessment of atherosclerotic plaques. Exogenous imaging contrast and therapeutic agents further enhance this imaging modality and provide significant benefits. Imaging contrast agents can significantly increase photoacoustic signal, resulting in enhanced plaque detection and characterization. The ability to use these particles to molecularly target markers of disease progression makes it possible to determine patient-specific levels of risk and plan treatments accordingly. With improved diagnosis, clinicians will be able to use therapeutic agents that are synergistic with IVPA imaging to treat atherosclerotic patients. Pre-clinical and clinical studies with relevance to IVPA imaging have shown promise in the area of diagnosis and therapeutics. In this review, we present a variety of imaging contrast agents that are either designed for or are compatible with IVPA imaging, cover uses of therapeutic agents that compliment this imaging modality, and discuss future directions of research in the field.

To predict volume of distribution at steady-state (V(ss)), empirical (e.g., allometry) and mechanistic (using physicochemical property data and plasma protein binding) methods have been used. None of these approaches has been able to predict V(ss) accurately for the total compliment of a wide range of drugs. Therefore, alternative approaches would be of value. This study evaluates the utility of in vitro nonspecific tissue-binding measurements in predicting V(ss) for a wide range of drugs in rats. Literature as well as proprietary compounds were studied. It was found that in vitro tissue-binding measurements combined with calculated effects of the pH partition hypothesis often predict V(ss) more accurately than other available mechanistic methods and that this approach can compliment existing methods. The V(ss) values for some compounds were not accurately predicted using either nonspecific tissue-binding experiments or other available mechanistic methods. The V(ss) for these drugs may not be describable by nonspecific tissue binding alone; there may be significant specific components to the mechanism of distribution for these drugs, such as pH-dependent uptake into lysosomes (primarily strongly basic drugs), active transport, and/or enterohepatic recirculation. A lack of prediction for certain drugs warrants further investigation into these mechanisms and their application to more accurate prediction of V(ss) by mechanistic means.

BACKGROUND

There are potential advantages to engaging medical students in the feedback process, but efforts to do so have yielded mixed results. The purpose of this study was to evaluate a student-focused feedback instructional session in an experimental setting.

METHODS

Medical students were assigned randomly to either the intervention or control groups and then assigned randomly to receive either feedback or compliments. Tests of knowledge, skills, and attitudes were given before and after the intervention.

RESULTS

There was a significant gain of knowledge and skill in the group that received instruction. Satisfaction was higher after compliments in the control group but higher after feedback in the instructional group. There was no change in the subject's willingness to seek feedback.

CONCLUSIONS

A student-focused component should be carefully included as part of an overall effort to improve feedback in surgical education. The role of medical student attitudes about feedback requires further investigation.

Inhaled antibiotics are not usually considered outside the setting of cystic fibrosis or Pneumocystis jiroveci prophylaxis. However, because they deliver high drug concentrations at the site of infection with negligible systemic absorption and toxicity, they are logical compliments to standard intravenous therapy for severe nosocomial pneumonias -- particularly those caused by multiresistant organisms. Older studies that have shown marginal or no benefit have either applied inhaled antibiotics indiscriminately to low risk populations, or have used crude delivery systems, such as hand atomizers or poured it into the endotracheal tube. Although inhaled antibiotics cannot be recommended for prevention of nosocomial pneumonia at this time, a few studies involving prophylaxis have shown promising trends, particularly in high-risk patients with predisposing conditions. The greatest potential of inhaled antibiotics lies in the treatment of severe healthcare-associated pneumonia caused by a multiresistant organism. The method of delivery is extremely important. Trials that have shown the most benefit, even against pathogens most difficult to eradicate and in damaged lungs, have used optimized delivery systems. Most authorities recommend using ultrasonic or vibrating disk nebulizers to generate particle sizes between 1 and 5 microm that are crucial for deposition in terminal bronchioles and alveoli. Inhaled liposomal amphotericin has also demonstrated encouraging results in animal trials. Recently, inhaled phytochemicals were successfully employed in the treatment of a patient with primary pulmonary tuberculosis. When used selectively in high-risk patients, or in the treatment of established pneumonia, inhaled antibiotics have not been associated with development of resistant organisms.

Multiphoton microscopy allows investigators the opportunity to study dynamic events within the functioning kidney and during acute kidney injury. This enables investigators to follow complex multifactorial processes in the kidney with improved spatial and temporal resolution, and sensitivity. Furthermore, the ability to obtain volumetric data (3-D) makes quantitative 4-D (time) analysis possible. Finally, use of up to three fluorophores concurrently in multiphoton microscopy allows for three different or interactive processes to be observed simultaneously. Therefore, this approach compliments existing molecular, biochemical and pharmacologic techniques by allowing for direct visualization at the cellular and subcellular levels for molecules without the requirement for fixation. Its use in acute kidney injury is in its infancy but offers much promise for unraveling the complex interdependent processes known to contribute to cell injury and organ failure.

A novel fabrication technique has been developed for creating high density (6.25 electrodes/mm(2)), out of plane, high aspect ratio silicon-based convoluted microelectrode arrays for neural and retinal prostheses. The convoluted shape of the surface defined by the tips of the electrodes could compliment the curved surfaces of peripheral nerves and the cortex, and in the case of retina, its spherical geometry. The geometry of these electrode arrays has the potential to facilitate implantation in the nerve fascicles and to physically stabilize it against displacement after insertion. This report presents a unique combination of variable depth dicing and wet isotropic etching for the fabrication of a variety of convoluted neural array geometries. Also, a method of deinsulating the electrode tips using photoresist as a mask and the limitations of this technique on uniformity are discussed.

In search of causative factors of social anxiety disorder (SAD), classical conditioning has been discussed as a potential trigger mechanism for many years. Recent findings suggest that the social relevance of the unconditioned stimulus (US) might play a major role in learning theories of SAD. Thus, this study applied a social conditioning paradigm with disorder-relevant US to examine the electrocortical correlates of affective learning. Twenty-four high socially anxious (HSA) and 23 age- and gender-matched low socially anxious (LSA) subjects were conditioned to 3 different faces flickering at a frequency of 15 Hz which were paired with auditory insults, compliments or neutral comments (US). The face-evoked electrocortical response was measured via steady-state visually evoked potentials and subjective measures of valence and arousal were obtained. Results revealed a significant interaction of social anxiety and conditioning, with LSA showing highest cortical activity to faces paired with insults and lowest activity to faces paired with compliments, while HSA did not differentiate between faces. No group differences were discovered in the affective ratings. The findings indicate a potentially impaired ability of HSA to discriminate between relevant and irrelevant social stimuli, which may constitute a perpetuating factor of SAD.

A single expressing copy of the human protamine domain was randomly inserted into an intron of Cyp2c38. The transgenic locus was shown to recapitulate the level of expression observed in normal human testis while not perturbing endogenous protamine expression. The development of an interspecies tiling array was pursued to enable direct comparison of the orthologous protamine domains in a single experiment. Probe design was adapted to generate species-specific high resolution probe sets that would tolerate repetitive elements. Results from competitive hybridizations demonstrate that interspecies tiling arrays are a valuable tool for parallel analysis of highly similar DNA sequences. This approach provides a rapid and reliable means of interrogating samples prior to deep sequencing analysis. These arrays should readily compliment most DNA isolation and analysis techniques such as ChIP, nuclease sensitivity and nuclear matrix association assays.

OBJECTIVE

To evaluate the diagnostic values of double-balloon enteroscopy (DBE) and abdominal computed tomography (CT) in small bowel disease.

METHODS

Seventy eight DBE procedures were carried out in 70 patients, 40 males and 30 females; aged 47.7 (16 - 83) with suspected small bowel disease, all of whom received gastroscopy, colonoscopy, and abdominal CT examination at the same time. The diagnostic value of DBE was compared with that of CT.

RESULTS

Seventeen kinds of small bowel lesions were detected, mainly including Crohn's disease, adenocarcinoma, gastrointestinal stroma tumor, vascular deformity, lymphoma, diverticulum, and polyp. There were no complications and all procedures were tolerated well. The mean duration of procedure was 110 min (30 - 240 min). Nineteen patients received surgical intervention. The diagnostic yield rate of DBE was 57.1% (40/70), significantly higher than that of CT (31.4%, 22/70, P < 0.01). The positive diagnosis rate of DBE combined with CT was 62.9% (44/70), not significant different from that of the DBE alone (P>> 0.05).

CONCLUSIONS

DBE shows a significantly higher diagnostic yield than CT in patients with suspected small bowel disease, and thus should be selected for the initial diagnosis. DBE Combined with CT did not increase the diagnostic yield. However, CT not only provides direction of intubation for DBE, but also clearly depicts the small bowel wall and extraenteric alterations. DBE and CT compliment each other in examining the patients with suspected small bowel disease.

BACKGROUND

Histoplasmosis has a textbook cytologic description with numerous intracellular organisms that are readily apparent on routine stains. This is based on series and reports describing histoplasmosis in immunosuppressed patients with disseminated disease. With the advent of ultrasound-guided (US) fine-needle aspiration (FNA) techniques, a marked increase in the cytologic diagnosis of histoplasmosis in immunocompetent patients is noted.

METHODS

A search identified all cytology cases diagnosed with Histoplasma within the past 10 years. Cases were reviewed, along with patient demographic, clinical, and laboratory data.

RESULTS

A total of 40 FNA cases of histoplasmosis were identified. Patients ranged in age from 15 years to 86 years. There were 23 female patients and 17 male patients; 37 were immunocompetent and 3 were immunosuppressed. Sixteen patients were being staged for primary tumors of other sites; others presented with primary pulmonary symptoms or histoplasmosis was noted incidentally. Specimens were composed of bland acellular necrosis, most commonly with granulomas (77.5%); only rare intracellular organisms were present on routine stains, and variable extracellular organisms were noted on Grocott methenamine silver stain (GMS) stain. GMS stain on direct smears was found to be more sensitive than cell block. Laboratory studies for urine antigen, yeast, and mycelial antibody (by compliment fixation), serum antibody (by immunodiffusion), and culture were positive in 11.8%, 59.1%, 4.5%, 47.6%, and 3.4% of cases, respectively.

CONCLUSIONS

In an endemic region, histoplasmosis presents more commonly in immunocompetent patients as localized fibrocaseous disease on FNA and is often identified by high-resolution imaging. FNA is increasingly used in the diagnosis because of endoscopic ultrasound and endobronchial ultrasound. GMS stain on direct smears is more sensitive than cell block. In general, laboratory tests have low sensitivity in this patient population.

Evidence from several laboratories strongly suggests that brain capillaries play a dynamic role in the regulation of the internal environment of the brain and, further, that these activities are under neuroendocrine control. First, brain capillaries exhibit a number of anatomical and biochemical features unique to membranes known to regulate water and electrolyte permeability. These include tight junctions between endothelial cells, a high mitochondrial content and a unique compliment of intracellular enzymes. Second, brain capillaries appear to be functionally innervated by adrenergic neurons originating in brain. Finally, brain capillaries exhibit several functional characteristics of membranes that dynamically regulate water and electrolyte permeabilities. These include a restricted permeability to water, a prompt and reversible increase in water permeability to transient hyperosmolarity, a prompt and reversible decrease in permeability to increase perfusion pressure, a change in permeability associated with activation of the central as well as peripheral sympathetic nervous system, and an increase in permeability to centrally administered vasopressin as well as angiotensin II.

BACKGROUND

The 308-nm excimer laser is a recent development in the treatment of psoriasis vulgaris, palmoplantar psoriasis, and psoriasis of the scalp. The XeCl excimer emits a 308-nm wavelength beam of light that is monochromatic and coherent. These properties allow selectivity when used as phototherapy against a psoriatic lesion while sparing healthy surrounding tissue.

OBJECTIVE

In this manuscript, we review recent updates on the efficacy of excimer and its most recent trials in psoriasis.

METHODS

A review of the medical literature in Pubmed database was performed using the terms 'psoriasis' and '308 nm excimer laser'. All trials to date that studied the 308-nm excimer including those that compared the excimer with other modalities were included.

RESULTS

Eighteen trials show positive results surrounding the efficacy of the excimer. Selectivity of the 308-nm excimer, when compared with non-selective narrowband UVB (NB-UVB) phototherapy allows one to adjust the fluency to the lesion. The excimer may also stand superior to NB-UVB in its efficacy of mechanism.

CONCLUSIONS

Excimer is a useful and effective treatment for psoriasis that may be used as a compliment to topical medications as well as NB-UVB. However, large randomized trials with long-term follow-up are needed to further support this.

Acute cholecystitis, acute cholangitis, and acute pancreatitis represent the most common biliary tract emergencies. Most are due to gallstones in the gallbladder and bile ducts. Acute cholecystitis is treated by surgery in most cases. Laparoscopic cholecystectomy combined with endoscopic sphincterotomy may become more common in the future for treatment of acute cholecystitis as well as in cases of acute cholangitis and pancreatitis if the bile ducts are cleared of gallstones. Although the role of either surgery or endoscopic treatment may be more clearly defined in some biliary tract emergencies, in other situations either modality may be appropriate or they may compliment each other. Most biliary emergencies should be managed by gastroenterologists, surgeons, and radiologists working together in a harmonious fashion.

Electronic simulation of generalized vertebrate cone retina consists of 43 X 41 grid of red-, green-, and blue-sensitive cones. Each retinal element is simulated by a linear summator in series with a leaky integrator and spatial-temporal properties are developed by spatial organization of cone mosaic into unit hexagons and interplay of antagonistic inputs of differing time courses. Model has full compliments of horizontal and bipolar cells including color- and non-color coding as well as single- and double-opponent receptive fields for bipolar cells. Electronic simulation also has negative feedback from L-horizontal cells to cones. Ganglion cells are formed by convergence of 7 bipolar cells, either all same and thus homogeneous, or else with a central-DPBC (or HPBC) and 6 surround-HPBCs (or DPBCs) and thus non-homogeneous. Responses of color- and non-color-coded ganglion cells as well as single- and double-opponents are investigated with stationary and moving light spots using white and colored lights. While responses to stationary light spots are predictable from digital models, responses to moving spots are complicated by differing time lags of components involved in total response. Therefore, responses to moving stimuli are more readily simulated by analogue models.

A bovine lens "native" plasma membrane fraction containing its full compliment of extrinsic proteins was prepared by sucrose density centrifugation of the water insoluble fraction. The major membrane fraction was found at the 25/45% sucrose interface. This fraction contained 73% of the total water insoluble phospholipid, 74% of the total water insoluble cholesterol and 58% of the total urea-insoluble protein. Only 9% of the total urea-soluble protein was membrane associated (extrinsic protein), most (75%) was recovered from the pellet. The major intrinsic protein (8 M-urea-insoluble) of the membrane fraction was MIP28, with lesser amounts of MP17. Extrinsic proteins (8 M-urea-soluble) were examined by SDS-PAGE, isoelectric focusing, immunoblotting and amino acid composition analysis. Approximately 70% of the total extrinsic protein appeared to be alpha A-crystallins and modified alpha A-crystallins. About 20% of the extrinsic protein was apparently beta- and gamma-crystallins. The remainder contained presumed cytoskeletal proteins and perhaps other unidentified polypeptides. The native plasma membrane was found distributed throughout the lens with only minor differences in the quantitative composition of the membrane fraction. We have concluded that the native membrane fraction represents the lens plasma membrane with its extrinsic proteins which exist in vivo. These extrinsic proteins appeared to be primarily acidic alpha-crystallin polypeptides with minor amounts of beta- and gamma-crystallins, and presumed cytoskeletal elements. We speculate that these extrinsic proteins may serve as a nucleation site for the association of other water insoluble protein through protein-protein interactions such as those found in the non-membrane associated urea-soluble protein. Together, these interactions may form a structured cytoplasmic matrix important for the maintenance of lens transparency.

Quantitative analysis of protein complex stoichiometries and mobilities are critical for elucidating the mechanisms that regulate cellular pathways. Fluorescence fluctuation spectroscopy (FFS) techniques can measure protein dynamics, such as diffusion coefficients and formation of complexes, with extraordinary precision and sensitivity. Complete calibration and characterization of the microscope instrument is necessary in order to avoid artifacts during data acquisition and to capitalize on the full capabilities of FFS techniques. We provide an overview of the theory behind FFS techniques, discuss calibration procedures, provide protocols, and give practical considerations for performing FFS experiments. One important parameter recovered from FFS measurements is the relative molecular brightness that can correlate with oligomerization. Three methods for measuring molecular brightness (fluorescence correlation spectroscopy, photon-counting histogram, and number and brightness analysis) recover similar values when measuring samples under ideal conditions in vitro. However, examples are given illustrating that these different methods used for calculating molecular brightness of fluorescent molecules in cells are not always equivalent. Methods relying on spot measurements are more prone to bleaching and movement artifacts that can lead to underestimation of brightness values. We advocate for the use of multiple FFS techniques to study molecular brightnesses to overcome and compliment limitations of individual techniques.

BACKGROUND

Gain-of-function mutations in the voltage-gated sodium channel (Nav1.5) are associated with the long-QT-3 (LQT3) syndrome. Nav1.5 is densely expressed at the intercalated disk, and narrow intercellular separation can modulate cell-to-cell coupling via extracellular electric fields and depletion of local sodium ion nanodomains. Models predict that significantly decreasing intercellular cleft widths slows conduction because of reduced sodium current driving force, termed "self-attenuation." We tested the novel hypothesis that self-attenuation can "mask" the LQT3 phenotype by reducing the driving force and late sodium current that produces early afterdepolarizations (EADs).

RESULTS

Acute interstitial edema was used to increase intercellular cleft width in isolated guinea pig heart experiments. In a drug-induced LQT3 model, acute interstitial edema exacerbated action potential duration prolongation and produced EADs, in particular, at slow pacing rates. In a computational cardiac tissue model incorporating extracellular electric field coupling, intercellular cleft sodium nanodomains, and LQT3-associated mutant channels, myocytes produced EADs for wide intercellular clefts, whereas for narrow clefts, EADs were suppressed. For both wide and narrow clefts, mutant channels were incompletely inactivated. However, for narrow clefts, late sodium current was reduced via self-attenuation, a protective negative feedback mechanism, masking EADs.

CONCLUSIONS

We demonstrated a novel mechanism leading to the concealing and revealing of EADs in LQT3 models. Simulations predict that this mechanism may operate independent of the specific mutation, suggesting that future therapies could target intercellular cleft separation as a compliment or alternative to sodium channels.

A primary limiting factor for cancer treatment is normal tissue toxicity. Targeted cancer treatment can potentially maximize cancer cure and minimize normal tissue toxicity. Physical energy can be used to activate inert oncologic drugs. X-rays have an advantage over other forms of physical energy because tissue penetration and precise localization can be achieved. Radiation can be used to control drug delivery through radiation-inducible gene therapy. Radiation-guided drug delivery systems involve the targeting of immunoconjugates to radiation-inducible neoantigens induced by irradiation of neoplasms. Magnetic fields can compliment these technologies by drawing magnetic particles containing oncologic drugs toward an externally applied magnetic field. The field of targeted drug delivery by use of external radiation fields will ultimately bring new delivery systems into clinical trials. This review highlights radiation-guided cancer drug delivery systems, at preclinical and clinical stages of development, to tumors and tumor blood vessels.