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Synthesis and SAR studies of the title compounds have resulted in the identification of structural and physicochemical parameter (Vw) contributing for antiarrhythmic activity. Among the two most promising compounds 3a & 3b, the 3a has shown antiarrhythmic activity comparable to quinidine.
Synthesis and QSAR studies of the title compounds have resulted in the identification of structural and physicochemical parameters (MR, sigma(o), sigma(m), sigma(p)) contributing to antitubercular activity. Among these, carbamoyl phenyl ring substituted at 3 and 4 position with NO(2) group or 2 position with Cl or OCH(3) group shows >90% inhibition against H(37)Rnu comparable to other substituted phenyls.
A new technology termed SDIFA is developed to improve the mass resolution of linear matrix-assisted laser desorption/ionization time-of-flight mass spectrometry in oligonucleotide analysis. Unlike the currently used delayed extraction method, SDIFA allows electrical isolation of the sample holder from ion extraction/acceleration and selectively samples part of the desorbed ions, thereby reducing the initial velocity distribution and improving resolution. In addition, a method was introduced to improve the space focusing of TOF. Isotope-limited mass resolution was obtained for oligonucleotides of up to 62 mer, and the true instrumental resolution reaches to 1,800 at 19.2 kDa. It was also demonstrated that excellent resolution was obtained across a large mass range using a single setting of acquisition parameters. This feature allows unambiguous identification of multiple A/T heterozygote samples in a mass range of 5,200-7,800 Da. Moreover, compared with DE, the performance of SDIFA was more stable, reproducible, and less dependent on the experimental conditions including the laser power, sample spots, sample substrates, delayed time, and extraction field strength. This enhanced ease of data acquisition is the key to automated spectrum acquisition.
OBJECTIVE: Assessment of longterm ophthalmic outcome in juvenile chronic arthritis (JCA) with emphasis on visual acuity and identification of disease-related parameters associated with rheumatic eye affection. MATERIAL: Sixty-five adults (52 females, 13 males) with a history of or still active JCA were assessed an average of 26.7 years after disease onset. METHODS: Cross-sectional, longterm, follow-up study including complete ophthalmological and rheumatological examinations. RESULTS: Evidence of ocular complications was found in 13 subjects (20%): 10 had had recurrent iritis, two band keratopathy, and one diplopia due to rheumatoid eye muscle involvement. The three single eyes with poor sight (<0.1) were all in the complication subgroup. Binocularly, all but one patient scored at least 6/9 as best corrected visual acuity; one, however, had severe glaucoma-impaired visual fields. The refractive range was -8.12 to +6.0 D. There were no cases of keratoconjunctivitis sicca. Iritis was associated with early disease onset (p = 0.02), longer disease duration (p = 0.02) and a positive antinuclear antibodies (ANA) (p = 0.02). CONCLUSION: Ophthalmic complications were recorded in 20% of the study group, primarily in ANA positive patients with pauciarticular onset JCA. In addition to the two patients with severely affected bilateral visual status (3%), one of the 65 patients had acquired unilateral blindness. Half of the complications were late in that they were first recorded after the age of 16 years. Otherwise, the findings were in keeping with other studies of visual prognosis using non-selected series.
One of the major challenges in cancer research is to generate molecular profiles of tumours and establish correlations between genetic changes and clinical parameters by screening technologies. The identification of tumour-specific gene targets has potential diagnostic and therapeutic implications. Metaphase comparative genomic hybridisation has been used to detect relative DNA-sequence copy number gains (including high-level amplifications of chromosomal regions) and copy number losses in human neoplasms. In the past, metaphase comparative genomic hybridisation has been shown to be a powerful genome-wide screening method and this has considerably advanced our understanding of renal cancer biology. Novel molecular technologies, including array-based comparative genomic hybridisation, fluorescence in situ hybridisation (FISH), cDNA and tissue microarrays will serve to facilitate further characterisation of candidate genes residing in chromosomal regions defined by metaphase comparative genomic hybridisation. This review concentrates on the application of metaphase comparative genomic hybridisation in the area of renal cancer research and summarises data obtained from comparative genomic hybridisation studies.
Modern therapy for inflammatory bowel disease implies that therapy should be disease modifying rather than merely symptomatic. To achieve this goal, induction and maintenance of bowel healing are mandatory. Long-term bowel healing results in fewer hospitalizations and less surgery. Only immunosuppression therapy and biological approaches, or a combination of both, result in long-term healing of the bowel mucosa. Unsolved issues are when these drugs should be initiated and whether we should aim at eradicating the bowel inflammation from the onset of therapeutic intervention immediately following diagnosis. Identification of genetic and serologic parameters which allow prediction of the course of the disease would be useful for identifying patients who need aggressive treatment early in the disease. Once total control of the disease is achieved, long-term maintenance of a healed bowel is important. We hypothesize that changing the gut flora, e.g. using probiotics, may allow maintenance of bowel healing after induction with biologicals and immunosuppression.
Pharmacodynamics provides a rational basis for optimizing dosing regimens by describing the relationship between drug, host and antimicrobial effect. The successful identification of meaningful pharmacodynamic outcome parameters can, therefore, greatly assist clinicians in making objective prescribing decisions rather than relying on static in vitro MIC data. While pharmacodynamic outcome parameters have been proposed for select antimicrobial agents, their clinical application remains to be defined fully. Quinolone antibiotics are generally considered to have concentration-dependent bactericidal activity and peak/MIC and AUC/MIC ratios have been identified as possible pharmacodynamic predictors of clinical and microbiological outcome as well as the development of bacterial resistance. Investigators have suggested that AUC/MIC ratios of 100-125 or peak/MIC ratios of >10 are required to predict clinical and microbiological success and to limit the development of bacterial resistance. These conclusions are derived primarily from studies of Gram-negative bacteria, and recent data suggest that these ratios may not be applicable for Streptococcus pneumoniae, where an AUC/MIC ratio of <40 appears to be a more accurate predictor. There is considerable variation in pharmacodynamic calculations and outcome parameters appear to be quinolone- and pathogen-specific. Additional prospective clinical research is needed to characterize quinolone pharmacodynamic parameters and answer unresolved questions regarding optimal pharmacodynamic outcome predictors for Gram-positive bacteria, anaerobes and atypical respiratory pathogens.
Increasing research initiatives in head and neck cancer over the past 5 years have resulted in the identification of several 'new' biologic parameters which may be of prognostic importance. This review discusses the limitations of traditional parameters and outlines several promising developments in the study of proliferation markers, molecular biology, immunobiology and flow cytometry as they relate to head and neck cancer.
The role of salvage prostatectomy for radio-recurrent prostate cancer remains unclear. Recurrent prostate cancer after radiation therapy is in many cases biologically aggressive. It is unclear whether the biologic aggressiveness of radio-recurrent prostate cancer is due to time-dependent cancer clonal evolution (potentially induced by radiation damage), or is due to an innately aggressive tumor secondary to overexpression or mutation of apoptotic inhibitors that render these tumors resistant to radiation. Recent studies examined the role of DNA ploidy, p53 and bcl-2 expression, proliferative indices and glutathione S-transferase-pi in predicting response to radiation therapy or salvage prostatectomy. Because of the potential for significant morbidity after salvage prostatectomy, preoperative parameters that aid in the identification of the patients who are most likely to benefit from surgery are needed.
BACKGROUND: The low reproducibility of the QT dispersion (QTD) method is a major reason why it is not used in clinics. The purpose of this study was to develop QT dispersion parameters with better reproducibility and identification of patients with a high risk of ventricular arrhythmia or death. METHODS AND RESULTS: Three institutions using different methods for measuring QT intervals provided QT databases, which included more than 3500 twelve-lead surface ECGs. The data represented low and high risk subjects from the following groups: the normal population EpiSet (survivors vs dead from cardiovascular causes), acute myocardial infarction patients AmiSet (survivors vs dead) and remote myocardial infarction patients ArrSet (with vs without a history of ventricular arrhythmia). The EpiSet, AmiSet, and the ArrSet contributed with N = 122, 0, and 110 ECGs for reproducibility analysis, and 3244, 446, and 100 ECGs for the analysis of prognostic accuracy. The prognostic accuracy was measured as the area under the Receiver Operator Curve. The QT intervals were divided into six QT pairs; the longest pair consisted of the longest and the shortest QT intervals etc. The QT dispersion trend (QTDT) was defined as the slope of the linear regression of the N longest QT pairs after estimation of missing QT intervals by interpolation of measured QT intervals. The QTMAD and the QTSTD methods were defined as twice the mean absolute deviation and the standard deviation of the N longest QT pairs. The reproducibility was improved by 27% and 19% in the EpiSet and the ArrSet relative to the reproducibility of QTD. The accuracy improved for the EpiSet and the ArrSet and was maintained for the AmiSet. CONCLUSIONS: By using the three longest and the three shortest QT intervals in QTDT, QTMAD, or QTSTD, the reproducibility improved significantly while maintaining or improving the prognostic accuracy compared to QTD.
Utilizing a simple model in which the acoustic wave function is a sum of independent Gaussian wave packets, the relative intensity variance or scintillation index (SI) is analytically calculated. The model has an unspecified probability density function (PDF) for wave packet amplitudes and Gaussian PDFs for travel-time-induced and non-travel-time-induced phase shifts; amplitudes and both phase shifts are assumed to be mutually uncorrelated. It is shown that a proper treatment of the mean field is required to obtain the saturation value, SI = 1, in the limit of a large number of interfering wave packets. The analytic formulas for SI allow identification of important wave packet parameters in the approach to saturation. Criteria are identified for both broadband and narrow-band cases for which the approach to saturation is from above and below 1. It is demonstrated that the broadband approach to saturation is much slower than the narrow-band cases, since wave packets separated in time by more than an inverse bandwidth do not strongly contribute to interference. This effect is quantified by the time-bandwidth product. The model is also used to obtain an analytic expression for pulse time spread; it is shown that multipath conditions which favor a rapid approach to saturation do not favor large pulse spread.
A flow cytometry-based assay was used to simultaneously quantify X4 and R5 human immunodeficiency virus (HIV) envelope-mediated cell-to-cell viral transfer, cell death, and cell-to-cell fusion. In this assay, different anti-HIV envelope drugs showed characteristic inhibitory profiles for each measured parameter, allowing for the rapid identification of the mode of action of active compounds.
Beginning in 1990, gram-positive rods resembling Actinomyces pyogenes were found with increasing frequency in mixed cultures from various infectious processes, most of them from patients with otitis, empyema, pilonidal cysts, perianal abscesses, and decubitus ulcers. Ribotyping and hybridization showed that these gram-positive rods could be divided into five groups not related to known Actinomyces species. Biochemical markers for reliable differentiation into these groups, however, could not be found. Therefore, naming new species is not warranted unless parameters are discovered that allow identification without DNA hybridization. These gram-positive rods have been isolated only in mixed cultures with anaerobes, Staphylococcus aureus, Streptococcus "milleri," enterococci, and gram-negative rods. Their exact role in these possibly synergistic infections needs further investigation.
Segmental renal artery branches within the renal sinus were prospectively evaluated with color Doppler imaging and pulsed-Doppler spectral analysis in 56 patients before angiography. Waveforms were evaluated for the tardus and parvus abnormalities of prolonged acceleration time, diminished acceleration index, and loss of the normal early systolic compliance peak/reflective-wave complex (ESP). Findings obtained with these parameters were compared with the subsequent findings on angiograms to ascertain their efficacy in detection of hemodynamically significant (greater than or equal to 60%) renal arterial stenosis (RAS), which was present in 32 kidneys in 26 patients. Simple pattern-recognition analysis of ESP proved to be the best of the three parameters. Loss of ESP enabled identification of RAS with 95% sensitivity, 97% specificity, a 92% positive predictive value, a 98% negative predictive value, a 96% overall accuracy. On the basis of the high technical success rate, high sensitivity and specificity, and short examination time, waveform analysis for detection of tardus-parvus abnormalities, especially loss of ESP, of the segmental artery is recommended as an alternative to direct examination of the main renal arteries for evaluation of RAS.
The N-nitroso-compounds and the bacteriological contamination of gastric juice could represent a risk factor for cancer of the stomach when the mucosal barrier is altered. In the unresected stomach and gastric stump, the hypo-achlorhydria and bilopancreatic reflux permit the development of bacterial flora and the production of N-nitroso-compounds in the presence of nitrite. A survey was performed on 71 patients: 15 normal controls, 31 with gastroduodenal disease (9 gastrites, 10 gastric ulcers, 10 duodenal ulcers, 7 neoplasias), 20 patients with gastric resection (8 BI, 12 BII), using an endoscopic-histopathologic control and a chemical-bacteriological analysis of the gastric juice. We studied the gastric juice for the following parameters: pH, concentration of nitrite, identification of bacterial type, count and nitrate-reductase activity. An inverse relationship was found between the concentration of nitrite and the hydrogen ion concentration. In the alkaline gastric juice, we identified aerobic bacteria with nitrate-reductase activity and anaerobic bacteria. The latter has the ability to transform biliary salts into carcinogenic and cocarcinogenic compounds and to catalyze the nitrosations. The chemicobacteriological characteristics of the gastric juice from gastric ulcers (Johnson type I), atrophic gastrites, and resected stomachs lead one to think that there is a risk of carcinogenesis brought about by the N-nitroso-compounds.
Craniopharyngiomas are rare, mainly sellar/parasellar, epithelial tumors diagnosed during childhood or adult life. Histologically, two primary subtypes have been recognized (adamantinomatous and papillary) with an as yet, unclarified pathogenesis. They may present with a variety of manifestations (neurological, visual, and hypothalamo-pituitary). Despite their benign histological appearance, they often show an unpredictable growth pattern, which, combined with the lack of randomized studies, poses significant difficulties in the establishment of an optimal therapeutic protocol. This should focus on the prevention of recurrence(s), improvement of survival, reduction of the significant disease and treatment-related morbidity (endocrine, visual, hypothalamic, neurobehavioral, and cognitive), and preservation of the quality of life. Currently, surgical excision followed by external beam irradiation, in cases of residual tumor, is the main treatment option. Intracystic irradiation or bleomycin, stereotactic radiosurgery, or radiotherapy and systemic chemotherapy are alternative approaches; their place in the management plan remains to be assessed in adequately powered long-term trials. Apart from the type of treatment, the identification of clinical and imaging parameters that will predict patients with a better prognosis is difficult. The central registration of patients with these challenging tumors may provide correlates between treatments and outcomes and establish prognostic factors at the pathological or molecular level that may further guide us in the future.
BACKGROUND: Following natural disasters, mismanagement of the dead has consequences for the psychological well-being of survivors. However, no technical guidelines currently exist for managing mass fatalities following large natural disasters. Existing methods of mass fatality management are not directly transferable as they are designed for transport accidents and acts of terrorism. Furthermore, no information is currently available about post-disaster management of the dead following previous large natural disasters. METHODS AND FINDINGS: After the tsunami disaster on 26 December 2004, we conducted three descriptive case studies to systematically document how the dead were managed in Thailand, Indonesia, and Sri Lanka. We considered the following parameters: body recovery and storage, identification, disposal of human remains, and health risks from dead bodies. We used participant observations as members of post-tsunami response teams, conducted semi-structured interviews with key informants, and collected information from published and unpublished documents. Refrigeration for preserving human remains was not available soon enough after the disaster, necessitating the use of other methods such as dry ice or temporary burial. No country had sufficient forensic capacity to identify thousands of victims. Rapid decomposition made visual identification almost impossible after 24-48 h. In Thailand, most forensic identification was made using dental and fingerprint data. Few victims were identified from DNA. Lack of national or local mass fatality plans further limited the quality and timeliness of response, a problem which was exacerbated by the absence of practical field guidelines or an international agency providing technical support. CONCLUSIONS: Emergency response should not add to the distress of affected communities by inappropriately disposing of the victims. The rights of survivors to see their dead treated with dignity and respect requires practical guidelines and technical support. Mass fatality management following natural disasters needs to be informed by further field research and supported by a network of regional and international forensic institutes and agencies.
OBJECTIVE: The purpose of this study was to assess interobserver and intraobserver variability in evaluation of the reproducibility of quantitative data obtained in semiautomated postprocessing of CT perfusion data sets by observers of different levels of skill and experience and in fully automated postprocessing. MATERIALS AND METHODS: Twenty CT perfusion data sets were postprocessed by a neuroradiologist using an automated postprocessing program and by five observers (neuroradiology attending, neurology attending, radiology resident, senior and junior CT technologists) who received a brief training session in use of software for semiautomated postprocessing. For assessment of intraobserver variability, each observer repeated postprocessing of 10 CT perfusion data sets. Standard regions of interest were placed on identical locations for each observer's cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) maps of three brain regions: an ischemia-infarct region, normal cortical gray matter, and white matter. RESULTS: The variability in mean quantitative values of CBF, CBV, and MTT was 2.5-9.5% among all observers. Greater variability (20.4%) was introduced with the automated program. High correlation was found among all possible pairings of observers (r = 0.87-0.99). Low correlation was observed between automated postprocessing and postprocessing by all observers. Intraobserver variability in quantitative CT perfusion data ranged from 0.29% to 10.8%. High intraobserver correlation (r = 0.91-0.99) was found for the observers. CONCLUSION: Quantitative CBF, CBV, and MTT data obtained from postprocessing of CT perfusion data sets are reproducible among observers with varying levels of skill and experience. Observer interaction with the software is an important component for correct identification of user-defined parameters. Establishing a uniform and standard postprocessing technique is essential for maintaining good reproducibility.