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Accurate analysis is the foundation for successful rhinoplasty. A general outline for systematic analysis is presented. The importance of accurate recordkeeping and self-analysis is stressed. Examples illustrate the high points of the article.
A systematic analysis of hydrogen bonds between regulatory proteins and their DNA targets is presented, based on 28 crystallographically solved complexes. All possible hydrogen bonds were screened and classified into different types: those that involve the amino acid side-chains and DNA base edges and those that involve the backbone atoms of the molecules. For each interaction type, all bonds were characterized and a statistical analysis was performed to reveal significant amino acid-base interdependence. The interactions between the amino acid side-chains and DNA backbone constitute about half of the interactions, but did not show any amino acid-base correlation. Interactions via the protein backbone were also observed, predominantly with the DNA backbone. As expected, the most significant pairing preference was demonstrated for interactions between the amino acid side-chains and the DNA base edges. The statistically significant relationships could mostly be explained by the chemical nature of the participants. However, correlations that could not be trivially predicted from the hydrogen bonding potential of the residues were also identified, like the preference of lysine for guanine over adenine, or the preference of glutamic acid for cystosine over adenine. While Lys x G interactions were very frequent and spread over various families, the Glu x C interactions were found mainly in the basic helix-loop-helix family. Further examination of the side-chain-base edge contacts at the atomic level revealed a trend of the amino acids to contact the DNA by their donor atoms, preferably at position W2 in the major groove. In most cases it seems that the interactions are not guided simply by the presence of a required atom in a specific position in the groove, but that the identity of the base possessing this atom is crucial. This may have important implications in molecular design experiments.
BACKGROUND: The systematic analysis of morbidity and mortality for the Food and Drug Administration (FDA)-approved medical abortion regimen using mifepristone is possible using data from the FDA's Adverse Event Reporting System. OBJECTIVE: To assess mifepristone's mortality, morbidity, sentinel events, and quality of postmarketing surveillance using mifepristone adverse event reports (AERs). METHODS: Six hundred seven unique mifepristone AERs submitted to the FDA over a 4 year span were coded using the National Cancer Institute's Common Terminology Criteria for Adverse Events. Coding was based only on data in AERs and may underestimate severity and treatment rendered. Two board-certified obstetrician/gynecologists, the authors, made individual evaluations, compared them, and agreed upon final coding. RESULTS: The most frequent AERs were hemorrhage (n = 237) and infection (66). Hemorrhages included 1 fatal, 42 life threatening, and 168 serious cases; 68 required transfusions. Infections included 7 cases of septic shock (3 fatal, 4 life threatening) and 43 cases requiring parenteral antibiotics. Surgical interventions were required in 513 cases (235 emergent, 278 nonemergent). Emergent cases included 17 ectopic pregnancies (11 ruptured). Second trimester viability was documented in 22 cases (9 lost to follow-up, 13 documented fetal outcome). Of the 13 documented cases, 9 were terminated without comment on fetal morphology, 1 was enrolled in fetal registry, and 3 fetuses were diagnosed with serious malformations, suggesting a malformation rate of 23%. CONCLUSIONS: Hemorrhage and infection are the leading causes of mifepristone-related morbidity and mortality. AERs relied upon by the FDA to monitor mifepristone's postmarketing safety are grossly deficient due to extremely poor quality.
This chapter has been organized empirically, focusing on the types of approaches that have been taken to understand BFCS function. This approach reflects the state of our knowledge about the behavioral and psychological functions of the BFCS. Considerable information has been gathered in the very short time that the BFCS has been the object of intense investigation. The results from the neurotoxic lesions and from the HACU studies provide some points of consistency and some puzzling differences. Both approaches to the study of basal forebrain function suggest that the MSA is involved in tasks that require spatial working memory; MSA lesions impaired choice accuracy, and HACU in the HIP was increased after performance. The pattern of results in simpler tasks is more difficult to interpret. In a left-right reference memory discrimination in a T-maze, MSA lesions did not impair acquisition or performance, whereas HACU in the HIP was activated during performance. This pattern of results suggests that although the MSA is engaged during this type of task, its activity is not necessary for normal performance. These, and other comparisons indicate the need for a systematic analysis of task demand (Olton, 1989b). Parametric manipulations of different task demands in a systematic fashion can indicate the extent to which the BFCS is involved in the function associated with each parametric manipulation. Ultimately, of course, the organization of this material should focus on particular psychological functions, rather than the techniques and procedures used to gather the information. Achieving this goal is going to require careful attention to the design of behavioral experiments so that definitive conclusions can be made about the extent to which the BFCS is involved in a given psychological function. A systematic application of task analysis can achieve this goal (Olton, 1986, 1989a, 1989b). For example, BFCS lesions in rats impair choice accuracy in spatial working memory tasks, and performance in these tasks engages the HACU system, at least in the HIP. If the spatial functions of this task involve the BFCS, then a nonspatial version of the task should produce a different pattern of results. If the spatial nature of the task is unimportant for BFCS function, then a nonspatial version of the task should produce the same results. By systematically changing one characteristic of the task at a time, the contribution of each component can be assessed.(ABSTRACT TRUNCATED AT 400 WORDS)
Serial analysis of gene expression (SAGE) is a powerful technique for the analysis of gene expression. A significant portion of SAGE tags, designated as orphan tags, however, cannot be reliably assigned to known transcripts. We used an improved reverse SAGE (rSAGE) strategy to convert human embryonic stem cell (hESC)-specific orphan SAGE tags into longer 3' cDNAs. We show that the systematic analysis of these 3' cDNAs permitted the discovery of hESC-specific novel transcripts and cis-natural antisense transcripts (cis-NATs) and improved the assignment of SAGE tags that resulted from splice variants, insertion/deletion, and single-nucleotide polymorphisms. More importantly, this is the first description of cis-NATs for several key pluripotency markers in hESCs and mouse embryonic stem cells, suggesting that the formation of short interfering RNA could be an important regulatory mechanism. A systematic large-scale analysis of the remaining orphan SAGE tags in the hESC SAGE libraries by rSAGE or other 3' cDNA extension strategies should unravel additional novel transcripts and cis-NATs that are specifically expressed in hESCs. Besides contributing to the complete catalog of human transcripts, many of them should prove to be a valuable resource for the elucidation of the molecular pathways involved in the self-renewal and lineage commitment of hESCs.
This study provided a systematic analysis of improvised tone sequences of autistic children, as compared to musical improvisations by normal and mentally retarded control subjects. The data indicate that autistic children's tone patterns, analyzed and scored for rhythm, restriction, complexity, rule adherence, and originality, almost reached the scores of normal children. The highest individual total score in the study was achieved by an autistic child. Autistic children scored significantly higher than a control group of mentally retarded individuals. The autistic children's tone sequences showed high scores on the rhythm, restriction, and originality scales which support the notion of unusual musical responsiveness and abilities when compared to results in other performance and behavioral areas. In terms of complexity and rule adherence, autistic children's tone sequences resembled those of the mentally retarded by being rather short and repetitive.
Fold recognition was applied to the systematic analysis of the all sequences encoded by the genome of Mycoplasma tuberculosis H37Rv in order to identify new putative glycosyltransferases. The search was conducted against a library composed of all known crystal structures of glycosyltransferases and some related proteins. A clear relationship appeared between some sequences and some folds. It appears necessary to complete the fold recognition approach with a statistical approach in order to identify the relevant data above the background noise. Exploratory data analysis was carried out using several methods. Analytical methods confirmed the validity of the approach, while predictive methods, although very preliminary in the present case, allowed for identifying a number of sequences of interest that should be further investigated. This new approach of combining bioinformatics and chemometrics appears to be a powerful tool for analysis of newly sequenced genomes. Its application to glycobiology is of great interest.
OBJECTIVES: Juvenile nasopharyngeal angiofibroma often recurs if the tumor is large. This report is a long-term follow-up of these cases. It establishes the prognostic values of tumor extensions, analyzes the anatomic factors involved in recurrences, describes the spontaneous evolution of remnants based on a radiographic follow-up, and evaluates the pertinence of complex combined surgical approaches for invasive tumors and the value of complementary endoscopy. STUDY DESIGN: Retrospective review of 44 cases treated between 1985 and 1996. METHODS: Statistical analysis of the correlation between recurrence and tumor extension as evaluated by systematic analysis of 18 putative tumor extensions on preoperative computed tomography scans. RESULTS: Invasion of the skull base affected two-thirds of the patients, and the rate of recurrence was 27.5%. Extensions to the infratemporal fossa, sphenoid sinus, base of pterygoids and clivus, the cavernous sinus (medial), foramen lacerum, and anterior fossa were correlated with more frequent recurrence. Long-term radiographic follow-up revealed putative residual disease in nine asymptomatic patients: these remnants gradually involuted. CONCLUSIONS: The data in the current study emphasize the prognostic value of skull base invasion and the difficulty of complete resection of extended lesions. Tumor remnants detected in symptom-free patients should be kept under surveillance by repeated computed tomography scan, since involution may occur. Recurrent symptoms may be treated by radiotherapy (30 Gy) rather than by extended combined procedures. Endoscopic surgery should be combined with surgery for better control of skull base extensions.
A meta-analysis was performed on published data on the caries-inhibiting effect of chlorhexidine treatment. The results of the various studies are difficult to evaluate because of various treatment procedures, dissimilar features of participants, and different presentations of study results. A meta-analysis provides a more structured approach than the traditional review, due to systematic analysis and numerical processing of the available information. The objectives of this meta-analysis were: (1) to assess a more accurate estimate of the caries-inhibiting effect of chlorhexidine treatment than provided by individual studies, and (2) to explore factors potentially modifying the effect of chlorhexidine treatment in caries prevention, i.e., the application method, application frequency, target population, the fluoride regime, and caries criteria. Caries reduction was expressed by the prevented fraction, indicating the percentage reduction of caries incidence in the chlorhexidine group. For all prevented fractions, 95% confidence intervals were calculated. The overall caries-inhibiting effect of the chlorhexidine treatment studies was 46% (95% CI = 35% - 57%). Multiple-regression analysis showed no significant influence on the prevented fractions for the variables "application method", "application frequency", "caries risk", "fluoride regime", "caries diagnosis", and "tooth surface".
The MIPS group [Munich Information Center for Protein Sequences of the German National Center for Environment and Health (GSF)] at the Max-Planck-Institute for Biochemistry, Martinsried near Munich, Germany, is involved in a number of data collection activities, including a comprehensive database of the yeast genome, a database reflecting the progress in sequencing the Arabidopsis thaliana genome, the systematic analysis of other small genomes and the collection of protein sequence data within the framework of the PIR-International Protein Sequence Database (described elsewhere in this volume). Through its WWW server (http://www.mips.biochem.mpg.de ) MIPS provides access to a variety of generic databases, including a database of protein families as well as automatically generated data by the systematic application of sequence analysis algorithms. The yeast genome sequence and its related information was also compiled on CD-ROM to provide dynamic interactive access to the 16 chromosomes of the first eukaryotic genome unraveled.
Cell fusion by microsurgery permits production of specified bicellular hybrid cells with very high efficiency. Systematic analysis of the fate of bicellular hybrids reveals fundamental properties of cells in accordance with cell type. Bicellular hybrids that do not proliferate survive 1-21 days; those that do proliferate form clones 8-9 days after fusion.
In this report, we describe the first systematic analysis of the genetic requirements for polyomavirus (Py) enhancer-activated viral DNA replication during the acute phase of infection in mice. Four mutants were made which substituted XhoI sites for conserved enhancer consensus sequences (adenovirus type 5 E1A, c-fos, simian virus 40, and a glucocorticoidlike consensus sequence). Viral DNA replication in infected mouse organs was measured by DNA blot analysis. Only the loss of the glucocorticoidlike consensus sequence element significantly reduced Py DNA replication in the kidneys, the primary target organ for viral replication. The loss of the c-fos, adenovirus type 5 E1A, or simian virus 40 consensus sequences, however, expanded organ-specific viral DNA replication, relative to wild-type Py, by allowing high-level replication in the pancreas or heart or both. Analysis of Py variants selected for replication in undifferentiated embryonal carcinoma cell lines (PyF441, PyF111) showed that there was little change in levels of viral DNA replication in kidneys and other organs as compared with those in the wild-type virus. If the entire B enhancer is deleted, only low overall levels of viral replication are observed. Wild-type levels of replication in the kidneys can be reconstituted by addition of a single domain from within the A enhancer (nucleotides 5094 to 5132) to the B enhancer deletion virus, suggesting that a single domain from the A enhancer can functionally substitute for the entire B enhancer. This also indicates that the determinants for kidney-specific replication are not found in the B enhancer.
Because no systematic analysis of drug fever has been done, there has been no means for testing the validity of published characterizations of this clinical entity. We reviewed the clinical characteristics of 51 episodes of drug fever in 45 patients hospitalized at two Dallas hospitals between 1959 and 1986, and 97 episodes reported in the English literature between 1966 and 1986. Unlike characterizations found in textbooks and review articles, we found relative bradycardia in a minority of cases reviewed; little risk associated with rechallenge unless underlying cardiovascular disease was present; no characteristic fever pattern; a highly variable lag time between the initiation of the offending agent and the onset of fever; an infrequent association with either rash or eosinophilia; and no apparent association of drug fever with systemic lupus erythematosus, atopy, female sex, or advanced age.
In 1998, the National Institutes of Health (NIH) formed the National Center for Complementary and Alternative Medicine (NCCAM) from what had formerly been the Office of Alternative Medicine. This presentation opens with a brief discussion on the history of the NIH and the development of CAM at the NIH before moving on to the work of the NCCAM. The NCCAM is moving toward an integration of CAM therapies into conventional medicine, when there is evidence for the value of CAM. One of twenty-five institutes or centers at the NIH, the NCCAM looks at evidence-based medicine and public health. In this context, "public health" means educating the public about its health. The NCCAM supports training to conduct research and plays an important role in disseminating information to the public and to health providers about what works and what is safe. This evolves into the concept of evidence-based medical and public-health practices, that is, making decisions on the basis of evidence from scientifically rigorous studies that are sufficiently large to provide a confident estimate of biologically and medically important benefits and risks. In the hierarchy of generating scientific evidence, randomized controlled trials are considered the "gold standard." The NCCAM entertains proposals for studies that come spontaneously from investigators, or, upon identifying an existing need that is not being met by the investigative community, the NCCAM can initiate a request for proposals. Every proposal is subjected to a rigorous application and review process. Another possible step in the assessment of the evidence from clinical trials is to do a systematic analysis of several studies to bring together all the information that is available. Systematic reviews of smaller studies that individually might have an insufficient sample size can assist in making treatment decisions, but, importantly, they can lead the NCCAM in the development of future, definitive studies. Training to conduct research is especially important to CAM. This presentation outlines several approaches the NCCAM has to training (see http://nccam.nih.gov).
TRPV4, a nonselective cation channel of the transient receptor potential (TRP) family, is gated by hypotonicity. Expression of TRPV4 mRNA has been detected in the circumventricular organs of the brain responsible for sensing systemic tonicity and in the kidney distal convoluted tubule (DCT), among other sites. No analysis of TRPV4 expression at the protein level has been undertaken and no systematic analysis of expression of this channel has been reported in the kidney. Via RNAse protection assay and immunoblotting, abundant expression of TRPV4 was detected in the cortex, medulla, and papilla. The expression pattern of TRPV4 was characterized in both rat and mouse kidney, which revealed similar patterns of immunoreactivity. TRPV4 expression was absent from the proximal tubule (PT) and descending thin limb (DTL), whereas the strongest expression was observed in the ascending thin limb (ATL). The thick ascending limb (TAL) was strongly positive as was the DCT and connecting tubule. Importantly, the water-permeant cells of the macula densa were unstained. Moderate TRPV4 expression was noted in all collecting duct portions and in papillary epithelium; intercalated cells (type A) exhibited a particularly strong signal. In all positive segments, TRPV4 expression was concentrated at the basolateral membrane. Therefore, TRPV4 is expressed in only those nephron segments that are constitutively (i.e., ATL, TAL, and DCT) or conditionally (i.e., collecting duct) water impermeant and where generation of a substantial transcellular osmotic gradient could be expected. TRPV4 expression is absent from nephron segments exhibiting constitutive water permeability and unregulated apical aquaporin expression (i.e., PT and DTL). These data, although circumstantial, are consistent with a role for TRPV4 in the response to anisotonicity in the mammalian kidney.
A systematic analysis of the conformation of deoxyribofuranose rings in DNA fragments has been described using two-dimensional nuclear Overhauser effect spectroscopy (2D NOESY). The approach is based on the interpretation of the intrasugar proton-proton distances which can be estimated using a low-mixing-time pure-absorption mode w1-scaled NOESY spectrum. The experimental distances are compared with the theoretical values calculated as a function of pseudorotation phase angle (P) describing the sugar geometries. The approach can be used as a complementary aid to J couplings for establishing sugar conformations in individual nucleotide units of DNA fragments. Using this strategy on d-ACATCGATGT, we observed that individual nucleotides exhibit O4'-endo sugar pucker. The results rule out possibilities of the existence of a fast equilibrium (on the NMR time scale) between C2'-endo (or S-domain) and C3'-endo (or N-domain) sugar puckers.
We implemented a proteomics approach to the systematical analysis of the alterations in the proteome of NIH3T3 cells transformed by oncogenic H-RasV12. Forty-four proteins associated with Ras-mediated transformation have been identified, and 28 proteins were not previously reported. RT-PCR analysis showed that approximately 44% of target proteins identified showed concomitant changes in mRNA abundance. A principal finding was the up-regulation of gankyrin, which was the first evidence to show that gankyrin pathway was implicated in Ras-activated transformation.
INTRODUCTION: Gastrointestinal (GI) complications following heart operation may be life-threatening. Systematic analysis of risk factors to allow early identification of patients at risk for GI complication may lead to the development of strategies to mitigate this complication as well as to optimize management after its occurrence. METHODS: Of 8709 consecutive patients undergoing heart operation during 7 years (1997-2003), 46 (0.53%) developed GI complications requiring surgical consultation. Preoperative, intraoperative, and postoperative predictors of complication and death were identified and compared with a control group. RESULTS: Significant (P < 0.05) preoperative predictors of complication were prior cerebrovascular accident (CVA), chronic obstructive pulmonary disease (COPD), type II heparin-induced thrombocytopenia, atrial fibrillation, prior myocardial infarction, renal insufficiency, hypertension, and need for intra-aortic balloon counter-pulsation. The most frequent serious GI complication was mesenteric ischemia, which developed in 31 (67%) patients. Twenty-two (71%) of these patients were explored, and 14 (64%) died within 2 days of heart operation. Of the 9 patients with mesenteric ischemia who were not explored, 7 (78%) died within 3 days of heart operation. Other complications included diverticulitis (5), pancreatitis (4), peptic ulcer disease (4), and cholecystitis (2). The mortality rate in this group of other diagnoses was lower (40%), and death occurred later (32 days) after heart operation (P = 0.03 compared with mesenteric ischemia). Predictors of death from GI complication included New York Heart Association (NYHA) class III and IV heart failure, smoking, chronic obstructive pulmonary disease, history of syncope, aspartate aminotransferase (AST) >600 U/L, direct bilirubin >2.4 mg/dL, pH < 7.30, and the need for >2 pressors. CONCLUSIONS: The most common catastrophic GI complication after cardiac surgery is mesenteric ischemia, which is frequently fatal. This complication may be a result of atheroembolization, heparin-induced thrombocytopenia, or hypoperfusion. Techniques to reduce the occurrence of and/or preemptively diagnosis postcardiotomy mesenteric ischemia are necessary to decrease its associated mortality.