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PubMed2006

SPECT imaging, immunohistochemical and behavioural correlations in the primate models of Parkinson's disease.

Dopamine active transporter (DAT) single photon emission computerised tomography (SPECT) is considered a useful and practical technique for early diagnosis of Parkinson's disease (PD) and assessment of its progression. The application of this technique, particularly as a surrogate marker for therapeutic and neuroprotective trials in Parkinsonism, however, is dependent on pathological validation. In the absence of human studies, we used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate models of Parkinsonism to verify correlation between the SPECT, immunohistochemical and behavioural data. The DAT SPECT data correlated strongly and significantly with the substantia nigra pars compacta tyrosine hydroxylase and Nissl cell counts as well as the behavioural scores. Within the limitations of small numbers inherent to such studies, this data provides the first attempt at pathological validation of SPECT in primates.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2002

Comorbidity of aerophagia in GERD patients: outcome of laparoscopic antireflux surgery.

BACKGROUND: While there is evidence that physiological data correlate poorly with quality-of-life data or patient-perceived symptom severity, most outcome studies of antireflux surgery still refer physiologic criteria. The aim of this prospective study was to establish whether concomitant aerophagia in GERD (gastroesophageal reflux disease) patients might influence the surgical outcome of laparoscopic 'floppy' Nissen fundoplication. METHODS: A total of 112 patients were divided into 2 subgroups: group 1 comprising GERD patients without aerophagia (n = 94; 84%); group 2 of GERD patients with concomitant aerophagia (n = 28; 16%). In all patients, requirements for surgery included an evaluation of symptoms (list of 17 symptoms; patients' grading from no--mild to moderate--severe), quality of life (Gastrointestinal Quality of Life Index: GIQLI), esophagogastroduodenoscopy, esophageal manometry and 24-h pH monitoring. Additionally, we asked for any potential stress relations to GERD symptoms. Surgical outcome was assessed 3 months and 1 year postoperatively. RESULTS: In group 2 patients before surgery, we found a significantly higher percentage with a mild impairment of esophageal motility, with a subjectively and objectively dominant reflux in the upright position, with a lower grading of esophagitis or Barrett esophagus, and with a stronger belief that stress was in any relation to perceived symptoms compared with group 1 patients. Additionally, these patients perceived typical and untypical symptoms more intensively. Factors such as DeMeester score and lower esophageal sphincter pressure did not differ preoperatively, the same as after antireflux surgery. Both groups profit significantly from surgery-a continuous reduction of symptom severity and quality-of-life improvement was found. Group 1 patients showed an improvement in mean GIQLI from 93.4+/-8.3 points preoperatively to 123.1+/-7.3 and 122.9+/-9.0 points 3 months and 1 year postoperatively, whereas group 2 patients demonstrated a lower outcome, from 82.2+/-9.1 points to 112.4+/-8.1 and 116.8+/-7.9 points postoperatively. This lesser improvement is the result of preoperative symptoms such as belching, bloating or flatulence, which many patients had after surgery. In addition, some of the group 2 patients suffered from subjective mild to moderate heartburn or dysphagia, but without any objective correlation. CONCLUSION: GERD patients with concomitant aerophagia demonstrated less symptomatic relief than patients without aerophagia. Moreover, patients with aerophagia showed less quality-of-life improvement after laparoscopic antireflux surgery. There were no significant differences in physiological outcome data between groups. Surgery in GERD patients with symptoms relating to aerophagia should be approached with great care. An additional psychological intervention in these patients might improve surgical outcome.

Adult↗
PubMed1994

In vivo-in vitro correlation of myelotoxicity of 9-methoxypyrazoloacridine (NSC-366140, PD115934) to myeloid and erythroid hematopoietic progenitors from human, murine, and canine marrow.

BACKGROUND: 9-Methoxypyrazoloacridine (PZA) is an anticancer agent that shows selectivity of action for carcinomas over leukemias. It also has nearly equal potency against cycling and quiescent or hypoxic and normoxic target cells. Phase I trials of PZA in humans are nearing completion. PURPOSE: This study was conducted to determine (a) if PZA is directly inhibitory to hematopoietic cells and, if it is, to characterize the inhibition pharmacodynamically, (b) whether species-specific differences in direct toxicity could explain differences in myelosuppression in mice, dogs, and humans, and (c) whether in vitro data correlate with in vivo myelosuppression data. METHODS: In vitro clonogenic assays of hematopoietic progenitors of myeloid and erythroid lineages from human, canine, and murine femoral marrow were used to measure the direct toxicity of PZA. Results from these assays were compared on an area-under-the-curve (AUC) basis to clinical myelosuppression data. RESULTS: On the basis of maximum tolerated concentrations, canine hematopoietic progenitors are most susceptible to PZA, followed by human and then murine progenitors. We found no difference in susceptibility to PZA toxicity between the human progenitors of myeloid and erythroid lineages. Both concentration and duration of exposure contribute to the in vitro toxicity of PZA. In contrast to antimetabolites, the in vitro toxicity of PZA could be minimized at a given AUC by lowering drug concentration and prolonging the period of exposure. On an AUC basis, the in vitro data are consistent with limited in vivo myelosuppression data from preclinical models and correlate with neutropenia data from a phase I trial. CONCLUSIONS: PZA directly inhibits hematopoietic progenitors, an action that is responsible for the myelosuppression observed in humans. Human marrow appears able to compensate for the loss of up to 35% of its myeloid progenitors, in that peripheral neutrophil counts remain unchanged at that level of loss. Although in vivo studies show that prolonged infusion reduces myelosuppression at a given total dose in both rodent and canine models, pharmacokinetic differences make it unlikely that this approach will benefit human patients. IMPLICATIONS: The in vitro data quantitatively predict the AUCs at maximum tolerated dose in preclinical models and human patients. Thus, in vitro clonogenic assays of myelotoxic agents can provide data that make both preclinical toxicology testing and clinical trial planning and interpretation more efficient and accurate.

Acridines↗
PubMed1999

The solution structure and dynamics of human neutrophil gelatinase-associated lipocalin.

Human neutrophil gelatinase-associated lipocalin (HNGAL) is a member of the lipocalin family of extracellular proteins that function as transporters of small, hydrophobic molecules. HNGAL, a component of human blood granulocytes, binds bacterially derived formyl peptides that act as chemotactic agents and induce leukocyte granule discharge. HNGAL also forms a complex with the proenzyme form of matrix metalloproteinase-9 (pro-MMP-9, or progelatinase B) via an intermolecular disulphide bridge. This association allows the subsequent formation of ternary and quaternary metalloproteinase/inhibitor complexes that vary greatly in their metalloproteinase activities. The structure and dynamics of apo-HNGAL have been determined by NMR spectroscopy. Simulated annealing calculations yielded a set of 20 convergent structures with an average backbone RMSD from mean coordinate positions of 0. 79(+/-0.13) A over secondary structure elements. The overall rotational correlation time (13.3 ns) derived from15N relaxation data is consistent with a monomeric protein of the size of HNGAL (179 residues) under the experimental conditions (1.4 mM protein, pH 6.0, 24.5 degrees C). The structure features an eight-stranded antiparallel beta-barrel, typical of the lipocalin family. One end of the barrel is open, providing access to the binding site within the barrel cavity, while the other is closed by a short 310-helix. The free cysteine residue required for association with pro-MMP-9 lies in an inter-strand loop at the closed end of the barrel. The structure provides a detailed model of the ligand-binding site and has led to the proposal of a site for pro-MMP-9 association. Dynamic data correlate well with structural features, which has allowed us to investigate a mechanism by which a cell-surface receptor might distinguish between apo and holo-HNGAL through conformational changes at the open end of the barrel.

Acute-Phase Proteins↗
PubMed1994

PCR and immunoblot analyses of dystrophin in Becker muscular dystrophy.

The dystrophin gene was examined by PCR analysis in 30 Japanese patients with Becker muscular dystrophy (BMD). Fifteen PCR of these patients had exon deletion, generally, less than three exons. Muscle biopsies were also performed in 20 BMD patients (10 with sequence deletions, and 10 without detectable sequence deletions) in order to correlate PCR findings with immunoblot and immunostaining data. A patchy, heterogeneous membrane immunostaining pattern of reduced intensity was found, irrespective of the presence or absence of deletions. Immunoblotting studies demonstrated dystrophin of low molecular mass and quantity in BMD patients with deletion mutations, while a low quantity of dystrophin with an apparent wild type molecular mass was observed in nearly half the BMD patients without detectable deletions. However, these dystrophins were also found to have slightly abnormal molecular masses when the standard electrophoresis time was prolonged. This suggests that immunoblots and PCR data correlate well in patients with BMD. Additionally, it is suggested that immunoblot assays can detect abnormalities in dystrophin in the absence of detectable PCR deletions.

Adolescent↗
PubMed2002

Measuring of the piriform aperture in humans with 3D-SSD-CT-reconstructions.

Form and width of the osseous nasal pyramid exert significant impact on the effectiveness of nasal respiration. In planning a corrective rhinoplasty with osteotomies precise anatomic knowledge of piriform aperture can be of great benefit. Using 3D-reconstructions on the basis of spiral CTs of the paranasal sinuses the piriform aperture was measured for the first time in vivo. A collective of 116 patients from the Göttingen region in Lower Saxony (Central Germany) was examined in this way. For the upper width of the piriform aperture a mean value of 15.7 mm, for the lower width a mean value of 23.1 mm was found. This data correlates very well with the previously acquired data from human skulls. The spectrum of anatomic variations of the piriform aperture is discussed in regard to gender, age and race specific factors. 3D-reconstruction of spiral CTs can be recommended as the ideal preoperative examination previous to corrective rhinoplastic surgery.

Adolescent↗
PubMed2003

A human leucocyte antigen-DR1 transgene confers susceptibility to experimental allergic encephalomyelitis elicited by an epitope of myelin basic protein.

Much evidence now indicates that human leucocyte antigen (HLA) class I and class II transgenic (Tg) mice can be of value in analysing HLA-restricted presentation of T-cell epitopes relevant to experimental models of autoimmune diseases. One area where this has been applied is the characterization of myelin epitopes presented by HLA class II molecules in experimental model of multiple sclerosis (experimental allergic encephalomyelitis (EAE)). As a first step towards humanized disease models in HLA Tg mice, we have analysed immune response of lymph node cells of HLA-DR1 Tg mice immunized with the human myelin basic protein (MBP) peptides 13-33, 87-106 and 139-154 bound by HLA-DR1. We report here that HLA-DR1 Tg mice display a hierarchy of response in vivo and in vitro to MBP epitopes depending on the binding affinity to DRB*0101 molecule. In fact, the 13-33 epitope induced a strong T helper 1 (Th1) response accompanied by high T-cell precursor frequency and caused mild EAE, while the two other epitopes gave poor (139-154) or no disease (87-106), and these data correlate with in vitro Th1 response. These data could prove a useful tool in understanding the role played by different MBP epitopes in EAE.

Amino Acid Sequence↗
PubMed2000

Comparative physiology and biochemistry of rat and rabbit urinary bladder.

OBJECTIVE: To compare directly the biochemistry and contractile responses of rat and rabbit bladder to different stimuli. Materials and methods Sexually mature male New Zealand White rabbits and Sprague Dawley rats were compared. Each bladder was excised while the animal was anaesthetized; longitudinal bladder strips were cut and then mounted in an organ bath. Tension (2 g) was placed on all strips and each underwent field stimulation (FS) for a total of 20 s at 1-32 Hz, 1 ms and 80 V and was exposed to carbachol (100 micromol/L), ATP (2 mmol/L) and KCl (120 mmol/L). The tension was monitored continually using a polygraph and data stored digitally in a computer. The responses to each stimulus were determined as the maximum tension generated, maximum rate of tension generation and duration to a maximum response. The Ca2+- ATPase activity of the rat and rabbit bladder was determined. Bladder pressures were then predicted from the strip data using Laplace's law and compared with published values. RESULTS: Contractile responses (per unit tissue mass) of rat bladder strips were significantly greater than those of rabbit bladder strips at all frequencies of FS and to carbachol, KCl and ATP. The rate of contractile force generated by rat bladder strips in response to all stimuli were significantly greater than that generated by rabbit strips. Rabbit bladder strips took significantly longer to generate maximum tension than did rat bladder strips in response to pharmacological stimuli. In response to FS, rat strips took significantly longer than rabbit strips to generate maximum tension. Although the predicted rat bladder pressures were significantly greater than those for rabbit, the predicted pressures for both the rat and rabbit were significantly lower than the pressure responses of the isolated whole bladder model. The contractile data correlated well with the Ca2+-ATPase activity data; rat bladder had seven times the enzyme activity of rabbit bladder. CONCLUSION: Per unit mass, rat bladder is capable of generating more than five times the tension of rabbit bladder. Similarly, the rate of tension generation by rat bladder is three to five times greater than that by rabbit bladder. The duration to maximum tension generated in response to FS compared with pharmacological stimuli was affected by the inherent difference in the rate of contractile response to electrical activation compared with agents which diffuse through tissue, and by the difference in size between rat and rabbit bladder smooth muscle cells.

Adenosine Triphosphate↗
PubMed1976

Vectorcardiographic-hemodynamic correlations in adult aortic stenosis.

Thirty-nine vectorcardiographic (VCG) data from 45 patients with pure adult aortic stenosis have been tested as to their ability to reflect quantitatively the peak systolic left ventricular pressure (LVPSP), the left ventricular end diastolic pressure (LVEDP), and the X-ray estimated heart volume. VCG was recorded with the axial lead system and simple and multiple linear regression analyses were applied. Eight VCG data correlated significantly (p less than 0.001) with LVPSP, the best indicator being the maximum posterior dislocation in the Z lead (r = 0.65). Through multiple regression analysis a formula was derived which gave a correlation coefficient between observed and calculated pressures of 0.82. The best indicator of LVEDP was the maximum positive P amplitude in the X lead (r = 0.41). The relationship was, however, too poor to have practical significance. A good correlation was found between ST segment dislocation and heart volume (r = 0.65), in good accordance with previous observations as to the effect of right ventricular dilatation on the ECG. The study illustrates how ventricular volume and pressure exert different effects on the ECG, and how all the important hemodynamic aspects in aortic stenosis to some degree are reflected. Only the pressure correlations have, however, practical importance.

Aortic Valve Stenosis↗
PubMed2004

BAC microarray analysis of 15q11-q13 rearrangements and the impact of segmental duplications.

Chromosome 15q11-q13 is one of the most variable regions of the human genome, with numerous clinical rearrangements involving a dosage imbalance. Multiple clusters of segmental duplications are found in the pericentromeric region of 15q and at the breakpoints of proximal 15q rearrangements. Using sequence maps and previous global analyses of segmental duplications in the human genome, a targeted microarray was developed to detect a wide range of dosage imbalances in clinical samples. Clones were also chosen to assess the effect of paralogous sequences in the array format. In 19 patients analysed, the array data correlated with microsatellite and FISH characterisation. The data showed a linear response with respect to dosage, ranging from one to six copies of the region. Paralogous sequences in arrayed clones appear to respond to the total genomic copy number, and results with such clones may seem aberrant unless the sequence context of the arrayed sequence is well understood. The array CGH method offers exquisite resolution and sensitivity for detecting large scale dosage imbalances. These results indicate that the duplication composition of BAC substrates may affect the sensitivity for detecting dosage variation. They have important implications for effective microarray design, as well as for the detection of segmental aneusomy within the human population.

Chromosome Aberrations↗
PubMedDate not supplied

Detection of P-glycoprotein in solid tumors by flow cytometry.

P-glycoprotein (P-gp) detection by FCM (flow cytometry) was correlated with P-gp detection by immunohistochemical staining or Western blotting in K562 cell lines variably resistant to doxorubicin (DOX). A strong correlation was noted between the flow cytometric data and the degree of resistance assessed by thymidine incorporation assay (TIA). Of the human carcinomas tested, 37.5% were P-gp positive by flow cytometry. The flow cytometry data correlated strongly with the immunohistochemical staining (p < 0.001). Thirteen of the 15 P-gp positive tumors were resistant to DOX and vincristine (VCR) on TIA. Thus, P-gp detection by FCM correlates strongly with tumor sensitivity to DOX and VCR (p < 0.001).

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Application of multilevel models to morphometric data. Part 2. Correlations.

Multilevel organization of morphometric data (cells are "nested" within patients) requires special methods for studying correlations between karyometric features. The most distinct feature of these methods is that separate correlation (covariance) matrices are produced for every level in the hierarchy. In karyometric research, the cell-level (i.e., within-tumor) correlations seem to be of major interest. Beside their biological importance, these correlation coefficients (CC) are compulsory when dimensionality reduction is required. Using MLwiN, a dedicated program for multilevel modeling, we show how to use multivariate multilevel models (MMM) to obtain and interpret CC in each of the levels. A comparison with two usual, "single-level" statistics shows that MMM represent the only way to obtain correct cell-level correlation coefficients. The summary statistics method (take average values across each patient) produces patient-level CC only, and the "pooling" method (merge all cells together and ignore patients as units of analysis) yields incorrect CC at all. We conclude that multilevel modeling is an indispensable tool for studying correlations between morphometric variables.

Algorithms↗
PubMed1990

Simulating functional interactions in the brain: a model for examining correlations between regional cerebral metabolic rates.

A computer simulation model was developed to investigate the use of interregional correlations of cerebral metabolic rates to analyze functional interactions in the brain. The model generates simulated metabolic data for individual brain regions in a specified number of subjects, where there are defined functional couplings amongst the regions. Random numbers provide the variability seen in measured metabolic data. Correlational analysis is performed on these simulated data sets. The parameters of the model can be chosen so that simulated and actual metabolic data are very similar. The model demonstrates that the change in the correlation coefficient between normalized metabolic data in two brain regions is related to the change in the strength of the functional association between the two regions. The model also is used to explore the relations between patterns of correlations and the underlying sets of functional couplings. The results indicate that correlational analysis provides more information about regional involvement in neural systems than does region-by-region comparisons of absolute metabolic rates.

Adult↗
PubMed1988

Physical characterization of the herpes simplex virus latency-associated transcript in neurons.

RNA transfer (Northern) blot analysis was used to perform the physical characterization of the transcript expressed in murine sensory nerve ganglia latently infected with herpes simplex virus type 1. Most of this latency-associated transcript (LAT) was isolated in the poly(A)- fraction from ganglia. A smaller RNA species was also detected at less than 10% the abundance of the major one. LAT was not detected with probes from DNA outside the limits of the larger species. In situ hybridization data correlated well with Northern blot analysis; however, low levels of hybridization were seen with probes immediately outside the region of viral DNA giving positive Northern blot signals. S1 nuclease and primer extension mapping were used to locate the 5' end of the LAT 510 bases to the left of a KpnI site at 0.783 map units. The 3' end of the major latency-associated species was mapped to just within a 310-base-pair SmaI fragment located 660 to 970 base pairs to the right of the SalI site at 0.790 map units. These data were correlated with an analysis of the sequence of the DNA encoding this transcript and its possible function in the latent phase of infection.

Amino Acid Sequence↗
PubMed1998

Low-level long-range 1H-15N heteronuclear shift correlation at natural abundance using submicro NMR techniques

Gradient inverse-detected NMR methods have provided experimental access to long-range 1H-15N heteronuclear shift correlation data at natural abundance. When used in conjunction with newly developed submicro-inverse-detection gradient (SMIDG) NMR probes, sample size requirements are dramatically reduced. Long-range 1H-15N GHMBC data are shown for a 1 mg sample ( approximately 3 &mgr;mol, 0.11 M) of the alkaloid strychnine (1) dissolved in 30 &mgr;L of CDCl3. All of the correlations observed in previous studies using samples in the range of 20-40 mg in 5 mm NMR probes were observed in data acquired overnight on a 1 mg sample in a 1.7 mm SMIDG NMR probe. A previously unreported long-range correlation, 3JH-15a-N(19), was observed in data recorded over a weekend for the 1 mg sample. Data recorded over a weekend using a 1 &mgr;mol (334 &mgr;g) sample of strychnine (1) in 30 &mgr;L of CDCl3 contained the majority of the responses from the 1 mg sample. The practical limit of detection for long-range 1H-15N heteronuclear shift correlation data at natural abundance would appear to be approximately 1 &mgr;mol with data acquisition over a weekend or longer using present submicro-NMR probe technology.

Journal Article↗
PubMed2004

The effect of time after body discovery on the accuracy of retrospective weather station ambient temperature corrections in forensic entomology.

Weather station data are used by forensic entomologists to estimate ambient temperatures at body discovery sites. Correlation data from sites may also be collected to correct for site and station differences. This experiment tested the accuracy over time of retrospective weather data correction using linear regression between stations and sites. Temperatures were logged at six hypothetical body discovery sites during a seven-day period for which a hypothetical body lay in situ, and a further four correlation periods. The accuracy of weather data for hypothetical body in situ periods improved after correction in 22 of 24 correlations; however, mean predicted body in situ temperatures for sites differed significantly between correlation periods. Predicted temperatures generally rose with time after body removal, which correlated with rising site temperatures accompanying seasonal change. Therefore, practitioners should be cautious in making correlations if weather patterns during correlation differ greatly from those while the body was in situ.

Analysis of Variance↗
PubMed2005

Actigraphy in the critically ill: correlation with activity, agitation, and sedation.

OBJECTIVES: To determine the feasibility of continuous measurement of limb movement via wrist and ankle actigraphy (an activity measure) in critically ill patients and to compare actigraphy measurements with observed activity, subjective scores on sedation-agitation scales, and heart rate and blood pressure of patients. METHODS: In a prospective, descriptive, correlational study, all activity of 20 adult patients in medical and coronary care units in a university medical center were observed for 2 hours and documented. Wrist and ankle actigraphy, heart rate, and systolic and diastolic blood pressure data were collected every minute. The Comfort Scale and the Richmond Agitation-Sedation Scale were completed at the beginning of the observation period and 1 and 2 hours later. RESULTS: Wrist actigraphy data correlated with scores on the Richmond Agitation-Sedation Scale (r = 0.58) and the Comfort Scale (r = 0.62) and with observed stimulation and activity events of patients (r = 0.45). Correlations with systolic, diastolic, and mean arterial pressures were weaker. Wrist and ankle actigraphy data were significantly correlated (r = 0.69; P < .001); however, their mean values (wrist, 418; ankle, 147) were significantly different (t = 5.77; P < .001). CONCLUSIONS: Actigraphy provides a continuous recording of patients' limb movement. Actigraphy measurements correlate well with patients' observed activity and with subjective scores on agitation and sedation scales. Actigraphy may become particularly important as a continuous measurement of activity for use in behavioral research and may enhance early recognition and management of the excessive activity that characterizes agitation.

Adult↗
PubMedDate not supplied

Multivariate methods for binary longitudinal data with heterogeneous correlation over time.

Clustered binary data occur frequently in biostatistical work. One particular application is in binary longitudinal data, where several visits are available for the same individual. Several approaches have been proposed for the analysis of clustered binary data. In Rosner, a polychotomous logistic regression model was proposed which is a generalization of the beta-binomial distribution and allows for person- and visit-specific covariates, while controlling for clustering effects. One assumption of this model is that all pairs of visits within an individual are equally correlated, which may be inappropriate if several visits are available over a long follow-up period. In this paper, this approach is extended to allow for heterogeneous correlation over time. The total time period is divided into subintervals and a beta-binomial mixture model is introduced to estimate odds ratios relating outcomes for pairs of visits both within a subinterval as well as in different subintervals. To include covariates, an extension of the polychotomous logistic regression model is proposed, which allows one to estimate effects of person-, subinterval-, and visit-specific covariates, while controlling for clustering using the beta-binomial mixture model. This model is applied to the analysis of respiratory symptom data in children collected over a 14-year period in East Boston, MA, in relation to maternal and child smoking, where the unit is the child and symptom history is divided into early-adolescent and late-adolescent symptom experience.

Humans↗