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PubMed2000

Effects of treatment or/and vaccination on HIV transmission in homosexuals with genetic heterogeneity.

Several mutant genes in HIV co-receptors (e.g., CCR5, CCR2 and CXCR4) have been correlated with susceptibility to HIV or/and rate of progression to AIDS. Some of these genes have high allele frequencies in general populations. Their effects on the HIV/AIDS dynamics may be significant. To study such genetic heterogeneity, Hsu Schmitz [S.-F. Hsu Schmitz, A mathematical model of HIV transmission in homosexuals with genetic heterogeneity, J. Theoret. Med. (to appear)] proposed a one-sex model with susceptibles classified by genotype as having no, partial or full natural resistance to HIV infection and infecteds classified as rapid, normal or slow progressors. The example of CCR5-Delta32 mutation in San Francisco gay men indicated that the normal progressors are most responsible for disease spread. The per-partnership transmission rates of rapid and slow progressors are identified as key parameters. The present manuscript extends the previous one by considering the intervention of treatment or/and vaccination. Detailed investigations are illustrated by using the same example of CCR5-Delta32 mutation in San Francisco gay men. Treating only newly infected individuals or vaccinating only newly recruited susceptibles is not effective enough for disease control. When both measures are applied, the epidemic may be eradicated if the transmission rate of slow progressors is not too large, and treatments and vaccines in use are of decent quality.

AIDS Vaccines↗

PubMed1993

Regression analysis of grouped survival data: informative censoring and double sampling.

To analyze grouped survival data subject to informative censoring, we propose the following two-part model: a logistic regression model for the hazard for failure, given covariates and a logistic regression model for the hazard for informative censoring, given time of failure and covariates. We fit the model to survival data arising from a double sampling design: In a full follow-up (FF) sample subjects are followed after censoring, and in a partial follow-up (PF) sample subjects are not followed after censoring. We illustrate the methodology using data from a study of wound infection in which patients in the PF sample are censored by release from the hospital, whereas patients in the FF sample are followed after hospital release. We discuss identifiability when there is only a PF sample. We also consider how the allocation between the PF and FF samples affects the precision of estimates.

Follow-Up Studies↗

PubMed1999

Spectral analysis of a series of partially protected and deprotected tetrapeptides, analogues of AS-I phytotoxin.

A series of six tetrapeptides, analogues of AS-I phytotoxin, pathogenic to sunflower, have been synthesized either in solution and/or by solid phase methods and have been tested for phytotoxic activity in various plants and cytotoxic activity in three cancer cell lines. These peptides were identified as model compounds by fast atom bombardment (FAB), plasma desorption (PD), electrospray ionization (ESI) mass spectrometry and by 1H, 1H-1H, 13C and 1H-13C NMR. The data presented show that in protected tetrapeptides the molecular ion was easily identified whereas some difficulties appeared with the fully deprotected peptides. NMR spectra are given.

Magnetic Resonance Spectroscopy↗

PubMed1998

Clinicopathologic effects of cryotherapy on hepatic vessels and bile ducts in a porcine model.

BACKGROUND: The proximity of a hepatic tumor to major vessels and bile ducts limits the use of cryotherapy because of the potential damage to these structures. However, the effects of cryotherapy on major hepatic vessels and bile ducts are not well understood. METHODS: Nine pigs underwent laparotomy and intraoperative ultrasound to identify hepatic vessels larger than 5.0 mm. Cryotherapy consisting of two freeze-thaw cycles was performed, incorporating the identified vessel. In four pigs the Pringle maneuver was performed to determine the effects of partial vascular occlusion on the hepatic parenchyma and structures undergoing cryotherapy. The animals were sacrificed 30 days postoperatively, and the livers were processed for histologic examination. RESULTS: Eight of the nine livers had vessels larger than 5.0 mm incorporated into the iceball, with all vessels having evidence of infarction but remaining patent. All the livers had major bile ducts incorporated in the iceball, with eight having evidence of infarction. The Pringle maneuver had no real effect on the degree of vessel and bile duct infarction. There was no incidence of hepatic bleeding, liver fracture, bile leak, or hemobilia. CONCLUSIONS: Cryotherapy results in the infarction of major hepatic vessels and bile ducts but can be safely performed in the porcine model. Proximity of tumors to major vascular and biliary structures may not be a contraindication to the use of cryotherapy. Further studies are necessary to determine whether cryotherapy can be used in humans.

Animals↗

PubMed2000

High-frequency oscillatory ventilation in pediatric respiratory failure: a multicenter experience.

OBJECTIVE: The use of high-frequency oscillatory ventilation (HFOV) has increased dramatically in the management of respiratory failure in pediatric patients. We surveyed ten pediatric centers that frequently use high-frequency oscillation to describe current clinical practice and to examine factors related to improved outcomes. DESIGN: Retrospective, observational questionnaire study. SETTING: Ten tertiary care pediatric intensive care units. PATIENTS: Two hundred ninety patients managed with HFOV between January 1997 and June 1998. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were classified according to presence or absence of preexisting lung disease, symptomatic respiratory syncytial virus infection, or presence of cyanotic heart disease or residual right-to-left intracardiac shunt. In addition, patients for whom HFOV acutely failed were analyzed separately. Those patients with preexisting lung disease were significantly smaller, had a significantly higher incidence of pulmonary infection as the triggering etiology, and had a significantly greater duration of conventional ventilation before institution of HFOV compared with patients without preexisting lung disease. Stepwise logistic regression was used to predict mortality and the occurrence of chronic lung disease in survivors. In patients without preexisting lung disease, the model predicted a 70% probability of death when the oxygenation index (OI) after 24 hrs was 28 in the immunocompromised patients and 64 in the patients without immunocompromise. In the immunocompromised patients, the model predicted a 90% probability of death when the OI after 24 hrs was 58. In survivors without preexisting lung disease, the model predicted a 70% probability of developing chronic lung disease when the OI at 24 hrs was 31 in the patients with sepsis syndrome and 50 in the patients without sepsis syndrome. In the patients with sepsis syndrome, the model predicted a 90% probability of developing chronic lung disease when the OI at 24 hrs was 45. CONCLUSIONS: Given the number of centers involved and the size of the database, we feel that our results broadly reflect current practice in the use of HFOV in pediatric patients. These results may help in deciding which patients are most likely to benefit from aggressive intervention by using extracorporeal techniques and may help identify high-risk populations appropriate for prospective study of innovative modes of supporting gas exchange (e.g., partial liquid breathing or intratracheal pulmonary ventilation).

Blood Gas Analysis↗

PubMed1996

Washout kinetics of colloidal starch as a partial or full replacement for plasma exchange.

Colloidal starch has been used safely as a plasma expander and an erythrocyte sedimenting agent for over 25 years. However, there remains some concern in regard to the long term sequelae of the administration of large volumes of colloid starch such as would be administered if colloidal starch were used as a plasma replacement during serial plasma exchanges. We identified mathematical relations that allowed for the calculations of the theoretical circulating residual starch in a patient undergoing serial plasma exchanges and used it to model a variety of possible clinical scenarios. Following six one plasma volume exchanges, one would expect only 11, 13, 14, or 17% of the total infused starch to be remaining in the circulation. For example, in the case of a 4L exchange with full replacement, only the starch in 4.1 liters (4L x 6 exchanges x 17% = 4.1L) would be expected to remain in the circulation despite an infusion of 24 L (4L x 6 exchanges = 24L) of starch. The results suggest that relatively small amounts of starch would be expected to remain circulating relative to the large amounts infused following a series of plasma exchanges with partial or full starch replacement.

Colloids↗

PubMed1998

Basic anatomical and physiological differences between species should be considered when choosing combinations for use in models of hepatic xenotransplantation: an investigation of the guinea pig-to-rat combination.

Published data on the guinea pig-to-rat hepatic xenotransplant model describe problems concerning poor graft reperfusion. To further investigate this phenomenon, orthotopic liver xenotransplantation between weight-matched guinea pigs and rats were performed using Kamada's technique. On reperfusion, all cases had portal venous inflow block with hypoperfusion of the hepatic parenchyma. Histological examination showed no evidence of hyperacute rejection, although deposits of IgG2a and C3 but not IgM were identified within the central area of the liver. To increase blood inflow, arterialized partial liver grafts were performed without changing the outcome. We hypothesize that the hypoperfusion may be related to anatomical and physiological differences between the species. Guinea pig portal vein branches were found to have muscular walls susceptible to spasm, and portal blood flow is four times greater in the guinea pig than in the rat because the guinea pig intestine is both longer (two times as long) and of greater diameter. The combination of reperfusion injury, early immunological events, and the rat's lower portal blood flow induces spasm of the intrahepatic portal system resulting in hypoperfusion. These findings demonstrate the importance of recognizing basic anatomical and physiological differences between species when selecting xenotransplantation models.

Animals↗

PubMed1999

Recombinant anti-polyamine antibodies: identification of a conserved binding site motif.

Polyamines are small linear polycations found ubiquitously in eukaryotic cells. They are involved in nucleic acid and protein synthesis and rises in cellular polyamine levels have been correlated with cell proliferation. Antibodies to these molecules have potential as prognostic indicators of disease conditions and indicators of treatment efficacy. Antipolyamine monoclonal antibodies of differing but defined specificities have been generated in our laboratory using polyamine ovalbumin conjugates as immunogens. These antibodies show small but significant cross reactivities with other polyamine species; IAG-1 cross reacts with spermidine (8%), JAC-1 with spermine (6%) and JSJ-1 with both putrescine (11%) and spermine (6%). We have rescued and sequenced the heavy and light chain variable regions of all three of these antibodies. While the light chains of two antibodies, IAG-1 and JSJ-1, were 93% homologous at the amino acid level, none of the heavy chains displayed any significant sequence homology. However, computer-generated models of all three antibody binding sites revealed a three-dimensionally conserved polyamine binding site motif. The polyamine appears to bind into a negatively charged cleft lined with acidic and polar residues. The cleft is partially or completely closed at one end and the specificity of the interaction is determined by placement of acidic residues in the cleft. Aromatic residues contribute to polyamine binding interacting with the carbon backbone. The polyamine-binding motif we have identified is very similar to that observed in the crystal structure of PotD, the primary receptor of the polyamine transport system in Escherichia coli.

Amino Acid Sequence↗

PubMed1991

Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion and reperfusion in baboons.

BACKGROUND AND PURPOSE: Microvascular perfusion defects may accompany sustained occlusion and subsequent reperfusion of the middle cerebral artery; however, the nature of such "no-reflow" defects remains unclear. METHODS: In the absence of antithrombotic pretreatment, we documented lenticulostriatal microvascular flow integrity following 3-hour middle cerebral artery occlusion and 1-hour reperfusion in a baboon occlusion/reperfusion model by two methods identifying 1) microvascular occlusion and 2) microvascular patency. RESULTS: Microvascular "no-reflow" involved capillaries (vessels of 4.0-7.5 microns diameter) of the lenticulostriatal territory. Capillary reflow included 27-39% of all capaillaries in two subjects, indicating a significant reduction of perfusion from normal (2p = 0.045). In identical experimental preparations, single polymorphonuclear leukocytes completely occluded 4.7% of microvessels of capillary diameter in randomly selected fields, partially occluded 3.5% of postcapillary venules, and occluded 40% (four of 10) of capillaries in linear reconstruction along a 110 microns length. Circumferential contact between polymorphonuclear leukocytes and the luminal endothelial cell membranes was documented, with an intrecellular gap of, at most, 160 nm. Fibrin was found with degranulated platelets when the latter were associated with granulocytes, but not with polymorphonuclear leukocytes alone. CONCLUSIONS: The finding of capillary-obstructing polymorphonuclear leukocytes in the microvascular bed following middle cerebral artery reperfusion in focal ischemia in this model satisfies an essential requirement for postulating their role in early microvascular injury and the "no-reflow" phenomenon.

Animals↗

PubMed1998

Degradation pathway of CopA, the antisense RNA that controls replication of plasmid R1.

RNA decay in bacteria is carried out by a number of enzymes that participate in the coordinated degradation of their substrates. Endo- and exonucleolytic cleavages as well as polyadenylation are generally involved in determining the half-life of RNAs. Small, untranslated antisense RNAs are suitable model systems to study decay. A study of the pathway of degradation of CopA, the copy number regulator RNA of plasmid R1, is reported here. Strains carrying mutations in the genes encoding RNase E, polynucleotide phosphorylase (PNPase), RNase II and poly(A) polymerase I (PcnB/PAP I)--alone or in combination--were used to investigate degradation patterns and relative half-lives of CopA. The results obtained suggest that RNase E initiates CopA decay. Both PNPase and RNase II can degrade the major 3'-cleavage product generated by RNase E. This exonucleolytic degradation is aided by PcnB, which may imply a requirement for A-tailing. RNase II can partially protect CopA's 3'-end from PNPase-dependent degradation. Other RNases are probably involved in decay, since in rnb/pnp double mutants, decay still occurs, albeit at a reduced rate. Experiments using purified RNase E identified cleavage sites in CopA in the vicinity of, but not identical to, those mapped in vivo, suggesting that the cleavage site specificity of this RNase is modulated by additional proteins in the cell. A model of CopA decay is presented and discussed.

Bacterial Proteins↗

PubMed2006

Anti-HCV therapies in chimeric scid-Alb/uPA mice parallel outcomes in human clinical application.

Compounds with in vitro anti-hepatitis C virus (HCV) activity are often advanced directly into clinical trials with limited or no in vivo efficacy data. This limits prediction of clinical efficacy of compounds in the HCV drug pipeline, and may expose human subjects to unnecessary treatment effects. The scid-Alb-uPA mouse supports proliferation of transplanted human hepatocytes and subsequent HCV infection. Cohorts of genotype 1a HCV-infected mice were treated with interferon alpha-2b(IFN-alpha), BILN-2061 (anti-NS3 protease), or HCV371 (anti-NS5B polymerase). Mice treated with 1350 IU/g/day IFN-alpha intramuscularly for 10 to 28 days demonstrated reduced viral titers compared with controls in all five experiments (P < .05, t test); viral titers rebounded after treatment withdrawal. A more pronounced antiviral effect with IFN-alpha was seen in genotype 3a-infected mice. Pilot studies with BILN2061 confirmed exposure to 10X replicon EC50 at trough and reduced viral titer over 2 log at 4 days. In a second 7-day study, mean HCV RNA titers dropped 1.1 log in BILN2061-treated animals, 0.6 log in IFN-treated mice, and rose 0.2 log in controls (P = .013, ANOVA). Pre-existing mutants with partial resistance to BILN2061 were identified by sequencing both the human inoculum and sera from treated mice. The polymerase inhibitor HCV371 yielded a decline in HCV titers of 0.3 log relative to vehicle-treated controls (P = NS). Performance of all three antiviral regimens in the chimeric mouse model paralleled responses in humans. In conclusion, this system may help selection of lead compounds for advancement into human trials with an increased likelihood of clinical success while broadening the tools available for study of the biology of HCV infection.

Analysis of Variance↗

PubMed2004

Glycoconjugates of the urodele amphibian testis shown by lectin cytochemical methods.

Lectin histochemistry is a useful method that allows the in situ identification of the terminal sugar moieties of the carbohydrates that form the glycoconjugates. Moreover, when it is combined with chemical or enzymatic deglycosylation pretreatments, lectin histochemistry can be employed to determine if carbohydrates are linked to the protein core by means of an N- or O-glycosidic linkage or, indeed, to partially sequence the sugar chains. One of the most interesting model organs for the study of spermatogenesis is the amphibian urodele testis. However, this organ has not been very widely investigated with lectin histochemical research. In the last few years, we have carried out a research project to identify and locate glycoconjugates in the testis of the urodele Pleurodeles waltl, the Spanish newt, as a first approach to identify possible carbohydrates with key roles in spermatogenesis. Our findings reveal some glycan chains located in a fusome-like structure in early (diploid) germ cells, oligosaccharides with terminal GalNAc in the acrosome, the occurrence of glycan modifications in the acrosomal contents during spermiogenesis, and changes in glycan composition of follicle and interstitial cells during the spermatogenetic cycle. Furthermore, the similar labeling pattern of follicle and duct cells supports the hypothesis for a common origin of both cell types.

Animals↗

PubMed1997

An electrophysiological study of the selection of the color and shape of alphanumeric characters in response choice.

We examined the functional and temporal organization of task-directed selective processing of the color and shape of alphanumeric characters. Dependent variables were measures derived from event-related brain potentials (onset latency of selection negativity (SN) and the lateralized readiness potential). We found SNs related to the relevance for correct task-performance of the color, the global shape and the local shape of the characters. The onset latencies of these SNs suggested that color and global shape were identified at the same time and earlier than local shape. The absence of an SN to global shape if the color was irrelevant suggested that selection on the basis of the global shape depended hierarchically on that of color. Selection of the local shape was independent of color relevance. The lateralized readiness potentials suggested that response selection occurred when the conjunction of color, global shape and local shape had been identified. No evidence was found for temporal overlap between stimulus identification and response selection. These findings show that selective task-directed processing can be studied at multiple levels in a single paradigm. They are inconsistent with the central assumption of several continuous information transmission models that relevant partial information is used to activate associated responses as soon as it becomes available.

Adult↗

PubMed2004

Single-component magnetic conductors based on Mo3S7 trinuclear clusters with outer dithiolate ligands.

A trinuclear cluster complex containing the Mo(3)S(7) central unit coordinated to dithiolate ligands, in particular the organic dmit (1,3-dithia-2-thione-4,5-dithiolate) anion, has been used to prepare a single-component molecular conductor formed by the threefold symmetry magnetic building block Mo(3)S(7)(dmit)(3) (1). The [Mo(3)S(7)(dmit)(3)](2)(-) ([1](2)(-)) diamagnetic anion forms dimers by interaction between the electrophilic cluster axial sulfur atoms and the sulfur atoms of the outer dithiolate ligand. Additional contacts between adjacent dmit ligands result in chain formation. The two-electron oxidation of [1](2)(-) yields to a three-dimensional molecular solid formed by neutral Mo(3)S(7)(dmit)(3) (1) units with partially filled molecular orbitals, which exhibits sizable intermolecular electronic interactions together with a significant electron delocalization. It also contains large open channels. The interactions responsible for the conducting properties have been identified using a first-principle DFT approach and the calculated electronic structure has allowed us to model the magnetic behavior of the material with two competing antiferromagnetic interactions to produce a spin-frustrated extended network. The potential of this Mo(3)S(7) cluster complex to be modified together with the capability of filling the open channels with doping species paves the way to an entirely new set of molecular conductors and/or magnets.

Journal Article↗

PubMed2001

Planning of reach-and-grasp movements: effects of validity and type of object information.

Individuals are assumed to plan reach-and-grasp movements by using two separate processes. In 1 of the processes, extrinsic (direction, distance) object information is used in planning the movement of the arm that transports the hand to the target location (transport planning); whereas in the other, intrinsic (shape) object information is used in planning the preshaping of the hand and the grasping of the target object (manipulation planning). In 2 experiments, the authors used primes to provide information to participants (N = 5, Experiment 1; N = 6, Experiment 2) about extrinsic and intrinsic object properties. The validity of the prime information was systematically varied. The primes were succeeded by a cue, which always correctly identified the location and shape of the target object. Reaction times were recorded. Four models of transport and manipulation planning were tested. The only model that was consistent with the data was 1 in which arm transport and object manipulation planning were postulated to be independent processes that operate partially in parallel. The authors suggest that the processes involved in motor planning before execution are primarily concerned with the geometric aspects of the upcoming movement but not with the temporal details of its execution.

Adult↗

PubMed2004

Factors influencing serum cystatin C levels other than renal function and the impact on renal function measurement.

BACKGROUND: It is well known that serum creatinine may be used as a marker of renal function only if taking into account factors that influence creatinine production, such as age, gender, and weight. Serum cystatin C has been proposed as a potentially superior marker than serum creatinine, because serum cystatin C level is believed to be produced at a constant rate and not to be affected by such factors. However, there are limited data on factors that may influence serum cystatin C levels, and there are limited data comparing cystatin C-based estimates of renal function with creatinine-based estimates that adjust for such factors, especially in individuals with normal, or mildly reduced, renal function. METHODS: This was a cross-sectional study of 8058 inhabitants of the city of Groningen, The Netherlands, 28 to 75 years of age. Serum cystatin C and serum creatinine levels were measured, and creatinine clearance was determined from the average of two separate 24-hour urine collections. We performed multivariate analyses to identify factors independently associated with serum cystatin C levels after adjusting for creatinine clearance. Then, partial Spearman correlations were obtained after adjusting for factors that may influence serum cystatin C and creatinine levels. We also compared the goodness-of-fit (R(2)) of different multivariate linear regression models including serum cystatin C level and serum creatinine level for the outcome of creatinine clearance. RESULTS: Older age, male gender, greater weight, greater height, current cigarette smoking, and higher serum C-reactive protein (CRP) levels were independently associated with higher serum cystatin C levels after adjusting for creatinine clearance. After adjusting for age, weight, and gender, the partial Spearman correlations between creatinine and, respectively, serum cystatin C level and serum creatinine level were -0.29 (P < 0.001) and -0.42 (P < 0.001), respectively. The R(2) values for serum cystatin C level and serum creatinine level adjusted for age, weight, and gender were 0.38 and 0.42, respectively. The addition of cigarette smoking and serum CRP levels did not improve the R(2) value for the multivariate serum cystatin C-based model. CONCLUSION: Serum cystatin C appears to be influenced by factors other than renal function alone. In addition, we found no evidence that multivariate serum cystatin C-based estimates of renal function are superior to multivariate serum creatinine-based estimates.

Adult↗

PubMed1993

A 5'-3' exonuclease from Saccharomyces cerevisiae is required for in vitro recombination between linear DNA molecules with overlapping homology.

When two linear DNA molecules with overlapping, homologous ends were incubated with a yeast nuclear extract, they recombined at the region of homology to produce a joint molecule. We have identified a 5'-3' exonuclease in the extract that is likely to be responsible for the formation of the observed product. We propose that the exonuclease degrades each substrate to reveal regions of complementary sequence which anneal to form a recombinant product. Consistent with this model, we have partially purified the activity that promotes joint molecule formation and found it to cofractionate with a 5'-3' exonuclease activity through three consecutive chromatography steps. We have further characterized the reaction to determine the optimal length of homology. Substrates with homologous terminal overlaps of 29 to 958 bp were capable of product formation, whereas substrates with longer overlaps were not. Extracts prepared from a number of recombination-defective or nuclease-deficient strains revealed no defect in exonuclease activity, indicating that the reaction is likely to be dependent upon the product of an as yet unidentified gene.

Base Sequence↗

PubMed1996

Identification of the bud emergence gene BEM4 and its interactions with rho-type GTPases in Saccharomyces cerevisiae.

The Rho-type GTPase Cdc42p is required for cell polarization and bud emergence in Saccharomyces cerevisiae. To identify genes whose functions are linked to CDC42, we screened for (i) multicopy suppressors of a Ts- cdc42 mutant, (ii) mutants that require multiple copies of CDC42 for survival, and (iii) mutations that display synthetic lethality with a partial-loss-of-function allele of CDC24, which encodes a guanine nucleotide exchange factor for Cdc42p. In all three screens, we identified a new gene, BEM4. Cells from which BEM4 was deleted were inviable at 37 degrees C. These cells became unbudded, large, and round, consistent with a model in which Bem4p acts together with Cdc42p in polarity establishment and bud emergence. In some strains, the ability of CDC42 to serve as a multicopy suppressor of the Ts- growth defect of deltabem4 cells required co-overexpression of Rho1p, which is an essential Rho-type GTPase necessary for cell wall integrity. This finding suggests that Bem4p also affects Rho1p function. Bem4p displayed two-hybrid interactions with Cdc42p, Rho1p, and two of the three other known yeast Rho-type GTPases, suggesting that Bem4p can interact with multiple Rho-type GTPases. Models for the role of Bem4p include that it serves as a chaperone or modulates the interaction of these GTPases with one or more of their targets or regulators.

Amino Acid Sequence↗