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PubMed2004

Antioxidant-accelerated oxidative degradation: a case study of transition metal ion catalyzed oxidation in formulation.

Oxidation presents a constant challenge for formulation scientists trying to develop stable dosage forms. Antioxidants are commonly used in formulation to alleviate the oxidation problem but they do not always achieve the desired results. In this study, a case of antioxidant-accelerated oxidation degradation in formulation is reported. The oxidation mechanism of a development drug candidate (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (1) in solution was investigated under various oxidative conditions, which include at different oxygen level, with transition metal ion spiking, and under light exposure with presence of photosensitizer. Oxidative degradation products and kinetics were monitored by high-performance liquid chromatography (HPLC). Kinetic solvent isotope effects of I oxidation in formulation, under metal ion catalysis, and upon photocatalysis were obtained. Metal ion spiking, exposure to stainless steel, as well as introduction of antioxidants such as ascorbic acid, thioglycerol, and sodium bisulfate, accelerated the oxidative degradation. Treatment of the solution with metal chelating resin inhibited oxidation. Kinetic solvent isotope effects are in agreement with a metal-catalyzed oxidation mechanism and inconsistent with a singlet oxygen pathway. On the basis of kinetic data, an oxidative fragmentation mechanism initiated by a metal ion catalyzed active oxygen species is suggested as the primary pathway for the oxidative degradation of I. Other oxidative species may be implied in the long-term oxidative degradation. Because many antioxidants act as pro-oxidants in metal-catalyzed oxidation, controlling metal ion contamination level in the excipients and limiting available molecular oxygen are recommended for formulation development.

Antioxidants↗
PubMed1991

Cytokeratin phosphorylation, cytokeratin filament severing and the solubilization of the maternal mRNA Vg1.

During meiotic maturation, the cortical cytokeratin filament system of the Xenopus oocyte disappears (Klymkowsky, M. W., and L. A. Maynell. 1989. Dev. Biol. 134:479). Here we demonstrate that this disappearance results from the severing of cytokeratin filaments into a heterogenous population of oligomers, with S- values ranging from 12S and greater. Cytokeratin filament severing correlates with the hyperphosphorylation of the type II cytokeratin of the oocyte. Both the severing of cytokeratin filaments and cytokeratin hyperphosphorylation are reversed by treatment with cycloheximide. These data suggest that fragmentation of cytokeratin filaments is controlled, at least in part, by the phosphorylation of the type II cytokeratin, and that the cytokeratin kinase activity responsible is biosynthetically labile. Cytokeratin filaments have been suggested to anchor the maternal mRNA Vg1 to the vegetal cortex of the oocyte (Pondel, M., and M. L. King. 1988. Proc. Natl. Acad. Sci. USA. 85:7216). By injecting fractions containing active maturation promoting factor or a purified, mutant cyclin protein, we find that the bulk of the Vg1 mRNA in the oocyte can be solubilized under conditions that block the fragmentation of cytokeratin filaments, and that the fragmentation of cytokeratin filaments itself leads to the solubilization of only a minor fraction of the Vg1 mRNA. Thus, at best, cytokeratin filaments directly anchor only a minor fraction of the Vg1 mRNA in the oocyte. Moreover, factors distinct from maturation promoting factor appear to be required for the complete solubilization of Vg1 mRNA during oocyte maturation.

Actin Cytoskeleton↗
PubMed2002

Survival of patients with pulmonary tuberculosis: clinical and molecular epidemiologic factors.

Using restriction fragment-length polymorphism data, we conducted a retrospective cohort study of 139 adult patients with pulmonary tuberculosis to investigate the clinical impact of Mycobacterium tuberculosis infection with a clustered isolate. The cumulative all-cause mortality rate during treatment was 21%. Patients with clustered DNA fingerprint patterns had a reduced risk of death, compared with patients with unique patterns (hazard ratio [HR], 0.5; 95% confidence interval [CI], 0.2-1.1), but this finding was confounded by age (adjusted HR, 0.8; 95% CI, 0.4-1.8). After adjustment for age, the strongest predictors of death were such underlying illnesses as diabetes mellitus, renal failure, chronic obstructive pulmonary disease, and human immunodeficiency virus infection. We conclude that comorbidity and immunosuppression are important predictors of survival for patients with pulmonary tuberculosis in an inner-city cohort. Recently transmitted infection, as determined by use of DNA fingerprinting to classify patients' isolates as being either clustered or unique, was not independently associated with death.

Adolescent↗
PubMed2004

A parametric model for estimation of dispersal patterns applied to five passerine spatially structured populations.

Natal dispersal capture-recapture data from five fragmented populations of house sparrows, great tits, and blue tits were analyzed using maximum likelihood methods. A new two-parametric distribution was constructed that includes four distributions previously used as special cases in the literature. Dispersal standard deviations were estimated at 22.9 km for the house sparrows and ranged from 0.66 to 4.4 km for the tits. Female great tits and blue tits dispersed consistently further than males. Estimates of the shape parameter of the dispersal distribution ranged from 0.66 to 2.27, indicating strong to moderately leptokurtic dispersal displacements. There were significant effects of density on local immigration rates and a consistent tendency for immigration rates to depend underproportionally on local densities. Potential implications of the shape of the dispersal distribution for the spread of invading organisms were investigated and compared with previous results. It is shown that the wave speed, for a given dispersal standard deviation, depends only to some extent on leptokurtosis, provided that the intrinsic growth rate of the population is moderate or small. In estimating the dispersal standard deviation, however, incorrect assumptions about the degree of leptokurtosis can lead to a large bias in estimation and predictions.

Animal Migration↗
PubMed2001

Beat-to-beat analysis method for magnetocardiographic recordings during interventions.

Multichannel magnetocardiography (MCG) during exercise testing has been shown to detect myocardial ischaemia in patients with coronary artery disease. Previous studies on exercise MCG have focused on one or few time intervals during the recovery period and only a fragment of the data available has been utilized. We present a method for beat-to-beat analysis and parametrization of the MCG signal. The method can be used for studying and quantifying the changes induced in the MCG by interventions. We test the method with data recorded in bicycle exercise testing in healthy volunteers and patients with coronary artery disease. Information in all cardiac cycles recorded during the recovery period of exercise MCG testing is, for the first time, utilized in the signal analysis. Exercise-induced myocardial ischaemia was detected by heart rate adjustment of change in magnetic field map orientation. In addition to the ST segment, the T wave in the MCG was also found to provide information related to myocardial ischaemia. The method of analysis efficiently utilizes the spatial and temporal properties of multichannel MCG mapping, providing a new tool for detecting and quantifying fast phenomena during interventional MCG studies. The method can also be applied to an on-line analysis of MCG data.

Coronary Disease↗
PubMed2004

Caspase-dependent regulation of histone deacetylase 4 nuclear-cytoplasmic shuttling promotes apoptosis.

Histone deacetylases (HDACs) are important regulators of gene expression as part of transcriptional corepressor complexes. Here, we demonstrate that caspases can repress the activity of the myocyte enhancer factor (MEF)2C transcription factor by regulating HDAC4 processing. Cleavage of HDAC4 occurs at Asp 289 and disjoins the carboxy-terminal fragment, localized into the cytoplasm, from the amino-terminal fragment, which accumulates into the nucleus. In the nucleus, the caspase-generated fragment of HDAC4 is able to trigger cytochrome c release from mitochondria and cell death in a caspase-9-dependent manner. The caspase-cleaved amino-terminal fragment of HDAC4 acts as a strong repressor of the transcription factor MEF2C, independently from the HDAC domain. Removal of amino acids 166-289 from the caspase-cleaved fragment of HDAC4 abrogates its ability to repress MEF2 transcription and to induce cell death. Caspase-2 and caspase-3 cleave HDAC4 in vitro and caspase-3 is critical for HDAC4 cleavage in vivo during UV-induced apoptosis. After UV irradiation, GFP-HDAC4 translocates into the nucleus coincidentally/immediately before the retraction response, but clearly before nuclear fragmentation. Together, our data indicate that caspases could specifically modulate gene repression and apoptosis through the proteolyic processing of HDAC4.

Apoptosis↗
PubMed1999

A consensus map for loblolly pine (Pinus taeda L.). I. Construction and integration of individual linkage maps from two outbred three-generation pedigrees.

A consensus map for loblolly pine (Pinus taeda L.) was constructed from the integration of linkage data from two unrelated three-generation outbred pedigrees. The progeny segregation data from restriction fragment length polymorphism, random amplified polymorphic DNA, and isozyme genetic markers from each pedigree were recoded to reflect the two independent populations of parental meioses, and genetic maps were constructed to represent each parent. The rate of meiotic recombination was significantly greater for males than females, as was the average estimate of genome length for males (1983.7 cM [Kosambi mapping function (K)]) and females [1339.5 cM(K)]. The integration of individual maps allows for the synthesis of genetic information from independent sources onto a single consensus map and facilitates the consolidation of linkage groups to represent the chromosomes n = 12 of loblolly pine. The resulting consensus map consists of 357 unique molecular markers and covers approximately 1300 cM(K).

Chromosome Mapping↗
PubMed1984

Plasmids as epidemiological markers in nosocomial Legionnaires' disease.

Plasmid analysis was used in the investigation of an outbreak of nosocomial Legionnaires' disease in four patients. Serogroup 1 strains were isolated from two patients, the air-conditioning cooling tower, and two hot-water tanks. All serogroup 1 strains contained two plasmids with approximate molecular masses of 21 and 48 megadaltons (Mdal). The serogroup 1 strain found in the cooling-tower isolate also contained an additional 1.9 Mdal-plasmid. Restriction-endonuclease analysis of the 21-Mdal plasmid that was present in patient and hot water-tank isolates revealed identical EcoRI and HaeIII fragment patterns. Digestion of the similarly sized plasmid in the cooling-tower isolate resulted in a unique fragment pattern. The data provide direct bacteriologic evidence implicating the hot-water tanks rather than the cooling tower as the source of the infecting strain.

Cross Infection↗
PubMed1988

Mung bean nuclease exhibits a generalized gene-excision activity upon purified Plasmodium falciparum genomic DNA.

A novel set of reaction conditions for mung bean nuclease has been described in which Plasmodium genes were specifically excised as intact fragments from purified DNA. We have now determined that under the new conditions mung bean nuclease cleaves precisely at sites outside of the coding region of every P. falciparum gene for which the extent of the protein coding region in genomic DNA is known. We conclude that this enzyme activity is probably a general one for P. falciparum genes. Introns are not specifically cleaved, although one gene contained a cleavage site within an intron. There is no direct relationship between dA.dT-richness and sites of cleavage under these conditions. Also contrary to the expectations of a model based on cleavage at denaturation bubbles, there was no general relationship between the concentration of the DNA denaturant, formamide, and the size of the resulting gene-containing fragments. Thus, the data strongly suggest the involvement of an altered DNA structure near gene boundaries in determining the recognition sites for this enzyme activity.

Animals↗
PubMed2005

An analysis of the feasibility of short read sequencing.

Several methods for ultra high-throughput DNA sequencing are currently under investigation. Many of these methods yield very short blocks of sequence information (reads). Here we report on an analysis showing the level of genome sequencing possible as a function of read length. It is shown that re-sequencing and de novo sequencing of the majority of a bacterial genome is possible with read lengths of 20-30 nt, and that reads of 50 nt can provide reconstructed contigs (a contiguous fragment of sequence data) of 1000 nt and greater that cover 80% of human chromosome 1.

Chromosomes, Human, Pair 1↗
PubMed1999

Exposed peptide core of IgA1 hinge region in IgA nephropathy.

BACKGROUND: The human IgA1 hinge region is a very unique O-linked glycopeptide, and its sialylation and galactosylation recently were reported to be defective in the serum IgA1 derived from patients with IgA nephropathy (IgAN). This study was performed to examine the underglycosylation of the IgA1 hinge region and consequent exposure of the peptide core in IgAN. METHODS: A polyclonal antibody against a synthetic human IgA1 hinge peptide, PVPSTPPTP SPSTPPTPSPS, (anti-sHP ab) was raised in rabbits and shown specifically to recognize the IgA1 which was treated with neuraminidase, beta-galactosidase and alpha-N-acetylgalactosaminidase. The reactivity of the anti-sHP ab against the purified serum IgA1 was compared among the following three groups: 39 patients with IgAN, 30 patients with other renal diseases (ORD) and 21 healthy controls (HC) using an enzyme-linked immunosorbent assay. RESULTS: The reactivity was significantly higher in the IgAN group (mean +/- SD of OD 490 nm: 0.327 +/- 0.059) than in the ORD group (0.274 +/- 0.043, P=0.0002) and in the HC group (0.265 +/- 0.037, P<0.0001). No significant difference was observed between the latter two groups. The frequency of positive cases (> mean +/- 2SD of HC) was 46.2% (18/39) in the IgAN group, 6.7% (2/30) in the ORD group and 0% (0/21) in the HC group. CONCLUSIONS: It was suggested that the peptide core of the IgA1 hinge region is exposed aberrantly by a defective N-acetylgalactosaminylation and plays a possible role in the pathogenesis of IgAN.

Adolescent↗
PubMed1998

Inferring admixture proportions from molecular data.

We derive here two new estimators of admixture proportions based on a coalescent approach that explicitly takes into account molecular information as well as gene frequencies. These estimators can be applied to any type of molecular data (such as DNA sequences, restriction fragment length polymorphisms [RFLPs], or microsatellite data) for which the extent of molecular diversity is related to coalescent times. Monte Carlo simulation studies are used to analyze the behavior of our estimators. We show that one of them (mY) appears suitable for estimating admixture from molecular data because of its absence of bias and relatively low variance. We then compare it to two conventional estimators that are based on gene frequencies. mY proves to be less biased than conventional estimators over a wide range of situations and especially for microsatellite data. However, its variance is larger than that of conventional estimators when parental populations are not very differentiated. The variance of mY becomes smaller than that of conventional estimators only if parental populations have been kept separated for about N generations and if the mutation rate is high. Simulations also show that several loci should always be studied to achieve a drastic reduction of variance and that, for microsatellite data, the mean square error of mY rapidly becomes smaller than that of conventional estimators if enough loci are surveyed. We apply our new estimator to the case of admixed wolflike Canid populations tested for microsatellite data.

Animals↗
PubMed1995

Properties of a single-chain antibody containing different linker peptides.

Single-chain antibodies were constructed using six different linker peptides to join the VH and VL domains of an anti-2-phenyloxazolone (Ox) antibody. Four of the linker peptides originated from the interdomain linker region of the fungal cellulase CBHI and consisted of 28, 11, six and two amino acid residues. The two other linker peptides used were the (GGGGS)3 linker with 15 amino acid residues and a modified IgG2b hinge peptide with 22 residues. Proteolytic stability and Ox binding properties of the six different scFv derivatives produced in Escherichia coli were investigated and compared with those of the corresponding Fv fragment containing no joining peptide between the V domains. The hapten binding properties of different antibody fragments were studied by ELISA and BIAcoreTM. The interdomain linker peptide improved the hapten binding properties of the antibody fragment when compared with Fv fragment, but slightly increased its susceptibility to proteases. Single-chain antibodies with short CBHI linkers of 11, six and two residues had a tendency to form multimers which led to a higher apparent affinity. The fragments with linkers longer than 11 residues remained monomeric.

Amino Acid Sequence↗
PubMed1995

NMR observation of interactions in the combining site region of an antibody using a spin-labeled peptide antigen and NOESY difference spectroscopy.

A spin-labeled peptide antigen (TEMPOVEVPGSQHIDSQ) was used to measure NOESY difference spectra that show interactions in the binding site region of the Fab fragment of the anti-cholera toxin peptide antibody TE33. In addition to identification of peptide-Fab interactions and interactions within the bound peptide, these difference spectra show well-resolved cross peaks due to interactions within the large Fab fragment (50 kDa). These difference spectra indicate that the conformational changes in the Fab upon peptide binding are confined to the combining site region of the antibody. The NOESY difference spectra of selectively deuterated Fab molecules were used in combination with HOHAHA measurements to assign the interactions to amino acid type and to identify the interactions within the Fab as either inter- or intraresidue interactions. The assignment of interactions within the Fab to corresponding aromatic residues in the Fab sequence was facilitated by an earlier NMR-derived model calculated on the basis of NOE restraints on Fab-peptide and intra-bound-peptide distances. The new restraints on distances within the Fab, combined with the previously obtained restraints, were used to generate a refined NMR-derived model for the TE33-peptide complex.

Amino Acid Sequence↗
PubMed2000

Contribution of conventional axial computed tomography (nonhelical), in conjunction with panoramic tomography (zonography), in evaluating mandibular fractures.

Previous studies comparing the sensitivity between different radiological exams have concluded that conventional axial computed tomography (CT; nonhelical) is unsuitable in the assessment of mandibular fractures. Axial CT was shown to have a reduced sensitivity compared with plain radiographs and panoramic tomography because it missed nondisplaced fractures in the posterior portion of the mandible. Because the resolution of CT has improved from the time of these previous studies, the authors were interested in assessing whether axial CT (nonhelical) could now provide additional clinically useful information and enhance our understanding of mandibular fractures, beyond that obtained from panoramic tomography alone. In their study, 5 staff surgeons initially evaluated the panoramic tomograms and then the CT scans of 39 patients with 66 fractures. A series of four questions assessed the relative contribution of these two radiological exams in formulating an optimal operative plan for each patient. The authors found that axial CT provided supplementary information regarding missed fractures, comminution, and the exact size and degree of displacement of fracture fragments. This additional data could have changed the operative plan in a substantial proportion of patients (17 of 39). Axial CT demonstrated two missed parasymphyseal fractures (2 of 39 patients) that were not seen on these patients' panoramic tomograms. Axial CT also revealed undiscovered comminution or demonstrated fracture displacement more precisely in 39% of patients (15 of 39) and 24% of fractures (16 of 66). This study demonstrates that axial CT was clinically useful as an additional investigation to panoramic tomography. Axial CT helped elucidate further the nature of suspected mandibular fractures.

Humans↗
PubMed1999

Protective effect of bactericidal/permeability-increasing protein (rBPI21) in baboon sepsis is related to its antibacterial, not antiendotoxin, properties.

OBJECTIVE AND SUMMARY BACKGROUND DATA: The recombinant fragment of bactericidal/permeability-increasing protein, rBPI21, has potent bactericidal activity against gram-negative bacteria as well as antiendotoxin (lipopolysaccharide [LPS]) action. On the basis of these activities, the authors sought to discover whether rBPI21 would be protective in baboons with live Escherichia coli-induced sepsis and whether the potential protective effects of rBPI21 (together with antibiotics) would be more closely related to its antibacterial or LPS-neutralizing effects. METHODS: In a prospective, randomized, placebo-controlled subchronic laboratory study, the efficacy of rBPI21 or placebo was studied over 72 hours in chronically instrumented male baboons infused with live E. coli under antibiotic therapy. RESULTS: Intravenous rBPI21 attenuated sepsis-related organ failure and increased survival significantly. Bacteremia was significantly reduced in the rBPI21 group at 2 hours after the start of the E. coli infusion, whereas circulating LPS was less affected. The in vivo formation of tumor necrosis factor was significantly suppressed by the rBPI21 treatment regimen. Microcirculation and organ function were improved. CONCLUSIONS: In baboon live E. coli sepsis, the salutary effect of rBPI21 results from a more prevalent antibacterial than antiendotoxin activity.

Animals↗
PubMed1996

Platelet adhesion to late fibrinogen degradation products.

Evidence is emerging for the regulation of platelet function at sites of vascular injury or thrombosis by multiple platelet recognition sites in fibrinogen. This study examined the interaction of platelets with immobilized fibrinogen degradation products, fragments D and E. A 60 kDa D fragment (D60) and 30 kDa fragment E supported the adhesion of activated platelets in a static system, despite the absence of gamma chain 400-411 dodecapeptide and RGD sequences. Moreover, platelet adhesion to these fragments was incompletely inhibited by EDTA. In the absence of divalent cations, ADP-stimulated platelet adhesion to fragments D60 or E constituted 31 +/- 12% and 33 +/- 10% (mean +/- SD,n = 23) of adhesion to intact fibrinogen in the presence of divalent cations, respectively. This EDTA-resistant adhesion was distinctly modulated by thrombin which preferentially supported platelet adhesion to fragment E, and chymotrypsin which selectively supported platelet adhesion to fragment D60. Furthermore, two potent inhibitors of fibrinogen binding, the 10E5 monoclonal antibody directed against the GPIIb-IIIa complex and the RGDF peptide, inhibited EDTA-resistant platelet adhesion to fragment D60 but not to fragment E. These data suggest the presence of novel, non-RGD, non-dodecapeptide containing platelet recognition sequences in both fibrinogen D and E domains which support divalent cation dependent and independent platelet adhesion via potentially unique binding mechanisms.

Fibrin Fibrinogen Degradation Products↗
PubMed1999

Relapse rates after short-course (6-month) treatment of tuberculosis in HIV-infected and uninfected persons.

OBJECTIVE: To determine the rate of tuberculosis relapse among HIV-seropositive and -seronegative persons treated for active tuberculosis with short-course (6-month) therapy. DESIGN: Consecutive cohort study. SETTING: City of Baltimore tuberculosis clinic. PATIENTS: Tuberculosis patients treated between 1 January 1993 and 31 December 1996. INTERVENTION: Patients received 2 months of isoniazid, rifampin, pyrazinamide and ethambutol followed by 4 months of isoniazid and rifampin. MAIN OUTCOME MEASURE: Passive follow-up for tuberculosis relapse was performed through September 30, 1998. RESULTS: There were 423 cases of tuberculosis during the study period; 280 patients completed a 6-month course of therapy. Therapy was directly-observed for 94% of patients. Of those who completed therapy, 47 (17%) were HIV-seropositive, 127 (45%) were HIV-seronegative, and 106 (38%) had unknown HIV status. HIV-infected patients required more time to complete therapy (median 225 versus 205 days; P = 0.04) but converted sputum culture to negative within the same time period (median 77 versus 72 days; P = 0.43) as HIV-seronegative or unknown patients. Relapse occurred in three out of 47 (6.4%) HIV-infected patients compared to seven out of 127 (5.5%) HIV-seronegative patients (P = 1.0). Relapse rates also did not differ when HIV-seropositive patients were compared with HIV-seronegative and patients with unknown HIV status (6.4% versus 3.0%; P = 0.38). Of the 10 patients with tuberculosis relapse, restriction fragment length polymorphism data were available for five; all five relapse isolates matched the initial isolate. CONCLUSIONS: These results support current recommendations to treat tuberculosis in HIV-infected patients with short-course (6-month) therapy.

AIDS-Related Opportunistic Infections↗