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1.
Bioengineering (Basel) ; 9(10)2022 Oct 20.
Article in English | MEDLINE | ID: mdl-36290552

ABSTRACT

Considering the imminence of new SARS-CoV-2 variants and COVID-19 vaccine availability, it is essential to understand the impact of the disease on the most vulnerable groups and those at risk of death from the disease. To this end, the odds ratio (OR) for mortality and hospitalization was calculated for different groups of patients by applying an adjusted logistic regression model based on the following variables of interest: gender, booster vaccination, age group, and comorbidity occurrence. A massive number of data were extracted and compiled from official Brazilian government resources, which include all reported cases of hospitalizations and deaths associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Brazil during the "wave" of the Omicron variant (BA.1 substrain). Males (1.242; 95% CI 1.196-1.290) aged 60-79 (3.348; 95% CI 3.050-3.674) and 80 years or older (5.453; 95% CI 4.966-5.989), and hospitalized patients with comorbidities (1.418; 95% CI 1.355-1.483), were more likely to die. There was a reduction in the risk of death (0.907; 95% CI 0.866-0.951) among patients who had received the third dose of the anti-SARS-CoV-2 vaccine (booster). Additionally, this big data investigation has found statistical evidence that vaccination can support mitigation plans concerning the current scenario of COVID-19 in Brazil since the Omicron variant and its substrains are now prevalent across the entire country.

2.
Nat Mater ; 21(5): 547-554, 2022 May.
Article in English | MEDLINE | ID: mdl-35177785

ABSTRACT

Constitutive laws underlie most physical processes in nature. However, learning such equations in heterogeneous solids (for example, due to phase separation) is challenging. One such relationship is between composition and eigenstrain, which governs the chemo-mechanical expansion in solids. Here we developed a generalizable, physically constrained image-learning framework to algorithmically learn the chemo-mechanical constitutive law at the nanoscale from correlative four-dimensional scanning transmission electron microscopy and X-ray spectro-ptychography images. We demonstrated this approach on LiXFePO4, a technologically relevant battery positive electrode material. We uncovered the functional form of the composition-eigenstrain relation in this two-phase binary solid across the entire composition range (0 ≤ X ≤ 1), including inside the thermodynamically unstable miscibility gap. The learned relation directly validates Vegard's law of linear response at the nanoscale. Our physics-constrained data-driven approach directly visualizes the residual strain field (by removing the compositional and coherency strain), which is otherwise impossible to quantify. Heterogeneities in the residual strain arise from misfit dislocations and were independently verified by X-ray diffraction line profile analysis. Our work provides the means to simultaneously quantify chemical expansion, coherency strain and dislocations in battery electrodes, which has implications on rate capabilities and lifetime. Broadly, this work also highlights the potential of integrating correlative microscopy and image learning for extracting material properties and physics.

3.
Vaccine X ; 7: 100087, 2021 Apr.
Article in English | MEDLINE | ID: mdl-33817624

ABSTRACT

BACKGROUND: Maternal Tetanus, diphtheria, and acellular pertussis (Tdap) vaccination provides antibody transfer to newborn infants and may affect their antibody response to the primary vaccination series. This study aimed to assess the effect of Tdap vaccination during pregnancy on infant antibody response to the whole cell pertussis (DTwP) primary series. METHODS: Plasma from 318 pregnant women (243 Tdap-vaccinated and 75 unvaccinated) and their infants (cord blood) was collected at delivery; infant blood was again collected at 2 and 7 months, before and after their primary DTwP series. Anti-pertussis toxin (PT), pertactin (PRN), filamentous hemagglutinin (FHA), fimbriae 2/3 (FIM) and adenylate cyclase toxin (ACT) IgG antibodies were quantified by a microsphere-based multiplex antibody capture assay and anti-PT neutralizing antibodies by the Real Time Cell analysis system. RESULTS: Infant geometric mean concentrations (GMCs) of IgG anti-Tdap antigens were significantly higher (p < 0.001) among the Tdap-vaccinated (PT: 57.22 IU/mL; PRN: 464.86 IU/mL; FHA: 424.0 IU/mL), versus the unvaccinated group (4 IU/mL, 15.43 IU/mL, 31.99 IU/mL, respectively) at delivery. Anti-FIM and ACT GMCs were similar between the two groups. At 2 months of age, anti-PT, PRN, and FHA GMCs remained higher (p < 0.001) in the Tdap-vaccinated group (12.64 IU/mL; 108.76 IU/mL; 87.41 IU/mL, respectively) than the unvaccinated group (1.02 IU/mL; 4.46 IU/mL; 6.89 IU/mL). However, at 7 months, after receiving the third DTwP dose, the anti-PT GMC was higher (p = 0.016) in the unvaccinated group (7.91 IU/mL) compared to the vaccinated group (2.27 IU/mL), but without differences for anti-PRN, FHA, FIM and ACT GMCs. CONCLUSION: Elevated antibody levels suggest that maternal Tdap vaccination might protect infants until 2 months of age. Reduced anti-PT levels at 7 months indicate potential blunting of immune response in infants. Surveillance would help determine if blunting alters vaccine immunity and impacts pertussis prevention in infants.

4.
Planta Med ; 86(7): 505-515, 2020 May.
Article in English | MEDLINE | ID: mdl-32247285

ABSTRACT

Spondias mobin leaves have been traditionally used for treating cold sores. The study investigated the mechanism of antiherpes action of S. mombin extract, fractions, and geraniin. Different concentrations of samples were used to evaluate the in vitro antiherpes activity (anti-HSV-1) in virucidal, post-infection, attachment, and penetration assays. The mechanism of action of geraniin was investigated considering the glycoproteins gB and gD of HSV-1 surface as potential molecular targets. Molecular docking simulations were carried out for both in order to determine the possible binding mode position of geraniin at the activity sites. The binding mode position was posteriorly optimized considering the flexibility of the glycoproteins. The chemical analysis of samples was performed by LC-MS and revealed the presence of 22 substances, which are hydrolysable tannins, O-glycosylated flavonoids, phenolic acids, and a carbohydrate. The extract, tannin-rich fraction and geraniin showed important in vitro virucidal activity through blocking viral attachment but showed no relevant inhibition of viral penetration. The in silico approaches demonstrated a high number of potential strong intermolecular interactions as hydrogen bonds between geraniin and the activity site of the glycoproteins, particularly the glycoprotein gB. In silico experiments indicated that geraniin is at least partially responsible for the anti-herpes activity through interaction with the viral surface glycoprotein gB, which is responsible for viral adsorption. These results highlight the therapeutic potential of S. mombin anti-herpes treatment and provides support for its traditional purposes. However, further studies are required to validate the antiviral activities in vivo, as well as efficacy in humans.


Subject(s)
Anacardiaceae , Antiviral Agents , Herpes Simplex , Herpesvirus 1, Human , Herpesvirus 2, Human , Humans , Molecular Docking Simulation , Plant Extracts , Plant Leaves , Vero Cells , Virus Replication
7.
J Travel Med ; 21(5): 298-303, 2014.
Article in English | MEDLINE | ID: mdl-24889210

ABSTRACT

BACKGROUND: In February 2012, crew and passengers of a cruise ship sailing off the coast of São Paulo, Brazil, were hospitalized for acute respiratory illness (ARI). A field investigation was performed to identify the disease involved and factors associated. METHODS: Information on passengers and crew with ARI was obtained from the medical records of hospitalized individuals. Active case finding was performed onboard the ship. ARI was defined as the presence of one nonspecific symptom (fever, chills, myalgia, arthralgia, headache, or malaise) and one respiratory symptom (cough, nasal congestion, sore throat, or dyspnea). A case-control study was conducted among the crew. The cases were crew members with symptoms of influenza-like illness (ILI) (fever and one of the following symptoms: cough, sore throat, and dyspnea) in February 2012. The controls were asymptomatic crew members. RESULTS: The study identified 104 ARI cases: 54 (51.9%) crew members and 50 (49.1%) passengers. Among 11 ARI hospitalized cases, 6 had influenza B virus isolated in nasopharyngeal swab. One mortality among these patients was caused by postinfluenza Staphylococcus aureus pneumonia. The crew members housed in the two lower decks and those belonging to the 18- to 32-year-old age group were more likely to develop ILI [odds ratio (OR) = 2.39, 95% confidence interval (CI) 1.09-5.25 and OR = 3.72, CI 1.25-11.16, respectively]. CONCLUSIONS: In February 2012, an influenza B outbreak occurred onboard a cruise ship. Among crew members, ILI was associated with lower cabin location and younger age group. This was the first influenza outbreak detected by Brazilian public health authorities in a vessel cruising in South American waters.


Subject(s)
Disease Outbreaks , Influenza B virus/isolation & purification , Influenza, Human/epidemiology , Ships , Travel , Adolescent , Adult , Age Factors , Brazil/epidemiology , Case-Control Studies , Female , Humans , Infection Control , Influenza, Human/prevention & control , Male , Middle Aged
8.
Chirurg ; 82(9): 820, 822-7, 2011 Sep.
Article in German | MEDLINE | ID: mdl-21678104

ABSTRACT

The anterolateral thigh flap (ATL) has become a standard procedure in reconstructive microsurgery. In this study the results with the ALT for reconstruction in the head and neck area after tumor resection in 33 patients were retrospectively analyzed. Patients included 28 men and 5 women aged 47-70 years who suffered from intraoral and extraoral tumors. Satisfactory soft tissue coverage could be achieved in all patients and no flaps were lost. The ALT is a versatile free flap enabling reliable soft tissue reconstruction of complex defects in the head and neck region. Flap dissection and preparation of the recipient area can usually be performed simultaneously. Additional advantages include the long and strong caliber vascular pedicle, the low donor site morbidity and the different possibilities of tissue composition, making the ALT a workhorse flap in modern reconstructive microsurgery.


Subject(s)
Adenocarcinoma/surgery , Adenoma, Pleomorphic/surgery , Carcinoma, Squamous Cell/surgery , Free Tissue Flaps/blood supply , Microsurgery/methods , Otorhinolaryngologic Neoplasms/surgery , Adult , Aged , Anastomosis, Surgical/methods , Arteries/surgery , Female , Humans , Male , Middle Aged , Mouth Neoplasms/surgery , Oropharyngeal Neoplasms/surgery , Otorhinolaryngologic Neoplasms/radiotherapy , Paranasal Sinus Neoplasms/surgery , Postoperative Complications/surgery , Radiotherapy, Adjuvant , Reoperation , Retrospective Studies , Tissue and Organ Harvesting/methods , Veins/surgery
9.
J Appl Physiol (1985) ; 107(4): 1293-9, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19644034

ABSTRACT

A number of deposition models for humans, as well as experimental animals, have been described. However, no breath-by-breath deposition measurement in rats has been reported to date. The objective of this study is to determine lung deposition of micrometer-sized particles as a function of breathing parameters in the adult rat lung. A new aerosol photometry system was designed to measure deposition of nonhygroscopic, 2-mum sebacate particles in anesthetized, intubated, and spontaneously breathing 90-day-old Wistar-Kyoto rats placed in a size-adjusted body plethysmograph box. Instrumental dead space of the system was minimized down to 310 microl (i.e., approximately 20% of respiratory dead space). The system allows continuous monitoring of particle concentration in the respired volume. Breathing parameters, such as respiratory rate (f), tidal volume (Vt), as well as inspiration/expiration times, were also monitored at different levels of anesthesia. The results showed that Vt typically varied between 1.5 and 4.0 ml for regular breathing and between 4.0 and 10.0 ml for single-sigh breaths; f ranged from 40 to 200 breaths/min. Corresponding deposition values varied between 5 and 50%, depending on breath-by-breath breathing patterns. The best fit of deposition (D) was achieved by a bilinear function of Vt and f and found to be D = 11.0 - 0.09.f + 3.75.Vt. We conclude that our approach provides more realistic conditions for the measurement of deposition than conventional models using ventilated animals and allows us to analyze the correlation between breath-specific deposition and spontaneous breathing patterns.


Subject(s)
Decanoic Acids/metabolism , Dicarboxylic Acids/metabolism , Lung/metabolism , Respiration , Aerosols , Anesthesia , Animals , Decanoic Acids/administration & dosage , Dicarboxylic Acids/administration & dosage , Equipment Design , Exhalation , Inhalation , Inhalation Exposure , Intubation, Intratracheal , Male , Miniaturization , Models, Biological , Particle Size , Photometry , Plethysmography/instrumentation , Rats , Rats, Inbred WKY , Respiratory Dead Space , Respiratory Mechanics , Tidal Volume , Time Factors , Tissue Distribution
10.
Vaccine ; 27(33): 4483-9, 2009 Jul 16.
Article in English | MEDLINE | ID: mdl-19486955

ABSTRACT

In travellers often several pre-departure immunizations are indicated, thus data are needed about possible interactions between vaccines. This Phase 3 study investigated the immunogenicity and safety of IC51 (JE vaccine) and HAVRIX1440 (hepatitis A vaccine) when administered alone or concomitantly to healthy subjects. The immune response was compared between single and concomitant vaccination in terms of geometric mean titre (GMT) and seroconversion rate (SCR) on Days 28 and 56. Immunogenicity was comparable for the 2 vaccines whether given together or separately which suggests that travellers to such regions could receive the vaccinations concomitantly.


Subject(s)
Encephalitis, Japanese/prevention & control , Hepatitis A Vaccines/immunology , Hepatitis A/prevention & control , Japanese Encephalitis Vaccines/immunology , Adult , Encephalitis, Japanese/immunology , Female , Hepatitis A/immunology , Hepatitis A Antibodies/blood , Hepatitis A Antibodies/immunology , Hepatitis A Vaccines/administration & dosage , Hepatitis A Vaccines/adverse effects , Humans , Japanese Encephalitis Vaccines/administration & dosage , Japanese Encephalitis Vaccines/adverse effects , Male , Single-Blind Method , Vaccines, Inactivated/administration & dosage , Vaccines, Inactivated/adverse effects , Vaccines, Inactivated/immunology , Young Adult
12.
Vaccine ; 21(25-26): 3575-83, 2003 Sep 08.
Article in English | MEDLINE | ID: mdl-12922085

ABSTRACT

Two randomized, double blind dose comparison studies were conducted in 595 children in Austria and Germany with an albumin-free and thiomersal-free tick-borne encephalitis (TBE) vaccine. Vaccinated subjects of an age between 6 months and 12 years randomly assigned received either the full adult dose or half the adult dose. Results from vaccinated children under 1 year of age at the time of the first vaccination (159 subjects) showed an age dependent immune response. There were significantly fewer adverse systemic events (e.g. fever reactions). In children who received only half the adult dose, while seroconversion was not significantly different (93% versus 98%) after the second vaccination, and 100% for both groups after the third vaccination. Based on these results, it is recommended to vaccinate children between the ages of 1 and 12 years with half the adult dose.


Subject(s)
Antibodies, Viral/biosynthesis , Antigens, Viral/adverse effects , Antigens, Viral/immunology , Encephalitis Viruses, Tick-Borne/immunology , Encephalitis, Tick-Borne/prevention & control , Viral Vaccines/adverse effects , Viral Vaccines/immunology , Aging/immunology , Antibodies, Viral/analysis , Austria , Child , Child, Preschool , Dose-Response Relationship, Drug , Double-Blind Method , Encephalitis, Tick-Borne/immunology , Female , Germany , Humans , Immunization , Immunoglobulin G/analysis , Immunoglobulin G/biosynthesis , Infant , Male
13.
Handchir Mikrochir Plast Chir ; 35(1): 57-62, discussion 63, 2003 Jan.
Article in German | MEDLINE | ID: mdl-12772064

ABSTRACT

This is a report about 1000 endoscopic carpal tunnel release procedures using a single-portal system. Not a single iatrogenic lesion was found out at the follow-up check. Under consideration of certain technical details there is no risk of lesions.


Subject(s)
Arthroscopes , Carpal Tunnel Syndrome/surgery , Postoperative Complications/etiology , Adolescent , Adult , Aged , Aged, 80 and over , Carpal Tunnel Syndrome/physiopathology , Equipment Design , Female , Follow-Up Studies , Humans , Iatrogenic Disease , Male , Median Nerve/physiopathology , Middle Aged , Neurologic Examination , Postoperative Complications/physiopathology , Postoperative Complications/surgery , Reoperation
14.
Acta Physiol Scand ; 174(4): 367-75, 2002 Apr.
Article in English | MEDLINE | ID: mdl-11942924

ABSTRACT

To assess the contribution of genetic background to respiratory mechanics, we developed a ventilator unit to measure lung function parameters in the mouse. We studied two commonly used inbred mice strains originating from Mus musculus domesticus (C57BL/6 and C3HeB/FeJ) and a third strain derived from Mus musculus molossinus [Japanese fancy mouse 1 (JF1)]. The ventilator allows for accurate performance of the different breathing manoeuvres required for measuring in- and expiratory reserve capacity, quasi-static and dynamic compliance, and airway resistance. In combination with a mass spectrometer for monitoring gas concentrations, single-breath manoeuvres were performed and He-expirograms obtained, from which dead space volume and slope of phase III were determined. From each strain and each sex, 10, 2-month old animals were studied immediately after being killed by an intraperitoneal overdose of xylazine and ketamine. C3HeB/FeJ and C57BL/6 exhibited comparable lung volumes. In male C3HeB/FeJ mice, e.g. vital capacity (VC) was 1072 +/- 79 microL, inspiratory reserve capacity 782 +/- 88 microL, and dead space volume at total lung inflation 216 +/- 18 microL. Lung volumes of JF1 were significantly lower (e.g. VC 611 +/- 53 microL, P < 0.01) even when normalized to body weight. In all three strains, specific lung volumes were significantly higher in females than in males, possibly explained by a higher oxygen demand during pregnancy and lactation, both of which fill most of their life times. Static compliance in C3HeB/FeJ was 64.3 +/- 5.4 microL cmH2O-1. It was smaller in C57BL/6 and JF1 mice, even when related to the lung volume. Analysis of the degree of genetic vs. non-genetic components of the phenotypic variation revealed that at least 80% of the total variation of lung volumes and static compliance in the mixed population is attributable to genetic differences between individuals. These differences will be verified in further studies by segregation and genetic linkage analysis.


Subject(s)
Lung/physiology , Respiratory Mechanics/genetics , Sex Characteristics , Animals , Female , Lung Volume Measurements/instrumentation , Male , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Phenotype , Reproducibility of Results , Species Specificity , Total Lung Capacity/physiology
15.
ALTEX ; 18(1): 50-4, 2001.
Article in German | MEDLINE | ID: mdl-11248852

ABSTRACT

Influenza viruses for production are presently produced in embryonated hen"s eggs. This conventional standard methodology is extremely cumbersome; it requires millions of eggs and an extensive purification to reduce the amount of contaminating egg proteins and to minimise the risk of allergies against egg albumin. The shortage of eggs in a pandemic situation, the selection of egg-adapted variants and the presence of adventitious viruses has emphasised the necessity for production of Influenza vaccines on a well characterised stable cell line. Our established serum and protein free Vero cell technology has been successfully adapted to large scale production of a huge variety of Influenza virus strains. The production in 1200 liter fermenter cultures under serum free conditions gave antigen yields comparable to the conventional embryonated egg technology. The development of a rapid and efficient purification scheme resulted in a safe high purity vaccine which was at least as immunogenic as conventional egg-derived vaccines in a mouse model. Clinical trials in the UK, Poland and Austria demonstrated that the Vero cell derived influenza vaccine is well tolerated, safe and highly immunogenic in humans.


Subject(s)
Influenza Vaccines/biosynthesis , Animals , Cell Culture Techniques/methods , Chlorocebus aethiops , Clinical Trials as Topic , Culture Media, Serum-Free , Eggs , Humans , Influenza A virus/growth & development , Influenza B virus/growth & development , Influenza Vaccines/therapeutic use , Safety , Vero Cells
16.
Hepatology ; 32(3): 618-25, 2000 Sep.
Article in English | MEDLINE | ID: mdl-10960458

ABSTRACT

Hepatitis C virus (HCV) is an important cause of chronic liver disease worldwide. Development of vaccines to prevent HCV infection, or at least prevent progression to chronicity, is a major goal. In mice and rhesus macaques, a DNA vaccine encoding cell-surface HCV-envelope 2 (E2) glycoprotein stimulated stronger immune responses than a vaccine encoding intracellular E2. Therefore, we used DNA encoding surface-expressed E2 to immunize chimpanzees 2768 and 3001. Chimpanzee 3001 developed anti-E2 after the second immunization and antibodies to hypervariable region 1 (HVR1) after the third immunization. Although chimpanzee 2768 had only low levels of anti-E2 after the third immunization, an anamnestic response occurred after HCV challenge. CTL responses to E2 were not detected before challenge, but a strong response was detected after HCV challenge in chimpanzee 2768. An E2-specific CD4+ response was detected in chimpanzee 2768 before challenge and in both chimpanzees postchallenge. Three weeks after the last immunization, animals were challenged with 100 50% chimpanzee-infectious doses (CID(50)) of homologous monoclonal HCV. As a control, a naive chimpanzee was inoculated with 3 CID(50) of the challenge virus. The vaccine did not generate sterilizing immunity because both vaccinated chimpanzees were infected. However, both vaccinated chimpanzees resolved the infection early whereas the control animal became chronically infected. Compared with the control animal, hepatitis appeared earlier in the course of the infection in both vaccinated chimpanzees. Therefore, DNA vaccine encoding cell surface-expressed E2 did not elicit sterilizing immunity in chimpanzees against challenge with a monoclonal homologous virus, but did appear to modify the infection and might have prevented progression to chronicity.


Subject(s)
Antibodies, Monoclonal/immunology , DNA/genetics , Hepacivirus/immunology , Hepatitis C/immunology , Hepatitis C/prevention & control , Pan troglodytes/immunology , Plasmids/genetics , Vaccination , Viral Envelope Proteins/genetics , Animals , CD4-Positive T-Lymphocytes/immunology , Female , Hepatitis C/blood , Hepatitis C/physiopathology , T-Lymphocytes, Cytotoxic/immunology
17.
Vox Sang ; 77 Suppl 1: 72-9, 1999.
Article in English | MEDLINE | ID: mdl-10529694

ABSTRACT

A complex consisting of activated factor X (FX) (enzyme) and prothrombin (substrate), both highly purified from human plasma and virus inactivated, was formulated, characterised biochemically as well as in animal studies, and given the name Partial Prothrombinase (PPT). In vitro, PPT shortened the clotting time of a high-titre human factor VIII (FVIII) inhibitor plasma in a manner similar to that of the activated prothrombin complex concentrate FEIBA and triggered coagulation in plasma samples in which factor V (FV) is present. In vivo, the ability of PPT to activate coagulation in both chimpanzees and baboons was equivalent to that of FEIBA. PPT also triggered coagulation in a von Willebrand factor(vWF)-deficient dog and controlled bleeding in rabbits with antibody-induced haemophilia A. Thus, studying the mechanism of action of PPT also explains the therapeutic principle of FEIBA.


Subject(s)
Factor Xa/pharmacology , Prothrombin/pharmacology , Animals , Antibodies , Blood Coagulation/drug effects , Blood Coagulation Factors/analysis , Blood Coagulation Factors/chemistry , Blood Coagulation Factors/pharmacology , Disease Models, Animal , Dogs , Factor VIII/immunology , Female , Hemophilia A/chemically induced , Hemophilia A/drug therapy , Hemorrhage , Humans , Male , Pan troglodytes , Papio , Prothrombin/analysis , Rabbits , Thrombin/biosynthesis , Thrombin/drug effects , Time Factors , von Willebrand Diseases/drug therapy
18.
Dev Biol Stand ; 98: 101-10; discussion 111, 1999.
Article in English | MEDLINE | ID: mdl-10494963

ABSTRACT

Influenza vaccine production is dependent on the availability of embryonated hen eggs for virus growth. This is an extremely cumbersome system with many disadvantages with respect to selection of virus variants and the presence of adventitious viruses. We have developed an alternative cell culture system which allows rapid production of large volumes of vaccine. The WHO-approved Vero cell line was used in serum-free culture to grow many influenza strains to high titre. This system could be scaled-up to allow vaccine production with a 1200 litre fermenter. A purification scheme was developed which resulted in a high purity whole virus vaccine. This was demonstrated to be at least as immunogenic as a conventional egg-derived preparation.


Subject(s)
Influenza A virus/immunology , Influenza Vaccines/immunology , Virus Cultivation , Animals , Chick Embryo , Chlorocebus aethiops , Culture Media, Serum-Free , Fermentation , Influenza A virus/growth & development , Pan troglodytes , Vero Cells
19.
Blood ; 94(5): 1637-47, 1999 Sep 01.
Article in English | MEDLINE | ID: mdl-10477688

ABSTRACT

Although proteolytic processing of pro-von Willebrand factor (pro-vWF) resulting in free propeptide and mature vWF is known to be initiated intracellularly, vWF released from endothelial cells may contain a high proportion of incompletely processed pro-vWF. Because pro-vWF is only rarely detectable in normal human plasma, we investigated whether extracellular processing of pro-vWF is possible. A recombinant preparation (rpvWF) containing both pro-vWF and mature vWF subunits was infused into 2 pigs and 1 dog with severe von Willebrand disease, 2 mice with a targeted disruption of the vWF gene, and 2 healthy baboons. Total vWF antigen (vWF:Ag), free propeptide, and pro-vWF were measured using enzyme-linked immunosorbent assay techniques in blood samples drawn before and after infusion. vWF:Ag increased promptly. No pro-vWF could be detected when the first postinfusion sample was drawn after 30 minutes (pigs) or 60 minutes (mice), but pro-vWF was detectable for short periods when postinfusion samples were drawn after 15 minutes (dog) or 5 minutes (baboons). In contrast, free propeptide was increased at the first timepoint measured, suggesting that it was generated from the pro-vWF in the rpvWF preparation. vWF multimers were analyzed in the rpvWF preparation and in plasma samples drawn before and after infusion of rpvWF using ultra-high resolution 3% agarose gels to allow separation of homo- and hetero-forms of the vWF polymers. Within 30 minutes after infusion in the pigs, 1 hour in the dog and the mice, and within 2 hours in the baboons, the multimer pattern had changed to that typically seen in mature vWF. These data indicate that propeptide cleavage from unprocessed vWF can occur extracellularly in the circulation. The enzyme or enzymes responsible for this cleavage in plasma remain to be identified.


Subject(s)
Protein Precursors/metabolism , von Willebrand Diseases/metabolism , von Willebrand Factor/metabolism , Animals , Dogs , Humans , Mice , Protein Precursors/administration & dosage , Protein Processing, Post-Translational , Recombinant Proteins/administration & dosage , Recombinant Proteins/blood , Swine , von Willebrand Diseases/drug therapy , von Willebrand Factor/administration & dosage
20.
Antimicrob Agents Chemother ; 43(8): 2038-42, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10428932

ABSTRACT

The effects of therapeutically relevant concentrations of the human immunodeficiency virus (HIV) proteinase inhibitors saquinavir and indinavir on the in vitro proteinase activity of Candida albicans were investigated with isolates from HIV-infected and uninfected patients with oral candidiasis. After exposure to the HIV proteinase inhibitors, proteinase activity was significantly reduced in a dose-dependent manner. These inhibitory effects, which were similar to that of pepstatin A, and the reduced virulence phenotype in experimental candidiasis after application of saquinavir indicate the usefulness of these HIV proteinase inhibitors as potential anticandidal agents.


Subject(s)
AIDS-Related Opportunistic Infections/microbiology , Anti-HIV Agents/pharmacology , Aspartic Acid Endopeptidases/antagonists & inhibitors , Candida albicans/enzymology , Candidiasis, Oral/microbiology , HIV Infections/microbiology , HIV Protease Inhibitors/pharmacology , Indinavir/pharmacology , Saquinavir/pharmacology , Aspartic Acid Endopeptidases/isolation & purification , Aspartic Acid Endopeptidases/metabolism , Candida albicans/drug effects , Candida albicans/isolation & purification , Dose-Response Relationship, Drug , Fungal Proteins/antagonists & inhibitors , Humans , Pepstatins/pharmacology
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