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| Publications of Aimee K Zaas :recent first alphabetical combined listing:
%% Papers Published
@article{fds191204,
Author = {A Zaas and P Scheel and A Venbrux and DB Hellmann},
Title = {Large artery vasculitis following recombinant hepatitis B
vaccination: 2 cases.},
Journal = {The Journal of rheumatology},
Volume = {28},
Number = {5},
Pages = {1116-20},
Year = {2001},
Month = {May},
ISSN = {0315-162X},
Keywords = {Adult • Angiography, Digital Subtraction • Female
• Hepatitis B • Hepatitis B Vaccines • Humans
• Middle Aged • Renal Artery Obstruction •
Subclavian Artery* • Takayasu Arteritis •
Vaccines, Synthetic • adverse effects • adverse
effects* • etiology* • prevention & control •
radiography},
Abstract = {We describe 2 women who developed large artery vasculitis
shortly after receiving recombinant hepatitis B vaccination.
One patient developed Takayasu's arteritis, the other a
vasculitis involving subclavian and renal arteries. Both
developed renal failure. Whether the vasculitis was caused
by the vaccination is not known. Although small vessel
vasculitis following hepatitis B vaccination has been
reported a number of times, large vessel vasculitis
associated with hepatitis B vaccination has been reported
only once. These cases suggest that large artery vasculitis
should be added to the list of possible side effects of
hepatitis B vaccination.},
Language = {eng},
Key = {fds191204}
}
@article{fds191215,
Author = {AK Zaas and X Song and P Tucker and TM Perl},
Title = {Risk factors for development of vancomycin-resistant
enterococcal bloodstream infection in patients with cancer
who are colonized with vancomycin-resistant
enterococci.},
Journal = {Clinical infectious diseases : an official publication of
the Infectious Diseases Society of America},
Volume = {35},
Number = {10},
Pages = {1139-46},
Year = {2002},
Month = {November},
ISSN = {1537-6591},
url = {http://dx.doi.org/10.1086/342904},
Keywords = {Bacteremia • Enterococcus faecium* • Female •
Gram-Positive Bacterial Infections • Humans • Male
• Middle Aged • Neoplasms • Risk Factors
• Vancomycin Resistance • complications* •
epidemiology • etiology • microbiology •
microbiology* • physiology*},
Abstract = {Vancomycin-resistant Enterococcus faecium (VRE) is a common
nosocomial isolate, especially among patients with cancer.
VRE infections have substantial attributable mortality among
patients with cancer. The purpose of this study was to
identify risk factors for developing bloodstream infection
with VRE in patients with cancer who are colonized with VRE.
VRE colonization was prospectively identified in 197
patients with cancer during 4-year period, of whom 179 (91%)
had complete records for evaluation. Of these 179 patients,
24 (13.4%) developed hospital-acquired VRE bloodstream
infections. Risk factors for VRE bloodstream infection
included vancomycin use (relative risk [RR], 1.98; 95%
confidence interval [CI], 1.25-3.14), diabetes mellitus (RR,
3.91; 95% CI, 1.20-12.77), gastrointestinal procedures (RR,
4.56; 95% CI, 1.05-19.7), and acute renal failure (RR, 3.10;
95% CI, 1.07-8.93). Strategies for preventing VRE
bloodstream infection in VRE-colonized patients with cancer
should include limiting vancomycin use and, perhaps,
gastrointestinal procedures.},
Language = {eng},
Doi = {10.1086/342904},
Key = {fds191215}
}
@article{fds191221,
Author = {D Le and A Zaas},
Title = {Cases from the Osler Medical Service at Johns Hopkins
University. Left atrial myxoma.},
Journal = {The American journal of medicine},
Volume = {113},
Number = {8},
Pages = {694-6},
Year = {2002},
Month = {December},
ISSN = {0002-9343},
Keywords = {Biopsy, Needle • Cardiac Surgical Procedures •
Echocardiography, Transesophageal • Follow-Up Studies
• Heart Atria • Heart Catheterization • Heart
Neoplasms • Humans • Immunohistochemistry •
Male • Middle Aged • Myxoma • Thoracotomy
• Tomography, X-Ray Computed • methods •
methods* • pathology • surgery* •
ultrasonography*},
Language = {eng},
Key = {fds191221}
}
@article{fds191211,
Author = {RW Grow and A Zaas},
Title = {Cases from the Osler Medical Service at Johns Hopkins
University.},
Journal = {The American journal of medicine},
Volume = {114},
Number = {2},
Pages = {153-5},
Year = {2003},
Month = {February},
ISSN = {0002-9343},
Keywords = {Abdominal Pain • Acute Disease • Adult •
Chronic Disease • Diagnosis, Differential •
Diarrhea • Female • Hepatitis, Alcoholic •
Hepatorenal Syndrome • Humans • Jaundice •
Liver • Liver Diseases • complications* •
diagnosis* • etiology • etiology* • pathology
• pathology*},
Abstract = {A 37-year-old woman presented with increasing abdominal pain
and jaundice. Six weeks before admission, she developed
persistent diarrhea and jaundice of the skin. She also
bruised easily, and her gums bled. In the subsequent weeks,
her appetite decreased, she was fatigued, and she had
nausea, vomiting, and abdominal distension. She had a
history of drinking 1 quart of vodka every day for 20 years,
with brief periods of abstinence; she stopped consuming
alcohol 11 days before admission because it no longer
provided symptomatic relief. Her past medical history was
also notable for depression, including a suicide attempt 4
years earlier. She did not smoke, use illicit drugs, or have
unprotected sexual intercourse. She had received no blood
transfusions and had not traveled recently. She took no
medications, except for occasional ibuprofen. On physical
examination, she was thin and deeply jaundiced, and she
trembled and responded slowly to questions. She was afebrile
but tachypneic, and she had orthostatic hypotension. Her
HEENT examination was notable for scleral and sublingual
icterus, as well as crusted blood on her gums and teeth. The
jugular veins were flat. The cardiac examination revealed
tachycardia (heart rate, 103 beats per minute) without
murmurs, rubs, or gallops. The abdomen was nontender and
protuberant, with hypoactive bowel sounds; the spleen was
not palpable, and there was no fluid wave or caput medusae.
The liver percussed to 18 cm, with a smooth edge extending
10 cm below the costal margin. She had cutaneous
telangiectases on her chest and bilateral palmar erythema.
There was no peripheral edema. The neurologic examination
was notable for asterixis. Her stool was guaiac positive.
Laboratory studies revealed the following values:
hematocrit, 21.2%; white blood cells, 17,310/mm(3); ammonia,
42 micromol/L; serum creatinine, 3.9 mg/dL; serum urea
nitrogen, 70 mg/dL; albumin, 2.1 g/dL; total bilirubin, 26.8
mg/dL; alanine aminotransferase, 14 U/L; aspartate
aminotransferase, 77 U/L; alkaline phosphatase, 138 U/L;
prothrombin time, 103 seconds (international normalized
ratio, 10.6); and urinary sodium, <5 mg/dL. Urinalysis
revealed an elevated specific gravity and numerous muddy
granular casts. Hepatitis A, B, and C serologies were
negative. On abdominal ultrasound examination, there was no
ascites, and the liver was echogenic. The portal and hepatic
veins were patent, and the hepatic arteries were normal. The
spleen measured 14 cm. What is the diagnosis?},
Language = {eng},
Key = {fds191211}
}
@article{fds191229,
Author = {MJ McGirt and A Zaas and HE Fuchs and TM George and K Kaye and DJ
Sexton},
Title = {Risk factors for pediatric ventriculoperitoneal shunt
infection and predictors of infectious pathogens.},
Journal = {Clinical infectious diseases : an official publication of
the Infectious Diseases Society of America},
Volume = {36},
Number = {7},
Pages = {858-62},
Year = {2003},
Month = {April},
ISSN = {1537-6591},
url = {http://dx.doi.org/10.1086/368191},
Keywords = {Adolescent • Child • Child, Preschool •
Humans • Infant • Infant, Newborn •
Prosthesis-Related Infections • Risk Factors •
Staphylococcal Infections • Staphylococcus aureus*
• Ventriculoperitoneal Shunt • adverse effects*
• epidemiology • microbiology*},
Abstract = {Identification of risk factors for shunt infection and
predictors of infectious pathogens may improve current
methods to prevent and treat shunt infections. We reviewed
data on 820 consecutive ventriculoperitoneal (VP) shunt
placement procedures in 442 pediatric patients at our
institution during 1992-1998. Ninety-two shunts (11%)
developed infection a median of 19 days (interquartile
range, 11-35 days) after insertion. Premature birth
(relative risk [RR], 4.81; 95% confidence interval [CI],
2.19-10.87), previous shunt infection (RR, 3.83; 95% CI,
2.40-6.13), and intraoperative use of the neuroendoscope
(RR, 1.58; 95% CI, 1.01-2.50) were independent risk factors
for shunt infection. The bacterial organisms early after
shunt surgery (<14 days) were the same as those late after
shunt surgery (>14 days). As determined by an analysis of
the 92 infected shunts, hospital stay of >3 days at the time
of shunt insertion (odds ratio [OR], 5.27; 95% CI,
1.15-25.3) and prior Staphylococcus aureus shunt infection
(OR, 5.91; 95% CI, 1.35-25.9) independently increased the
odds that S. aureus was the causal pathogen.},
Language = {eng},
Doi = {10.1086/368191},
Key = {fds191229}
}
@article{fds191217,
Author = {C Passaretti and A Zaas},
Title = {Cases from the Osler medical service at Johns Hopkins
University.},
Journal = {The American journal of medicine},
Volume = {114},
Number = {7},
Pages = {613-6},
Year = {2003},
Month = {May},
ISSN = {0002-9343},
Keywords = {Endocytosis • Female • Humans • Middle Aged
• Multiple Myeloma • Plasma Cells •
diagnosis* • physiology* • physiopathology*},
Abstract = {A 56-year-old black woman with diabetes mellitus was
admitted for hypoglycemia and confusion. Her past medical
history included breast cancer, for which she had undergone
a left lumpectomy and then mastectomy for in-breast
recurrence. Her oral intake had decreased during the past
month because of increasing discomfort from left-sided chest
pain. During this period, she continued to take pioglitazone
for diabetes at her originally prescribed dose. The
patient's mental status improved quickly after taking orange
juice and intravenous glucose, but the chest pain persisted.
The pain, which was described as an ache along the left
costal margin, increased with palpation, deep inspiration,
or coughing. She had recently presented with similar
complaints at another hospital where she had been prescribed
a muscle relaxant that provided no relief from the pain. She
also reported a 14-lb weight loss during the previous 3
months, as well as fatigue, weakness, and aches in her legs
and arms. She denied fevers, chills, sweats, abdominal pain,
nausea, or recent trauma. Laboratory values at the time of
admission were: calcium, 11.8 mg/dL; total protein, 11.1
mg/dL; albumin, 3.2 g/dL; creatinine, 1.0 mg/dL; and
hematocrit, 29.3%, with a mean corpuscular volume of 89.3.
Chest radiography revealed a lytic lesion in the left
lateral fourth rib and left humerus (). Serum and urine
protein electrophoresis revealed a monoclonal spike in the
gamma region consistent with monoclonal gammopathy. The
serum spike was quantified at 3.78 g/dL. A skeletal survey
showed many small well-defined lytic lesions in the skull
(with one 1.5-cm lytic lesion in the upper posterior
parietal bone), arms, and legs. A bone scan showed multiple
foci of increased uptake in the right and left ribs as well
as the proximal portion of the left femur. The peripheral
blood smear revealed rouleaux formation () and plasma cells
(). What is the diagnosis?},
Language = {eng},
Key = {fds191217}
}
@article{fds191226,
Author = {J Piccini and A Zaas},
Title = {Cases from the Osler Medical Service at Johns Hopkins
University. Digitalis toxicity with bidirectional
ventricular tachycardia.},
Journal = {The American journal of medicine},
Volume = {115},
Number = {1},
Pages = {70-1},
Year = {2003},
Month = {July},
ISSN = {0002-9343},
Keywords = {Aged • Anti-Arrhythmia Agents • Atrial
Fibrillation • Digitalis Glycosides •
Electrocardiography • Female • Humans • Risk
Factors • Tachycardia, Ventricular • Telemetry
• adverse effects* • blood • chemically
induced* • diagnosis • drug therapy •
methods},
Language = {eng},
Key = {fds191226}
}
@article{fds191224,
Author = {J Piccini and A Zaas},
Title = {Cases from the Osler Medical Service at Johns Hopkins
University. Diffuse colonic angiodysplasia with chronic iron
deficiency anemia.},
Journal = {The American journal of medicine},
Volume = {115},
Number = {3},
Pages = {245-8},
Year = {2003},
Month = {August},
ISSN = {0002-9343},
Keywords = {Anemia, Iron-Deficiency • Angiodysplasia • Chronic
Disease • Colonic Diseases • Colonoscopy •
Dyspnea • Female • Hematologic Tests • Humans
• Iron • Middle Aged • Physical Examination
• blood • complications* • diagnosis •
etiology • etiology* • methods •
therapy},
Language = {eng},
Key = {fds191224}
}
@article{fds191237,
Author = {R Toonkel and A Zaas},
Title = {Cases from the Osler Medical Service at Johns Hopkins
University.},
Journal = {The American journal of medicine},
Volume = {115},
Number = {6},
Pages = {497-500},
Year = {2003},
Month = {October},
ISSN = {0002-9343},
Keywords = {Aged • Carcinoma, Hepatocellular • Humans •
Imaging, Three-Dimensional • Liver • Liver
Neoplasms • Male • Neoplastic Cells, Circulating*
• Portal Vein* • Tomography, X-Ray Computed •
complications* • diagnosis • pathology},
Language = {eng},
Key = {fds191237}
}
@article{fds191219,
Author = {AK Zaas and M Boyce and W Schell and BA Lodge and JL Miller, JR
Perfect},
Title = {Risk of fungemia due to Rhodotorula and antifungal
susceptibility testing of Rhodotorula isolates.},
Journal = {Journal of clinical microbiology},
Volume = {41},
Number = {11},
Pages = {5233-5},
Year = {2003},
Month = {November},
ISSN = {0095-1137},
Keywords = {Antifungal Agents • Humans • Microbial Sensitivity
Tests • Mycoses • Rhodotorula • drug effects*
• isolation & purification • microbiology* •
pathogenicity* • pharmacology*},
Abstract = {Rhodotorula infections occur among patients with
immunosuppression and/or central venous catheters. Using
standardized methods (NCCLS M27-A), we determined the
antifungal susceptibilities of 10 Rhodotorula bloodstream
infection isolates. Patient information was collected for
clinical correlation. The MICs of amphotericin B and
posaconazole were the lowest, and the MICs of triazoles and
echinocandins were higher than those of other antifungal
agents.},
Language = {eng},
Key = {fds191219}
}
@article{fds191212,
Author = {WJ Steinbach and DK Benjamin Jr and SA Trasi and JL Miller and WA
Schell, AK Zaas and WM Foster, JR Perfect},
Title = {Value of an inhalational model of invasive
aspergillosis.},
Journal = {Medical mycology : official publication of the International
Society for Human and Animal Mycology},
Volume = {42},
Number = {5},
Pages = {417-25},
Year = {2004},
Month = {October},
ISSN = {1369-3786},
Keywords = {Administration, Inhalation • Animals •
Aspergillosis* • Aspergillus fumigatus • Disease
Models, Animal* • Humans • Lung • Lung
Diseases, Fungal* • Male • Mice • drug
effects • drug therapy • microbiology •
pathogenicity* • pathology},
Abstract = {Animal models of invasive aspergillosis have been used for
virulence studies and antifungal efficacy evaluations but
results have been inconsistent. In an attempt to reproduce
human infection, many Aspergillus animal models have
utilized a 'pulmonary route' for delivery of conidia,
largely through intranasal instillation. However, several
radiolabeled particle studies have shown that aerosol
delivery is preferable to intranasal instillation to create
a more homogenous delivery to the lungs. We hypothesized
that an inhalational model would be more robust for studies
of invasive aspergillosis pathogenesis and antifungal
therapy. We developed an inhalational model of Aspergillus
fumigatus infection using a Hinners inhalation chamber and
demonstrated by quantitative polymerase chain reaction that
this new inhalational model creates a more homogenous murine
pneumonia, facilitating analysis of mutant strains and
treatment regimens.},
Language = {eng},
Key = {fds191212}
}
@article{fds191214,
Author = {AK Zaas and BD Alexander},
Title = {New developments in the diagnosis and treatment of
infections in lung transplant recipients.},
Journal = {Respiratory care clinics of North America},
Volume = {10},
Number = {4},
Pages = {531-47},
Year = {2004},
Month = {December},
ISSN = {1078-5337},
url = {http://dx.doi.org/10.1016/j.rcc.2004.06.001},
Keywords = {Adult • Female • Graft Rejection • Graft
Survival • Humans • Incidence • Lung
Diseases, Fungal • Lung Transplantation • Male
• Middle Aged • Pneumonia, Bacterial •
Pneumonia, Viral • Postoperative Complications •
Prognosis • Risk Assessment • Severity of Illness
Index • Survival Analysis • adverse effects*
• diagnosis* • epidemiology • methods •
mortality • therapy},
Abstract = {Infections remain a serious and common problem in lung
transplant recipients. Recent years have seen an explosion
in the knowledge regarding this major cause of morbidity and
mortality. Novel diagnostic and therapeutic techniques are
revolutionizing the approach to infectious diseases in
transplant recipients. Multicenter trials will expand the
scope of diagnosis and management of these infections. A
team approach by transplant physicians and infectious
diseases experts is critical to the success of managing
these complex patients.},
Language = {eng},
Doi = {10.1016/j.rcc.2004.06.001},
Key = {fds191214}
}
@article{fds191222,
Author = {AK Zaas and WJ Steinbach},
Title = {Micafungin: the US perspective.},
Journal = {Expert review of anti-infective therapy},
Volume = {3},
Number = {2},
Pages = {183-90},
Year = {2005},
Month = {April},
ISSN = {1744-8336},
url = {http://dx.doi.org/10.1586/14787210.3.2.183},
Keywords = {Animals • Antifungal Agents • Clinical Trials as
Topic • Echinocandins • Humans • Lipopeptides
• Lipoproteins • Mycoses • Peptides, Cyclic
• Safety • drug therapy* • standards •
therapeutic use*},
Abstract = {Invasive fungal infections cause considerable morbidity and
mortality in nosocomial settings and amongst
immunocompromised hosts. Invasive candidiasis and
aspergillosis remain the most common invasive fungal
infections, with Candida spp. constituting the fourth most
common bloodstream infection in the USA. Currently available
antifungal therapies include the polyene, antimetabolite,
allylamine, azole and echinocandin drug classes. Micafungin,
approved in March 2005 by the Food and Drug Administration
for use in the USA, has shown safety and efficacy for the
treatment of candidiasis and aspergillosis in clinical
trials in Japan, Europe and South Africa. Micafungin holds
promise as a first-line treatment option for candidiasis, as
well as prophylaxis against invasive fungal infections
during periods of neutropenia in high-risk
patients.},
Language = {eng},
Doi = {10.1586/14787210.3.2.183},
Key = {fds191222}
}
@article{fds191207,
Author = {AK Zaas and DA Schwartz},
Title = {Innate immunity and the lung: defense at the interface
between host and environment.},
Journal = {Trends in cardiovascular medicine},
Volume = {15},
Number = {6},
Pages = {195-202},
Year = {2005},
Month = {August},
ISSN = {1050-1738},
url = {http://dx.doi.org/10.1016/j.tcm.2005.07.001},
Keywords = {Animals • Defensins • Environment • Humans
• Immunity, Cellular • Immunity, Innate •
Lung • Lung Diseases • immunology •
immunology* • metabolism • physiology •
physiology*},
Abstract = {The lung serves as a major interface between the host and
the external environment. As such, numerous lines of defense
protect the host from inhaled potential pathogens. A breach
in pulmonary innate immunity can lead to deleterious
outcomes, such as pneumonia and disseminated infection.
Pulmonary innate immunity, the first line of defense, is
mediated by airway and alveolar epithelial cells as well as
resident and recruited leukocytes. This article will discuss
the key cellular and secreted components of the pulmonary
innate immune system.},
Language = {eng},
Doi = {10.1016/j.tcm.2005.07.001},
Key = {fds191207}
}
@article{fds191225,
Author = {AK Zaas and BD Alexander},
Title = {Echinocandins: role in antifungal therapy,
2005.},
Journal = {Expert opinion on pharmacotherapy},
Volume = {6},
Number = {10},
Pages = {1657-68},
Year = {2005},
Month = {August},
ISSN = {1744-7666},
url = {http://dx.doi.org/10.1517/14656566.6.10.1657 },
Keywords = {Animals • Antifungal Agents • Echinocandins •
Fungal Proteins • Humans • Mycoses •
Peptides, Cyclic • chemistry • drug therapy •
microbiology • pharmacology • therapeutic
use*},
Abstract = {Novel therapies to treat invasive fungal infections have
revolutionised the care of patients with candidiasis,
aspergillosis and other less common fungal infections.
Physicians in the twenty first century have access to safer
versions of conventional drugs (i.e., lipid amphotericin B
products), extended-spectrum versions of established drugs
(i.e., voriconazole), as well as a new class of antifungal
agents; the echinocandins. The increased number of options
in the antifungal armamentarium is well timed, as the
incidence of both invasive candidiasis and invasive
aspergillosis, and the financial burden associated with
these infections, have increased significantly in the past
several decades. The increasing incidence of fungal
infections has risen in parallel with the increase in
critically ill and immunocompromised patients. Candida is
the fourth most common bloodstream isolate, approximately
50% of which are non-albicans species. Estimates suggest
there to be 9.8 episodes of invasive candidiasis per 1000
admissions to surgical intensive care units, with
attributable mortality at 30% and cost per episode of
US44,000 dollars. The burden of candidiasis is even higher
in the paediatric population, with Candida being the second
most common bloodstream infection. The increase in
non-albicans candidiasis mandates the introduction of new
antifungal agents capable of treating these often
azole-resistant isolates. In addition, there has been a rise
in the incidence of invasive aspergillosis, the most common
invasive mould infection following haematopoietic stem cell
transplantation, with an estimated incidence of 10 - 20%.
The mortality associated with invasive aspergillosis has
increased by 357% since 1980. Unfortunately, the overall
survival rate among patients treated with amphotericin B,
and even voriconazole, remains suboptimal, as evidenced by
the failure of treatment in 47% of patients in the landmark
voriconazole versus amphotericin B trial. Given the
increasing incidence and suboptimal outcomes of these
serious fungal infections, novel therapies represent an
opportunity for significant advancement in clinical care.
The current challenge is to discover the optimal place for
the echinocandins in the treatment of invasive fungal
infections.},
Language = {eng},
Doi = {10.1517/14656566.6.10.1657 },
Key = {fds191225}
}
@article{fds191213,
Author = {WJ Steinbach, JR Perfect and CH Cabell and VG Fowler and GR Corey and JS
Li, AK Zaas and DK Benjamin Jr},
Title = {A meta-analysis of medical versus surgical therapy for
Candida endocarditis.},
Journal = {The Journal of infection},
Volume = {51},
Number = {3},
Pages = {230-47},
Year = {2005},
Month = {October},
ISSN = {1532-2742},
url = {http://dx.doi.org/10.1016/j.jinf.2004.10.016},
Keywords = {Adolescent • Adult • Antifungal Agents •
Candida • Candidiasis • Child • Child,
Preschool • Endocarditis • Humans • Infant
• Infant, Newborn • Treatment Outcome •
classification • drug effects • drug therapy
• drug therapy* • microbiology • mortality
• surgery • surgery* • therapeutic
use*},
Abstract = {OBJECTIVE: The optimal management of Candida infective
endocarditis (IE) is unknown. METHODS: We reviewed all 879
cases of Candida IE reported from 1966-2002 in the
peer-reviewed literature to better understand the role of
medical and surgical therapies. This review included 163
patients from 105 reports that met our inclusion criteria:
31 cases treated with antifungal monotherapy, 25 cases
treated with medical antifungal combination therapy, and 107
cases treated with adjunctive surgical plus medical
antifungal therapy. We also used meta-analytic techniques to
evaluate 22 observational case-series (72 patients) of the
105 reports with two or more patients with definite Candida
IE. RESULTS: We found that in patients who underwent
adjunctive surgery there was a lower reported proportion of
deaths [prevalence odds ratio (POR)=0.56; 95% confidence
interval (CI)=0.16, 1.99)]. Higher mortality was noted in
patients treated prior to 1980 (POR=2.03; 95% CI=0.55,
7.61), treated with antifungal monotherapy (POR=1.49; 95%
CI=0.39, 5.81), infected with Candida parapsilosis
(POR=1.51; 95% CI=0.41, 5.52), or with left-sided
endocarditis (POR=2.36; 95% CI=0.55, 10.07). CONCLUSIONS:
Medical antifungal therapy of Candida IE is poorly
characterized, and recent antifungal developments lend
promise for those patients who cannot undergo
surgery.},
Language = {eng},
Doi = {10.1016/j.jinf.2004.10.016},
Key = {fds191213}
}
@article{fds191216,
Author = {AK Zaas and ES Dodds Ashley and BD Alexander, MD Johnson, JR
Perfect},
Title = {Caspofungin for invasive candidiasis at a tertiary care
medical center.},
Journal = {The American journal of medicine},
Volume = {119},
Number = {11},
Pages = {993.e1-6},
Year = {2006},
Month = {November},
ISSN = {1555-7162},
url = {http://dx.doi.org/10.1016/j.amjmed.2006.02.029},
Keywords = {Antifungal Agents • Candida albicans • Candida
glabrata • Candida tropicalis • Candidiasis •
Drug Administration Schedule • Echinocandins •
Female • Humans • Male • Medical Records
• North Carolina • Peptides, Cyclic •
Retrospective Studies • Severity of Illness Index
• Treatment Outcome • administration & dosage
• diagnosis • drug effects • drug therapy*
• epidemiology • therapeutic use*},
Abstract = {BACKGROUND: Caspofungin is emerging as first-line therapy
for invasive candidiasis. Data on the use of caspofungin for
treatment for invasive candidiasis are limited to clinical
trials and case reports. We report a single-center
experience with 104 consecutive courses of caspofungin for
the treatment of invasive candidiasis to evaluate a
real-world performance of this drug. METHODS: A
retrospective chart review of patients receiving caspofungin
at a tertiary care medical center was performed. Patient
information and microbiologic data were abstracted from
patient charts and electronic medical records. RESULTS: Of
241 patients receiving caspofungin for all indications, 122
(51%) had proven invasive candidiasis. There were 104
treatment courses for candidiasis in 99 patients available
for review. Bloodstream (66%) and abdominal infections (25%)
were the most common sites of infection. Most infections
were non-albicans (80/104, 77%; including patients infected
with more than one species). Clinical cure rates at the end
of therapy were 83% (57/69) for bloodstream infections and
84% (22/26) for abdominal infections. Caspofungin did not
clear candidiasis in 14 episodes (microbiologic cure rate
75%, 42/56). CONCLUSIONS: The clinical use of caspofungin
has been successful in the treatment of invasive
candidiasis, even in patients with prior antifungal
exposure. In this unselected review, caspofungin performed
similarly as in clinical trials, and clinicians should
consider caspofungin as first-line therapy for invasive
candidiasis, particularly non-albicans species.},
Language = {eng},
Doi = {10.1016/j.amjmed.2006.02.029},
Key = {fds191216}
}
@article{fds191203,
Author = {SS Giles and AK Zaas and MF Reidy, JR Perfect, JR
Wright},
Title = {Cryptococcus neoformans is resistant to surfactant protein A
mediated host defense mechanisms.},
Journal = {PloS one},
Volume = {2},
Number = {12},
Pages = {e1370},
Year = {2007},
ISSN = {1932-6203},
url = {http://dx.doi.org/10.1371/journal.pone.0001370},
Keywords = {Animals • Bronchoalveolar Lavage Fluid •
Cryptococcus neoformans • Macrophages, Alveolar •
Mice • Mice, Knockout • Phagocytosis •
Pulmonary Surfactant-Associated Protein A • Rats •
Rats, Sprague-Dawley • genetics • immunology
• microbiology • physiology*},
Abstract = {Initiation of a protective immune response to infection by
the pathogenic fungus Cryptococcus neoformans is mediated in
part by host factors that promote interactions between
immune cells and C. neoformans yeast. Surfactant protein A
(SP-A) contributes positively to pulmonary host defenses
against a variety of bacteria, viruses, and fungi in part by
promoting the recognition and phagocytosis of these
pathogens by alveolar macrophages. In the present study we
investigated the role of SP-A as a mediator of host defense
against the pulmonary pathogen, C. neoformans. Previous
studies have shown that SP-A binds to acapsular and
minimally encapsulated strains of C. neoformans. Using in
vitro binding assays we confirmed that SP-A does not
directly bind to a fully encapsulated strain of C.
neoformans (H99). However, we observed that when C.
neoformans was incubated in bronchoalveolar fluid, SP-A
binding was detected, suggesting that another alveolar host
factor may enable SP-A binding. Indeed, we discovered that
SP-A binds encapsulated C. neoformans via a previously
unknown IgG dependent mechanism. The consequence of this
interaction was the inhibition of IgG-mediated phagocytosis
of C. neoformans by alveolar macrophages. Therefore, to
assess the contribution of SP-A to the pulmonary host
defenses we compared in vivo infections using SP-A null mice
(SP-A-/-) and wild-type mice in an intranasal infection
model. We found that the immune response assessed by
cellular counts, TNFalpha cytokine production, and fungal
burden in lungs and bronchoalveolar lavage fluids during
early stages of infection were equivalent. Furthermore, the
survival outcome of C. neoformans infection was equivalent
in SP-A-/- and wild-type mice. Our results suggest that
unlike a variety of bacteria, viruses, and other fungi,
progression of disease with an inhalational challenge of C.
neoformans does not appear to be negatively or positively
affected by SP-A mediated mechanisms of pulmonary host
defense.},
Language = {eng},
Doi = {10.1371/journal.pone.0001370},
Key = {fds191203}
}
@article{fds191206,
Author = {H Aziz and A Zaas and GS Ginsburg},
Title = {Peripheral blood gene expression profiling for
cardiovascular disease assessment.},
Journal = {Genomic medicine},
Volume = {1},
Number = {3-4},
Pages = {105-12},
Year = {2007},
ISSN = {1871-7934},
url = {http://dx.doi.org/10.1007/s11568-008-9017-x},
Abstract = {Whole blood gene expression profiling has the potential to
be informative about dynamic changes in disease states and
to provide information on underlying disease mechanisms.
Having demonstrated proof of concept in animal models, a
number of studies have now tried to tackle the complexity of
cardiovascular disease in human hosts to develop better
diagnostic and prognostic indicators. These studies show
that genomic signatures are capable of classifying patients
with cardiovascular diseases into finer categories based on
the molecular architecture of a patient's disease and more
accurately predict the likelihood of a cardiovascular event
than current techniques. To highlight the spectrum of
potential applications of whole blood gene expression
profiling approach in cardiovascular science, we have chosen
to review the findings in a number of complex cardiovascular
diseases such as atherosclerosis, hypertension and
myocardial infarction as well as thromboembolism, aortic
aneurysm, and heart transplant.},
Language = {eng},
Doi = {10.1007/s11568-008-9017-x},
Key = {fds191206}
}
@article{fds191205,
Author = {ES Dodds Ashley and AK Zaas and AF Fang and B Damle, JR
Perfect},
Title = {Comparative pharmacokinetics of voriconazole administered
orally as either crushed or whole tablets.},
Journal = {Antimicrobial agents and chemotherapy},
Volume = {51},
Number = {3},
Pages = {877-80},
Year = {2007},
Month = {March},
ISSN = {0066-4804},
url = {http://dx.doi.org/10.1128/AAC.01263-06},
Keywords = {Adolescent • Adult • Antifungal Agents • Area
Under Curve • Cross-Over Studies • Female •
Humans • Male • Middle Aged • Pyrimidines
• Tablets • Triazoles • administration &
dosage • adverse effects • pharmacokinetics*},
Abstract = {Voriconazole is a triazole antifungal agent used to treat
serious, invasive fungal infections including aspergillosis
and candidemia. Limitations with existing formulations of
voriconazole including restricted utility in patients with
renal dysfunction (intravenous preparation) and the
unavailability of an oral suspension in some countries make
the administration of crushed tablets desirable in many
clinical scenarios. However, concerns that this approach may
alter the systemic absorption of voriconazole exist.
Therefore, an open-label, randomized, two-way crossover
comparative pharmacokinetic (PK) study using healthy
volunteers was performed to compare these methods of tablet
administration. In a random sequence, subjects received
voriconazole tablets either crushed or whole. The
voriconazole dose was 400 mg every 12 h for 1 day orally
followed by 200 mg every 12 h orally for 5.5 days. Study
periods were separated by 7 days. PK parameters were
determined by the noncompartmental method. An equivalence
approach with no-effect boundaries of 80 to 125% was used to
assess bioequivalence. Twenty healthy subjects (10 males;
aged 20 to 43 years) were enrolled in and completed the
study. The adjusted mean areas under the plasma
concentration-time curve from 0 to tau, where tau equals 12
h, for the crushed and whole tablet groups were 9,793 and
11,164 ng . h/ml, respectively (ratio, 87.72; 90% confidence
interval [CI], 80.97, 95.04). The ratio of the maximum
concentration of drug in serum for the crushed tablet versus
whole tablet arms was 94.94 (90% CI, 86.51, 104.22). The
only difference noted between groups was a slightly faster
time to maximum concentration of drug in serum when subjects
received crushed tablets, 0.5 h versus 1.5 h (90% CI, -0.75,
-0.25). Treatment-related adverse events occurred in 12
subjects receiving whole tablets and 9 subjects receiving
crushed tablets; all were mild. The administration of
crushed voriconazole tablets is bioequivalent to
whole-tablet administration.},
Language = {eng},
Doi = {10.1128/AAC.01263-06},
Key = {fds191205}
}
@article{fds191231,
Author = {JW Hollingsworth and S Shofer and A Zaas},
Title = {Successful treatment of Ochroconis gallopavum infection in
an immunocompetent host.},
Journal = {Infection},
Volume = {35},
Number = {5},
Pages = {367-9},
Year = {2007},
Month = {October},
ISSN = {0300-8126},
url = {http://dx.doi.org/10.1007/s15010-007-6054-7},
Keywords = {Aged • Antifungal Agents • Ascomycota •
Female • Humans • Mycoses • Pneumonia •
Radiography, Thoracic • drug therapy* • isolation
& purification* • microbiology* • therapeutic
use*},
Abstract = {Ochroconis gallopavum, a dematiaceous fungus, is a rare
cause disease in immunocompromised patients and epidemic
encephalitis in poultry. We report the first case of active
O. gallopavum pulmonary infection in an immunocompetent host
with rapid and complete response to oral antifungal
therapy.},
Language = {eng},
Doi = {10.1007/s15010-007-6054-7},
Key = {fds191231}
}
@article{fds191228,
Author = {AJ Reddy and AK Zaas and KE Hanson and SM Palmer},
Title = {A single-center experience with ganciclovir-resistant
cytomegalovirus in lung transplant recipients: treatment and
outcome.},
Journal = {The Journal of heart and lung transplantation : the official
publication of the International Society for Heart
Transplantation},
Volume = {26},
Number = {12},
Pages = {1286-92},
Year = {2007},
Month = {December},
ISSN = {1557-3117},
url = {http://dx.doi.org/10.1016/j.healun.2007.09.012},
Keywords = {Adult • Antiviral Agents • Cytomegalovirus •
Cytomegalovirus Infections • Drug Resistance, Viral
• Drug Therapy, Combination • Female •
Foscarnet • Ganciclovir • Genetic Predisposition
to Disease • Humans • Lung Transplantation* •
Male • Middle Aged • Mutation • Opportunistic
Infections • Phosphotransferases (Alcohol Group
Acceptor) • Postoperative Complications* •
Retrospective Studies • Treatment Outcome • drug
therapy* • etiology • genetics • therapeutic
use*},
Abstract = {BACKGROUND: Cytomegalovirus (CMV) disease is a major cause
of morbidity and mortality after lung transplantation
despite ganciclovir prophylaxis. The emergence of
ganciclovir-resistant CMV in lung transplant patients has
been reported, although the optimal strategy for the
management of these infections remains uncertain. A review
of the results of glanciclovir susceptibility testing in
lung transplant recipients was performed. METHODS: We found
54% (113 of 210) of lung transplant patients developed CMV
infection over a 4-year study period with
ganciclovir-resistant CMV infection occurring in >5% of
patients (6 of 113). The demographic and clinical
characteristics of patients who developed
ganciclovir-resistant vs -sensitive CMV infection were
similar, although 50% (3 of 6) patients who developed
resistance were CMV mismatched (D(+)/R(-) serology). All
patients' CMV isolates had mutations in the UL97 gene. In
addition, the 3 mismatch patients also had CMV with
mutations in the UL54 gene. RESULTS: Treatment with a
combination of foscarnet and ganciclovir or foscarnet alone
for ganciclovir-resistant infection led to a significant
reduction in virologic load in all patients (p = 0.03),
although transient increases in viremia were observed in
some patients early after treatment. Renal function worsened
after treatment, but overall it was not significantly
different from pre-treatment values (p = 0.07). CONCLUSIONS:
Single or combination therapy with foscarnet is effective
for treatment of ganciclovir-resistant isolates and
excessive concern regarding toxicity should not preclude
consideration of these treatments when clinically
indicated.},
Language = {eng},
Doi = {10.1016/j.healun.2007.09.012},
Key = {fds191228}
}
@article{fds191220,
Author = {S Garantziotis and JW Hollingsworth and AK Zaas and DA
Schwartz},
Title = {The effect of toll-like receptors and toll-like receptor
genetics in human disease.},
Journal = {Annual review of medicine},
Volume = {59},
Pages = {343-59},
Year = {2008},
ISSN = {0066-4219},
url = {http://dx.doi.org/10.1146/annurev.med.59.061206.112455},
Keywords = {Disease Susceptibility • Humans • Polymorphism,
Genetic • Signal Transduction • Toll-Like
Receptors • etiology* • physiology •
physiology*},
Abstract = {Toll-like receptors (TLRs) enable innate immune recognition
of endogenous and exogenous prototypic ligands. They also
orchestrate innate and adaptive immune response to
infection, inflammation, and tissue injury. Given their
significance in the immune response, it is not surprising
that genetic variations of TLRs can affect their function
and by extension affect the response of the organism to
environmental stimuli. The genetics of TLRs provides
important insights in gene-environment interactions in
health and disease, and it may enable scientists to assess
patients' susceptibility to diseases or predict their
response to treatments.},
Language = {eng},
Doi = {10.1146/annurev.med.59.061206.112455},
Key = {fds191220}
}
@article{fds191233,
Author = {AK Zaas and G Liao and JW Chien and C Weinberg and D Shore and SS Giles and KA
Marr, J Usuka and LH Burch and L Perera, JR Perfect and G Peltz and DA
Schwartz},
Title = {Plasminogen alleles influence susceptibility to invasive
aspergillosis.},
Journal = {PLoS genetics},
Volume = {4},
Number = {6},
Pages = {e1000101},
Year = {2008},
Month = {June},
ISSN = {1553-7404},
url = {http://dx.doi.org/10.1371/journal.pgen.1000101},
Keywords = {Alleles* • Animals • Aspergillosis •
Aspergillus fumigatus • Female • Genetic
Predisposition to Disease* • Humans • Lung
Diseases, Fungal • Mice • Mice, Inbred A •
Mice, Inbred AKR • Mice, Inbred BALB C • Mice,
Inbred C3H • Mice, Inbred C57BL • Mice, Inbred DBA
• Mice, Inbred MRL lpr • Mice, Inbred NZB •
Mice, Knockout • Plasminogen • Signal Transduction
• genetics* • immunology • microbiology*
• mortality • pathogenicity • pathology
• physiology},
Abstract = {Invasive aspergillosis (IA) is a common and life-threatening
infection in immunocompromised individuals. A number of
environmental and epidemiologic risk factors for developing
IA have been identified. However, genetic factors that
affect risk for developing IA have not been clearly
identified. We report that host genetic differences
influence outcome following establishment of pulmonary
aspergillosis in an exogenously immune suppressed mouse
model. Computational haplotype-based genetic analysis
indicated that genetic variation within the biologically
plausible positional candidate gene plasminogen (Plg; Gene
ID 18855) correlated with murine outcome. There was a single
nonsynonymous coding change (Gly110Ser) where the minor
allele was found in all of the susceptible strains, but not
in the resistant strains. A nonsynonymous single nucleotide
polymorphism (Asp472Asn) was also identified in the human
homolog (PLG; Gene ID 5340). An association study within a
cohort of 236 allogeneic hematopoietic stem cell transplant
(HSCT) recipients revealed that alleles at this SNP
significantly affected the risk of developing IA after HSCT.
Furthermore, we demonstrated that plasminogen directly binds
to Aspergillus fumigatus. We propose that genetic variation
within the plasminogen pathway influences the pathogenesis
of this invasive fungal infection.},
Language = {eng},
Doi = {10.1371/journal.pgen.1000101},
Key = {fds191233}
}
@article{fds191236,
Author = {AK Zaas},
Title = {Echinocandins: a wealth of choice--how clinically different
are they?},
Journal = {Current opinion in infectious diseases},
Volume = {21},
Number = {4},
Pages = {426-32},
Year = {2008},
Month = {August},
ISSN = {1535-3877},
url = {http://dx.doi.org/10.1097/QCO.0b013e328307c79c},
Keywords = {Antifungal Agents • Aspergillosis • Candidiasis
• Chemoprevention • Drug Therapy, Combination
• Echinocandins • Fungi • Humans •
Triazoles • drug effects • drug therapy •
drug therapy* • pharmacology • prevention &
control • therapeutic use • therapeutic
use*},
Abstract = {OBJECTIVE: The recent decade has been a 'golden age' for
antifungal therapy. The introduction of a novel class of
antifungals, the echinocandins, has revolutionized the
therapy for invasive candidiasis, provided increasing
options for antifungal prophylaxis in high-risk patients and
energized the debate regarding combination antifungal
therapy for invasive mycoses. RESULTS: Randomized,
controlled data exist for each echinocandin in the treatment
of invasive candidiasis, and experts largely believe the
agents to be equivalent in this setting. Future trials of
combined echinocandin-triazole therapy for invasive
aspergillosis are desired. Additionally, maximal dosing
limitations are being pursued. CONCLUSIONS: The
echinocandins as a class offer an advance in the treatment
of invasive candidiasis, an additional option for
prophylaxis and an attractive choice for the study of
combination antifungal therapy. Particularly for the major
indication (treatment of invasive candidiasis), major
clinical differences between agents have not been
noted.},
Language = {eng},
Doi = {10.1097/QCO.0b013e328307c79c},
Key = {fds191236}
}
@article{fds191209,
Author = {JW Baddley, JR Perfect and RA Oster and RA Larsen and GA Pankey and H
Henderson, DW Haas and CA Kauffman and R Patel and AK Zaas and PG
Pappas},
Title = {Pulmonary cryptococcosis in patients without HIV infection:
factors associated with disseminated disease.},
Journal = {European journal of clinical microbiology & infectious
diseases : official publication of the European Society of
Clinical Microbiology},
Volume = {27},
Number = {10},
Pages = {937-43},
Year = {2008},
Month = {October},
ISSN = {1435-4373},
url = {http://dx.doi.org/10.1007/s10096-008-0529-z},
Keywords = {Adult • Aged • Antigens, Fungal •
Cryptococcosis • Cryptococcus neoformans • Female
• Humans • Male • Meningitis, Cryptococcal
• Middle Aged • Pneumonia • Retrospective
Studies • Risk Factors • blood • diagnosis*
• isolation & purification* • microbiology*},
Abstract = {Cryptococcus neoformans is an uncommonly recognized cause of
pneumonia in HIV-negative patients. Because of its
propensity to disseminate to the meninges and other sites, a
lumbar puncture is recommended for patients with pulmonary
cryptococcosis, regardless of other risk factors. This study
explored clinical and laboratory features to help predict
which patients had pulmonary disease alone versus those who
had pulmonary plus extrapulmonary disease. A retrospective
chart review at 15 medical centers was performed from 1990
to 2000 of all HIV-negative patients who had pulmonary
cryptococcosis. Demographic, clinical, radiographic, and
laboratory features were evaluated to determine factors that
differentiated those patients who had extrapulmonary
disease. Among 166 patients who had pulmonary
cryptococcosis, 122 had pulmonary infection only and 44 had
pulmonary plus extrapulmonary (disseminated) disease. A
negative serum cryptococcal antigen titer was more common in
patients with pulmonary disease alone (p < 0.01).
Multivariate analysis demonstrated that patients who had
disseminated disease were more likely than those who only
had pulmonary disease to have cirrhosis (p = 0.049),
headache (p < 0.001), weight loss (p = 0.003), fever (p =
0.035), altered mental status (p < 0.001), and to be
receiving high-dose corticosteroids (p = 0.008). In this
large cohort of HIV-negative patients with pulmonary
cryptococcosis, there were easily distinguished clinical and
laboratory features among patients with pulmonary disease
alone versus those with pulmonary plus extrapulmonary
disease. These findings may be helpful in the evaluation of
HIV-negative patients with pulmonary cryptococcosis with
regard to the need for lumbar puncture or to search for
disseminated disease.},
Language = {eng},
Doi = {10.1007/s10096-008-0529-z},
Key = {fds191209}
}
@article{fds191218,
Author = {LE Cowen and SD Singh, JR Köhler and C Collins and AK Zaas and WA
Schell, H Aziz and E Mylonakis, JR Perfect and L Whitesell and S
Lindquist},
Title = {Harnessing Hsp90 function as a powerful, broadly effective
therapeutic strategy for fungal infectious
disease.},
Journal = {Proceedings of the National Academy of Sciences of the
United States of America},
Volume = {106},
Number = {8},
Pages = {2818-23},
Year = {2009},
Month = {February},
ISSN = {1091-6490},
url = {http://dx.doi.org/10.1073/pnas.0813394106},
Keywords = {Animals • Antifungal Agents • Fluconazole •
Fungi • HSP90 Heat-Shock Proteins • Humans •
Male • Mice • Microbial Sensitivity Tests •
Mycoses • drug effects • drug therapy •
genetics • microbiology • pharmacology •
physiology* • physiopathology • therapeutic use
• therapy*},
Abstract = {Invasive fungal infections are a leading cause of mortality
among immunocompromised individuals. Treatment is
notoriously difficult with the limited armamentarium of
antifungal drugs, whose efficacy is compromised by host
toxicity, a limited activity spectrum, or the emergence of
drug resistance. We previously established that the
molecular chaperone Hsp90 enables the emergence and
maintenance of fungal drug resistance. For the most
prevalent fungal pathogen of humans, Candida albicans, Hsp90
mediates resistance to azoles, which inhibit ergosterol
biosynthesis and are the most widely deployed antifungals in
the clinic. For the emerging opportunistic pathogen
Aspergillus terreus, Hsp90 is required for basal resistance
to echinocandins, which inhibit beta(1, 3)-glucan synthesis
and are the only new class of antifungals to reach the
clinic in decades. Here, we explore the therapeutic
potential of Hsp90 inhibitors in fungal disease using a
tractable host-model system, larvae of the greater wax moth
Galleria mellonella, and a murine model of disseminated
disease. Combination therapy with Hsp90 inhibitors that are
well tolerated in humans and an azole rescued larvae from
lethal C. albicans infections. Combination therapy with an
Hsp90 inhibitor and an echinocandin rescued larvae from
infections with the most lethal mold, Aspergillus fumigatus.
In a murine model of disseminated candidiasis, genetic
compromise of C. albicans HSP90 expression enhanced the
therapeutic efficacy of an azole. Thus, harnessing Hsp90
provides a much-needed strategy for improving the treatment
of fungal disease because it enhances the efficacy of
existing antifungals, blocks the emergence of drug
resistance, and exerts broad-spectrum activity against
diverse fungal pathogens.},
Language = {eng},
Doi = {10.1073/pnas.0813394106},
Key = {fds191218}
}
@article{fds191234,
Author = {RS Shapiro and P Uppuluri and AK Zaas and C Collins and H Senn, JR
Perfect and J Heitman and LE Cowen},
Title = {Hsp90 orchestrates temperature-dependent Candida albicans
morphogenesis via Ras1-PKA signaling.},
Journal = {Current biology : CB},
Volume = {19},
Number = {8},
Pages = {621-9},
Year = {2009},
Month = {April},
ISSN = {1879-0445},
url = {http://dx.doi.org/10.1016/j.cub.2009.03.017},
Keywords = {Animals • Candida albicans • Candidiasis •
Cyclic AMP-Dependent Protein Kinases • Cyclic
Nucleotide Phosphodiesterases, Type 1 • Cyclic
Nucleotide Phosphodiesterases, Type 2 • Fungal Proteins
• GTPase-Activating Proteins • HSP90 Heat-Shock
Proteins • Humans • Hyphae • Isoenzymes
• Mice • Morphogenesis • Quorum Sensing
• Signal Transduction • cytology • genetics
• growth & development* • metabolism •
metabolism* • physiology • physiology* • ras
Proteins},
Abstract = {BACKGROUND: Hsp90 is an environmentally contingent molecular
chaperone that influences the form and function of diverse
regulators of cellular signaling. Hsp90 potentiates the
evolution of fungal drug resistance by enabling crucial
cellular stress responses. Here we demonstrate that in the
leading fungal pathogen of humans, Candida albicans, Hsp90
governs cellular circuitry required not only for drug
resistance but also for the key morphogenetic transition
from yeast to filamentous growth that is crucial for
virulence. This transition is normally regulated by
environmental cues, such as exposure to serum, that are
contingent upon elevated temperature to induce
morphogenesis. The basis for this temperature dependence has
remained enigmatic. RESULTS: We show that compromising Hsp90
function pharmacologically or genetically induces a
transition from yeast to filamentous growth in the absence
of external cues. Elevated temperature relieves
Hsp90-mediated repression of the morphogenetic program.
Hsp90 regulates morphogenetic circuitry by repressing
Ras1-PKA signaling. Modest Hsp90 compromise enhances the
phenotypic effects of activated Ras1 signaling whereas
deletion of positive regulators of the Ras1-PKA cascade
blocks the morphogenetic response to Hsp90 inhibition.
Consistent with the requirement for morphogenetic
flexibility for virulence, depletion of C. albicans Hsp90
attenuates virulence in a murine model of systemic disease.
CONCLUSIONS: Hsp90 governs the integration of environmental
cues with cellular signaling to orchestrate fungal
morphogenesis and virulence, suggesting new therapeutic
strategies for life-threatening infectious disease. Hsp90's
capacity to govern a key developmental program in response
to temperature change provides a new mechanism that
complements the elegant repertoire that organisms utilize to
sense temperature.},
Language = {eng},
Doi = {10.1016/j.cub.2009.03.017},
Key = {fds191234}
}
@article{fds191230,
Author = {SD Singh and N Robbins and AK Zaas and WA Schell, JR Perfect and LE
Cowen},
Title = {Hsp90 governs echinocandin resistance in the pathogenic
yeast Candida albicans via calcineurin.},
Journal = {PLoS pathogens},
Volume = {5},
Number = {7},
Pages = {e1000532},
Year = {2009},
Month = {July},
ISSN = {1553-7374},
url = {http://dx.doi.org/10.1371/journal.ppat.1000532},
Keywords = {Analysis of Variance • Animals • Antifungal Agents
• Azoles • Calcineurin • Candida albicans
• Candidiasis • DNA-Binding Proteins •
Disease Models, Animal • Drug Resistance, Fungal •
Echinocandins • Fungal Proteins • HSP90 Heat-Shock
Proteins • Lipopeptides • Male • Mice •
Stress, Physiological • Transcription Factors •
antagonists & inhibitors • drug effects • drug
therapy • genetics • metabolism • metabolism*
• microbiology • pharmacology •
pharmacology*},
Abstract = {Candida albicans is the leading fungal pathogen of humans,
causing life-threatening disease in immunocompromised
individuals. Treatment of candidiasis is hampered by the
limited number of antifungal drugs whose efficacy is
compromised by host toxicity, fungistatic activity, and the
emergence of drug resistance. We previously established that
the molecular chaperone Hsp90, which regulates the form and
function of diverse client proteins, potentiates resistance
to the azoles in C. albicans and in the model yeast
Saccharomyces cerevisiae. Genetic studies in S. cerevisiae
revealed that Hsp90's role in azole resistance is to enable
crucial cellular responses to the membrane stress exerted by
azoles via the client protein calcineurin. Here, we
demonstrate that Hsp90 governs cellular circuitry required
for resistance to the only new class of antifungals to reach
the clinic in decades, the echinocandins, which inhibit
biosynthesis of a critical component of the fungal cell
wall. Pharmacological or genetic impairment of Hsp90
function reduced tolerance of C. albicans laboratory strains
and resistance of clinical isolates to the echinocandins and
created a fungicidal combination. Compromising calcineurin
function phenocopied compromising Hsp90 function. We
established that calcineurin is an Hsp90 client protein in
C. albicans: reciprocal co-immunoprecipitation validated
physical interaction; Hsp90 inhibition blocked calcineurin
activation; and calcineurin levels were depleted upon
genetic reduction of Hsp90. The downstream effector of
calcineurin, Crz1, played a partial role in mediating
calcineurin-dependent stress responses activated by
echinocandins. Hsp90's role in echinocandin resistance has
therapeutic potential given that genetic compromise of C.
albicans HSP90 expression enhanced the efficacy of an
echinocandin in a murine model of disseminated candidiasis.
Our results identify the first Hsp90 client protein in C.
albicans, establish an entirely new role for Hsp90 in
mediating resistance to echinocandins, and demonstrate that
targeting Hsp90 provides a promising therapeutic strategy
for the treatment of life-threatening fungal
disease.},
Language = {eng},
Doi = {10.1371/journal.ppat.1000532},
Key = {fds191230}
}
@article{fds191232,
Author = {AK Zaas and M Chen and J Varkey and T Veldman and AO Hero 3rd and J Lucas and Y Huang and R Turner and A Gilbert and R Lambkin-Williams and NC Øien, B Nicholson and S Kingsmore and L Carin and CW Woods and GS
Ginsburg},
Title = {Gene expression signatures diagnose influenza and other
symptomatic respiratory viral infections in
humans.},
Journal = {Cell host & microbe},
Volume = {6},
Number = {3},
Pages = {207-17},
Year = {2009},
Month = {September},
ISSN = {1934-6069},
url = {http://dx.doi.org/10.1016/j.chom.2009.07.006},
Keywords = {Blood Cells • Cells, Cultured • Cohort Studies
• Gene Expression Profiling • Humans •
Influenza A virus • Influenza, Human • Respiratory
Tract Infections • Virus Diseases • Virus
Physiological Phenomena • diagnosis • diagnosis*
• genetics • genetics* • metabolism •
methods* • physiology • virology},
Abstract = {Acute respiratory infections (ARIs) are a common reason for
seeking medical attention, and the threat of pandemic
influenza will likely add to these numbers. Using human
viral challenge studies with live rhinovirus, respiratory
syncytial virus, and influenza A, we developed peripheral
blood gene expression signatures that distinguish
individuals with symptomatic ARIs from uninfected
individuals with >95% accuracy. We validated this "acute
respiratory viral" signature-encompassing genes with a known
role in host defense against viral infections-across each
viral challenge. We also validated the signature in an
independently acquired data set for influenza A and
classified infected individuals from healthy controls with
100% accuracy. In the same data set, we could also
distinguish viral from bacterial ARIs (93% accuracy). These
results demonstrate that ARIs induce changes in human
peripheral blood gene expression that can be used to
diagnose a viral etiology of respiratory infection and
triage symptomatic individuals.},
Language = {eng},
Doi = {10.1016/j.chom.2009.07.006},
Key = {fds191232}
}
@article{fds191202,
Author = {SL LaFayette and C Collins and AK Zaas and WA Schell and M
Betancourt-Quiroz, AA Gunatilaka, JR Perfect and LE
Cowen},
Title = {PKC signaling regulates drug resistance of the fungal
pathogen Candida albicans via circuitry comprised of Mkc1,
calcineurin, and Hsp90.},
Journal = {PLoS pathogens},
Volume = {6},
Number = {8},
Year = {2010},
ISSN = {1553-7374},
url = {http://dx.doi.org/10.1371/journal.ppat.1001069},
Keywords = {Animals • Antifungal Agents • Calcineurin •
Candida albicans • Drug Resistance, Fungal •
Fungal Proteins • HSP90 Heat-Shock Proteins •
Immunoblotting • Mice • Microbial Sensitivity
Tests • Mitogen-Activated Protein Kinases •
Protein Kinase C • Reverse Transcriptase Polymerase
Chain Reaction • Saccharomyces cerevisiae • Signal
Transduction • genetics • genetics* •
metabolism • metabolism* • pharmacology •
physiology},
Abstract = {Fungal pathogens exploit diverse mechanisms to survive
exposure to antifungal drugs. This poses concern given the
limited number of clinically useful antifungals and the
growing population of immunocompromised individuals
vulnerable to life-threatening fungal infection. To identify
molecules that abrogate resistance to the most widely
deployed class of antifungals, the azoles, we conducted a
screen of 1,280 pharmacologically active compounds. Three
out of seven hits that abolished azole resistance of a
resistant mutant of the model yeast Saccharomyces cerevisiae
and a clinical isolate of the leading human fungal pathogen
Candida albicans were inhibitors of protein kinase C (PKC),
which regulates cell wall integrity during growth,
morphogenesis, and response to cell wall stress.
Pharmacological or genetic impairment of Pkc1 conferred
hypersensitivity to multiple drugs that target synthesis of
the key cell membrane sterol ergosterol, including azoles,
allylamines, and morpholines. Pkc1 enabled survival of cell
membrane stress at least in part via the mitogen activated
protein kinase (MAPK) cascade in both species, though
through distinct downstream effectors. Strikingly,
inhibition of Pkc1 phenocopied inhibition of the molecular
chaperone Hsp90 or its client protein calcineurin. PKC
signaling was required for calcineurin activation in
response to drug exposure in S. cerevisiae. In contrast,
Pkc1 and calcineurin independently regulate drug resistance
via a common target in C. albicans. We identified an
additional level of regulatory control in the C. albicans
circuitry linking PKC signaling, Hsp90, and calcineurin as
genetic reduction of Hsp90 led to depletion of the terminal
MAPK, Mkc1. Deletion of C. albicans PKC1 rendered
fungistatic ergosterol biosynthesis inhibitors fungicidal
and attenuated virulence in a murine model of systemic
candidiasis. This work establishes a new role for PKC
signaling in drug resistance, novel circuitry through which
Hsp90 regulates drug resistance, and that targeting stress
response signaling provides a promising strategy for
treating life-threatening fungal infections.},
Language = {eng},
Doi = {10.1371/journal.ppat.1001069},
Key = {fds191202}
}
@article{fds191223,
Author = {SH Ahn and H Deshmukh and N Johnson and LG Cowell and TH Rude and WK Scott and CL Nelson and AK Zaas and DA Marchuk and S Keum and S Lamlertthon and BK
Sharma-Kuinkel, GD Sempowski and VG Fowler Jr},
Title = {Two genes on A/J chromosome 18 are associated with
susceptibility to Staphylococcus aureus infection by
combined microarray and QTL analyses.},
Journal = {PLoS pathogens},
Volume = {6},
Number = {9},
Pages = {e1001088},
Year = {2010},
ISSN = {1553-7374},
url = {http://dx.doi.org/10.1371/journal.ppat.1001088},
Keywords = {Animals • Apoptosis Regulatory Proteins •
Biological Markers • Blotting, Western •
Chemokines • Chromosome Mapping • Chromosomes,
Mammalian • Cytokines • Enzyme-Linked
Immunosorbent Assay • Flow Cytometry • Gene
Expression Profiling • Genetic Predisposition to
Disease* • Humans • Macrophages, Peritoneal •
Male • Mice • Mice, Inbred A • Mice, Inbred
C57BL • Neutrophils • Oligonucleotide Array
Sequence Analysis • Phenotype • Polymorphism,
Single Nucleotide • Quantitative Trait Loci • RNA,
Messenger • RNA, Small Interfering • Reverse
Transcriptase Polymerase Chain Reaction • Sepsis •
Staphylococcal Infections • Staphylococcus aureus
• antagonists & inhibitors • cytology •
genetics • genetics* • metabolism •
microbiology • pathogenicity • pathology •
pharmacology},
Abstract = {Although it has recently been shown that A/J mice are highly
susceptible to Staphylococcus aureus sepsis as compared to
C57BL/6J, the specific genes responsible for this
differential phenotype are unknown. Using chromosome
substitution strains (CSS), we found that loci on
chromosomes 8, 11, and 18 influence susceptibility to S.
aureus sepsis in A/J mice. We then used two candidate gene
selection strategies to identify genes on these three
chromosomes associated with S. aureus susceptibility, and
targeted genes identified by both gene selection strategies.
First, we used whole genome transcription profiling to
identify 191 (56 on chr. 8, 100 on chr. 11, and 35 on chr.
18) genes on our three chromosomes of interest that are
differentially expressed between S. aureus-infected A/J and
C57BL/6J. Second, we identified two significant quantitative
trait loci (QTL) for survival post-infection on chr. 18
using N(2) backcross mice (F(1) [C18A]xC57BL/6J). Ten genes
on chr. 18 (March3, Cep120, Chmp1b, Dcp2, Dtwd2, Isoc1,
Lman1, Spire1, Tnfaip8, and Seh1l) mapped to the two
significant QTL regions and were also identified by the
expression array selection strategy. Using real-time PCR, 6
of these 10 genes (Chmp1b, Dtwd2, Isoc1, Lman1, Tnfaip8, and
Seh1l) showed significantly different expression levels
between S. aureus-infected A/J and C57BL/6J. For two
(Tnfaip8 and Seh1l) of these 6 genes, siRNA-mediated
knockdown of gene expression in S. aureus-challenged
RAW264.7 macrophages induced significant changes in the
cytokine response (IL-1 beta and GM-CSF) compared to
negative controls. These cytokine response changes were
consistent with those seen in S. aureus-challenged
peritoneal macrophages from CSS 18 mice (which contain A/J
chromosome 18 but are otherwise C57BL/6J), but not C57BL/6J
mice. These findings suggest that two genes, Tnfaip8 and
Seh1l, may contribute to susceptibility to S. aureus in A/J
mice, and represent promising candidates for human genetic
susceptibility studies.},
Language = {eng},
Doi = {10.1371/journal.ppat.1001088},
Key = {fds191223}
}
@article{fds191227,
Author = {B Chen and M Chen and J Paisley and A Zaas and C Woods and GS Ginsburg and A
Hero 3rd, J Lucas and D Dunson and L Carin},
Title = {Bayesian inference of the number of factors in
gene-expression analysis: application to human virus
challenge studies.},
Journal = {BMC bioinformatics},
Volume = {11},
Pages = {552},
Year = {2010},
ISSN = {1471-2105},
url = {http://dx.doi.org/10.1186/1471-2105-11-552},
Keywords = {Bayes Theorem • Gene Expression Profiling • Gene
Expression* • Humans • Oligonucleotide Array
Sequence Analysis • Orthomyxoviridae • Respiratory
Syncytial Viruses • Rhinovirus • Virus
Physiological Processes* • genetics • metabolism
• methods • methods*},
Abstract = {BACKGROUND: Nonparametric Bayesian techniques have been
developed recently to extend the sophistication of factor
models, allowing one to infer the number of appropriate
factors from the observed data. We consider such techniques
for sparse factor analysis, with application to
gene-expression data from three virus challenge studies.
Particular attention is placed on employing the Beta Process
(BP), the Indian Buffet Process (IBP), and related
sparseness-promoting techniques to infer a proper number of
factors. The posterior density function on the model
parameters is computed using Gibbs sampling and variational
Bayesian (VB) analysis. RESULTS: Time-evolving
gene-expression data are considered for respiratory
syncytial virus (RSV), Rhino virus, and influenza, using
blood samples from healthy human subjects. These data were
acquired in three challenge studies, each executed after
receiving institutional review board (IRB) approval from
Duke University. Comparisons are made between several
alternative means of per-forming nonparametric factor
analysis on these data, with comparisons as well to
sparse-PCA and Penalized Matrix Decomposition (PMD), closely
related non-Bayesian approaches. CONCLUSIONS: Applying the
Beta Process to the factor scores, or to the singular values
of a pseudo-SVD construction, the proposed algorithms infer
the number of factors in gene-expression data. For real data
the "true" number of factors is unknown; in our simulations
we consider a range of noise variances, and the proposed
Bayesian models inferred the number of factors accurately
relative to other methods in the literature, such as
sparse-PCA and PMD. We have also identified a "pan-viral"
factor of importance for each of the three viruses
considered in this study. We have identified a set of genes
associated with this pan-viral factor, of interest for early
detection of such viruses based upon the host response, as
quantified via gene-expression data.},
Language = {eng},
Doi = {10.1186/1471-2105-11-552},
Key = {fds191227}
}
@article{fds191210,
Author = {AK Zaas and H Aziz and J Lucas, JR Perfect and GS
Ginsburg},
Title = {Blood gene expression signatures predict invasive
candidiasis.},
Journal = {Science translational medicine},
Volume = {2},
Number = {21},
Pages = {21ra17},
Year = {2010},
Month = {March},
ISSN = {1946-6242},
url = {http://dx.doi.org/10.1126/scitranslmed.3000715},
Keywords = {Algorithms • Animals • Bacteremia • Candida
albicans • Candidiasis • Disease Progression
• Gene Expression Profiling* • Male • Mice
• Mice, Inbred BALB C • Species Specificity •
Time Factors • blood* • diagnosis • genetics
• genetics* • isolation & purification* •
microbiology • pathogenicity*},
Abstract = {Candidemia is the fourth most common bloodstream infection,
with Candida albicans being the most common causative
species. Success in reducing the associated morbidity and
mortality has been limited by the inadequacy and time delay
of currently available diagnostic modalities. Focusing on
host response to infection, we used a murine model to
develop a blood gene expression signature that accurately
classified mice with candidemia and distinguished candidemia
from Staphylococcus aureus bacteremia. Validation of the
signature was achieved in an independent cohort of mice.
Genes represented in the signature have known associations
with host defense against Candida and other microorganisms.
Our results demonstrate a temporal pattern of host molecular
responses that distinguish candidemia from S. aureus-induced
bacteremia and establish a novel paradigm for infectious
disease diagnosis.},
Language = {eng},
Doi = {10.1126/scitranslmed.3000715},
Key = {fds191210}
}
@article{fds191208,
Author = {CD Pfeiffer and G Garcia-Effron and AK Zaas, JR Perfect and DS
Perlin, BD Alexander},
Title = {Breakthrough invasive candidiasis in patients on
micafungin.},
Journal = {Journal of clinical microbiology},
Volume = {48},
Number = {7},
Pages = {2373-80},
Year = {2010},
Month = {July},
ISSN = {1098-660X},
url = {http://dx.doi.org/10.1128/JCM.02390-09},
Keywords = {Adolescent • Adult • Aged • Antifungal Agents
• Candida • Candidiasis • Drug Resistance,
Fungal • Echinocandins • Female • Fungal
Proteins • Glucosyltransferases • Humans •
Lipopeptides • Male • Microbial Sensitivity Tests
• Middle Aged • administration & dosage •
complications • drug effects* • genetics •
genetics* • isolation & purification •
microbiology* • pharmacology • therapeutic
use*},
Abstract = {For Candida species, a bimodal wild-type MIC distribution
for echinocandins exists, but resistance to echinocandins is
rare. We characterized isolates from patients with invasive
candidiasis (IC) breaking through >or=3 doses of micafungin
therapy during the first 28 months of its use at our center:
MICs were determined and hot-spot regions within FKS genes
were sequenced. Eleven of 12 breakthrough IC cases
identified were in transplant recipients. The median
duration of micafungin exposure prior to breakthrough was 33
days (range, 5 to 165). Seventeen breakthrough isolates were
recovered: FKS hot-spot mutations were found in 5 C.
glabrata and 2 C. tropicalis isolates; of these, 5
(including all C. glabrata isolates) had micafungin MICs of
>2 microg/ml, but all demonstrated caspofungin MICs of >2
microg/ml. Five C. parapsilosis isolates had wild-type FKS
sequences and caspofungin MICs of 0.5 to 1 microg/ml, but
4/5 had micafungin MICs of >2 microg/ml. The remaining
isolates retained echinocandin MICs of <or=2 microg/ml and
wild-type FKS gene sequences. Breakthrough IC on micafungin
treatment occurred predominantly in severely
immunosuppressed patients with heavy prior micafungin
exposure. The majority of cases were due to C. glabrata with
an FKS mutation or wild-type C. parapsilosis with elevated
micafungin MICs. MIC testing with caspofungin identified all
mutant strains. Whether the naturally occurring polymorphism
within the C. parapsilosis FKS1 gene responsible for the
bimodal wild-type MIC distribution is also responsible for
micafungin MICs of >2 microg/ml and clinical breakthrough or
an alternative mechanism contributes to the nonsusceptible
echinocandin MICs in C. parapsilosis requires further
study.},
Language = {eng},
Doi = {10.1128/JCM.02390-09},
Key = {fds191208}
}
@article{fds191235,
Author = {M Chen and D Carlson and A Zaas and CW Woods and GS Ginsburg and A Hero
3rd and J Lucas and L Carin},
Title = {Detection of viruses via statistical gene expression
analysis.},
Journal = {IEEE transactions on bio-medical engineering},
Volume = {58},
Number = {3},
Pages = {468-79},
Year = {2011},
Month = {March},
ISSN = {1558-2531},
url = {http://dx.doi.org/10.1109/TBME.2010.2059702},
Abstract = {We develop a new bayesian construction of the elastic net
(ENet), with variational bayesian analysis. This modeling
framework is motivated by analysis of gene expression data
for viruses, with a focus on H3N2 and H1N1 influenza, as
well as Rhino virus and RSV (respiratory syncytial virus).
Our objective is to understand the biological pathways
responsible for the host response to such viruses, with the
ultimate objective of developing a clinical test to
distinguish subjects infected by such viruses from subjects
with other symptom causes (e.g., bacteria). In addition to
analyzing these new datasets, we provide a detailed analysis
of the bayesian ENet and compare it to related
models.},
Language = {eng},
Doi = {10.1109/TBME.2010.2059702},
Key = {fds191235}
}
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