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August 2002
Female genital
tract shedding of HIV-1
HIV-1 transmission from mother to child and between sexual partners
is likely to be related to plasma viral load. And female-to-male transmission
is likely to be as frequent as male-to-female transmission. Transmission
typically is due to direct contact with the virus in the genital tract.
Previous studies of HIV-1 shedding in the female genital tract have
been done in small cohorts or among African women. The authors conducted
a cross-sectional study involving a large cohort of HIV-1-infected
women to assess the nature of HIV-1 shedding in the genital tract.
They enrolled 311 HIV-positive women from Jan. 30, 1997 to July 1,
1998. These women were representative of a portion of the Women's
Interagency HIV Study, which was conducted at five sites nationwide.
The authors conducted clinical assessments, cultured HIV-1, and measured
RNA in peripheral blood mononuclear cells and genital secretions.
The presence of HIV-1 RNA or culturable virus in genital secretions
was defined as HIV-1 shedding. The authors found that HIV-1 RNA was
present in 57 percent of the women's genital secretions. Infectious
virus was detected in only six percent. Genital tract HIV shedding
was found in 80 percent of women with detectable plasma RNA and 78
percent of women with positive peripheral blood mononuclear cell cultures.
Thirty-three percent of women with less than 500 copies/mL of plasma
RNA and 39 percent of those with negative peripheral blood mononuclear
cell cultures also had genital tract shedding. The authors concluded
that plasma RNA concentration was the most important factor in predicting
genital HIV shedding, even among women receiving antiretroviral therapy.
HIV-1 shedding did occur in women with less than 500 copies/mL of
plasma HIV-1 RNA however, suggesting that a separate reservoir of
HIV-1 replication may exist in some women.
Kovacs A, Waserman SS, Burns D, et al. Determinants
of HIV-1 shedding in the genital tract of women. Lancet. 2001;358:1593-1601.
Reprints: Dr. Andrea Kovacs, Comprehensive Maternal-Child and Adolescent
HIV Management and Research Center, Los Angeles County and University of Southern
California Medical Center, University of Southern California Keck School of
Medicine, 1640 Marengo St., HRA Bldg., Los Angeles, CA 90033; akovacs@hsc.usc.edu
Cerebrospinal fluid
LDH isoenzymes
The normal lactic dehydrogenase isoenzyme pattern in cerebrospinal
fluid is LDH-1, 38 to 58 percent; LDH-2, 26 to 36 percent; LDH-3,
12 to 24 percent; LDH-4, one to seven percent; and LDH-5, zero to
five percent. Alterations of this pattern are indicative of different
disease states in the central nervous system. Patients with bacterial
meningitis, for example, tend to show elevated levels of LDH-4 and
LDH-5. The authors measured the levels of total LDH and LDH isoenzyme
concentrations in the CSF of children with arrested or progressive
hydrocephalus. They collected CSF from 10 patients, aged two to 16
months, who had hydrocephalus. The findings were compared to those
from 15 pediatric patients with normal results. The mean total LDH
in the CSF was significantly higher in patients with hydrocephalus
(101 ± 23.11 U/L) than in the controls (33.53 ± 5.75 U/L). In the
controls, LDH-1 was the main fraction, followed by LDH-2 and LDH-3.
Only small concentrations of LDH-4 and LDH-5 were detected. In contrast,
hydrocephalus patients showed lower concentrations of LDH-1 and higher
LDH-2 and LDH-3 concentrations. The differences between these results
and those of the controls were statistically significant (P<0.001).
LDH-4 and LDH-5 appeared to be unaffected in the hydrocephalus group.
Nussinovitch M, Volovitz B, Finkelstein J, et
al. Lactic dehydrogenase isoenzymes in cerebrospinal fluid associated
with hydrocephalus. Acta Paediatr. 2001;90:972-974.
Reprints: M. Nussinovitch, Dept. of Paediatrics C, Schneider Children's
Medical Centre of Israel, Petah Tikva, Israel 49202
ToRCH testing by
antigen microarray
Advances in automated microdeposition technologies have led to the
development of high-density ordered arrays of molecules, including
DNA and proteins and peptides. These microarrays may be an extremely
powerful tool for understanding functional relationships between a
large repertoire of genes or antigens. The authors developed such
a protein microarray for the ToRCH panel, printing antigens for Toxoplasma
gondii, rubella virus, cytomegalovirus, and herpes simplex virus
types 1 and 2. The antigens were printed on activated glass slides
using high-speed robotics. The detection limit of the resulting microarray
assay was 0.5 pg of IgG or IgM bound to the slides. The within-slide,
between-slide, and between-batch precision profile showed coefficients
of variation of 1.7 to 18 percent for all antigens. Overall, there
was a greater than 80 percent concordance in results obtained between
enzyme-linked immunosorbent assays and the microarrays in classifying
sera. The authors concluded that microarrays are suitable for the
serodiagnosis of infectious diseases and that the ToRCH assay performs
as well as ELISA.
Mezzasoma L, Bacarese-Hamilton T, Di Cristina
M, et al. Antigen microarrays for serodiagnosis of infectious diseases.
Clin Chem. 2002;48:121-130.
Reprints: Andrea Crisanti, Imperial College of Science, Technology and Medicine,
Dept. of Biology, Biomedical Sciences Building, 5th floor, Imperial College
Road, London SW7 2AZ, United Kingdom; acrs@ic.ac.uk
Antibiotics and
false-positive urine drug screens
Random drug testing has been a common practice in the workplace and
the criminal justice system, as well as under other circumstances.
The immunoassays used to conduct such screening tests generally are
very reliable and have relatively few false-positive results. It has
been reported as early as 1997, however, that quinolone antibiotics,
in particular ofloxacin, could result in false-positive test results
for opiates by the EMIT II (enzyme multiplied immunoassay technique)
assay (Syva, San Jose, Calif.). This finding does not appear to be
well-known, and the authors, upon encountering a case of false-positive
opiate screening with levofloxacin, studied the effects of quinolone
antibiotics on urine drug assays. From September 1998 to March 1999,
the authors confirmed the cross-reactivity of levofloxacin or ofloxacin
using five commercial opiate screening assays and working with six
healthy volunteers. The authors examined the activity of 13 quinolone
antibiotics—levofloxacin, ofloxacin, pefloxacin, enoxacin, moxifloxacin,
gatifloxacin, trovafloxacin, sparfloxacin, lomefloxacin, ciprofloxacin,
clinafloxacin, norfloxacin, and nalidixic acid. The main outcome measured
was the opiate assay threshold for a positive result of 300 ng/mL
of morphine. Nine of the quinolones caused assay results to rise above
the threshold for positive in at least one of the assays. Four of
the assay systems caused false-positive results for at least one quinolone,
and 11 of 13 compounds caused some opiate activity by at least one
assay system. At least one compound caused opiate assay activity in
all five assay systems. The quinolones most likely to cause false-positive
results were levofloxacin, ofloxacin, and pefloxacin. Positive results
were obtained in the urine from all six volunteers. The authors concluded
that greater attention should be focused on the problem of cross-reactivity
of quinolones with immunoassays for opiates.
Baden LR, Horowitz G, Jacoby H, et al. Quinolones
and false-positive urine screening for opiates by immunoassay technology.
JAMA. 2001;286:3115-3119.
Reprints: Dr. Lindsey R. Baden, Division of Infectious Diseases,
Brigham and Women's Hospital, 15 Francis St., PBB-A400, Boston,
MA 02115; lbaden@partners.org
C-reactive protein
and surgical complications
C-reactive protein levels generally have been found to be superior
to leukocyte counts and the erythrocyte sedimentation rate in detecting
surgical complications in patients with bacterial infections. They
have also been shown to reflect the extent of surgical trauma. Preoperative
C-reactive protein levels are considered a risk factor for predicting
postoperative outcomes. The time course or kinetics of change of C-reactive
protein levels are not well understood with respect to differentiating
infections from surgical trauma. The authors studied the kinetics
of C-reactive protein levels of 330 patients who had operative fracture
treatment. The measurements were obtained before and after surgery.
The pattern of C-reactive protein values was similar in all patients
who had an uneventful postoperative course. The peak level of C-reactive
protein occurred on the second postoperative day and was higher in
cases of femoral fractures (15.4 mg/dL) versus ankle fractures (3.5
mg/dL). In 47 patients with complicated postoperative recoveries,
C-reactive protein was useful as a marker for risk stratification
and as an early indicator of infection. Nine patients with deep wound
infections showed high rises of C-reactive protein, and seven of these
patients showed an elevation in C-reactive protein level before the
onset of clinical symptoms. A cut-off level of 14 mg/dL on the fourth
day after surgery was recorded for patients with deep wound infection.
Scherer MA, Neumaier M, von Gumppenberg S. C-reactive
protein in patients who had operative fracture treatment. Clin
Orthop. 2001;393:287-293.
Reprints: Dr. Michael A. Scherer, Dept. for Trauma and Reconstructive Surgery,
Abt. für Unfallchirurgie Ismaningerstr. 22, D-81675, University Hospital rechts
der Isar der TU-München, München, Germany
Methods for estimating
plasma bicarbonate in critically ill patients
Some researchers have questioned the reliability and applicability
of the constants in the Henderson-Hasselbalch equation when used to
estimate plasma bicarbonate concentration in critically ill patients.
An alternative to this approach is to measure total carbon dioxide,
but this method is undermined by the loss of carbon dioxide to the
atmosphere. A third approach is the Stewart approach to acid-base
physiology, which estimates the plasma bicarbonate concentration by
manipulating the strong-ion-gap equation. This method has not been
examined. Using data from a recent study of acid-base disorders in
critically ill patients, the authors asked, what is the agreement
in estimating plasma bicarbonate concentration between the Henderson-Hasselbalch,
enzymatic, and strong-ion-gap methods? The authors collected 100 data
sets from the records of routine daily blood samples from critically
ill patients. They constructed Bland-Altman diagrams and analyses
to compare the three methods. The authors proposed that bias greater
than ±1 mmol/L and limits of agreement wider than a bias of ±2 mmol/L
were clinically significant. Comparing the Henderson-Hasselbalch method
to the enzymatic method, the bias was 2.1 mmol/L and the limits of
agreement were -1.8 mmol/L to 5.9 mmol/L. In comparing the Henderson-Hasselbalch
method to the strong-ion-gap method, the bias was -9.1 mmol/L and
the limits of agreement were -17.1 mmol/L to -1.1 mmol/L. Finally,
comparing the enzymatic to the strong-ion-gap method, the bias was
-11.2 mmol/L and the limits of agreement were -18.2 mmol/L to -4.2
mmol/L. The authors concluded that there is poor agreement between
the two established methods and even poorer agreement between the
established assays and the strong-ion-gap method. The latter is too
inaccurate for clinical application.
Story DA, Poustie S, Bellomo R. Comparison of
three methods to estimate plasma bicarbonate in critically ill patients:
Henderson-Hasselbalch, enzymatic, and strong-ion-gap. Anaesth Intensive
Care. 2001;29:585-590.
Reprints: Dr. D.A. Story, Dept. of Anaesthesia, Austin and Repatriation
Medical Centre, Studley Road, Heidelberg, Victoria 3084, Australia
Candidate genetic
marker for bone mineral density variation
Osteoporosis is characterized by low bone mineral density measurements.
Population genetic evidence supports the concept that variation in
bone mineral density is under strong genetic control, with heritability
estimates ranging from 0.5 to 0.9. Molecular genetic studies of bone
mineral density variation have produced inconsistent findings. The
few linkage studies that have been reported have generated intriguing
results concerning the marker D11S987 on chromosome 11q12-13. Three
distinct Mendelian traits that are related to bone mineral density
have been reported in human pedigrees, with significant linkage to
chromosome 11q12-13. The traits are osteoporosis-pseudoglioma, autosomal
recessive osteopetrosis, and autosomal dominant high bone mass. Research
was undertaken to investigate a possible link between marker D11S987
and bone mineral density variation. The authors studied 374 sibling
pairs who showed significant linkage of D11S987 to normal BMD variation,
with a maximum logarithm of odds score of 3.5. A subsequent linkage
study involving 595 sibling pairs demonstrated reduced significance
for the linkage, with a LOD score greater than 2.2. The authors genotyped
five markers in a genomic region of about 27 cM centering on D11S987
and measured BMD in other traits, including weight, for 635 individuals
from 53 pedigrees. Each of these pedigrees was ascertained through
a proband with BMD Z-scores of less than -1.28 at the hip or spine.
Using several different analyses, the authors found little evidence
linking these five markers to BMD of the hip, wrist, and total body
bone mineral content. The maximum LOD score at D11S987 was 0.15. The
authors concluded that they could not exclude linkage of the D11S987
region to BMD variation, but there is no evidence linking the marker
to BMD in their study population.
Deng HW, Xu FH, Conway T, et al. Is population
bone mineral density variation linked to the marker D11S987 on chromosome
11q12-13? J Clin Endocrinol Metab. 2001;86: 3735-3741.
Reprints: Dr. Hong-Wen Deng, Osteoporosis Research Center, Creighton University,
601 N. 30th St., Ste. 6787, Omaha, NB 68131; deng@creighton.edu
Haptoglobin phenotypic
variation
Human haptoglobin is characterized by a genetic polymorphism involving
three distinct phenotypes—Hp 1-1, Hp 2-1, and Hp 2-2—that
are molecularly heterogeneous. Hp 1-1 is a small (86 kDa) molecule
of well-defined structure; Hp 2-1 is a set of heteropolymers between
86 and 300 kDa; and Hp 2-2 forms large macromolecular complexes of
170 to 1000 kDa. Hp-Hb complex formation is greatly influenced by
the Hp phenotypes. The hepatic clearance of free Hb in plasma, for
example, appears to be less efficient for the Hp 2-2 phenotype than
for other Hp phenotypes, and this produces a degree of oxidative stress
driven by iron. The authors postulated a relationship between Hp phenotypes
and iron status. They studied the Hp phenotypes of 717 healthy adults.
They measured serum indicators of body iron compartments: iron and
transferrin saturation, ferritin, and soluble transferrin receptors.
Intracellular iron status in human monocyte-macrophages was studied
by measuring cytosolic L- and H-ferritin concentrations as well as
the in vitro uptake of I-125 Hb-Hp complexes. In males, but not in
females, the Hp 2-2 phenotype was associated with higher serum iron
transferrin saturation and a higher ferritin concentration than the
Hp 1-1 or Hp 2-1 phenotypes. But soluble transferrin receptor concentrations
were lower. Serum ferritin correlated with monocyte L-ferritin content,
which was also highest in the male Hp 2-2 subgroup. The authors concluded
that the Hp 2-2 phenotype affects serum iron status markers in healthy
males and is associated with higher L-ferritin concentrations in monocyte-macrophages
because of an iron delocalization pathway that selectively occurs
in Hp 2-2 subjects.
Langlois MR, Martin ME, Boelaert JR, et al. The
haptoglobin 202 phenotype affects serum markers of iron status in
healthy males. Clin Chem. 2000;46:1619-1625.
Reprints: M.R. Langlois, Laboratory of Clinical Chemistry, University Hospital
Gent, De Pintelaan 185, B-9000 Gent, Belgium; michel.langlois@rug.ac.be
Selenium levels
in autopsy tissues in Poland
Selenium content varies from one tissue to another and one geographic
region to another depending on the selenium content of the soil. The
highest tissue levels of selenium normally occur in the kidney. Approximately
half this amount is found in the liver, and lower amounts are found
in the brain, lungs, and muscles. Selenium deficiency has been implicated
in certain human diseases, including cardiovascular disease and cancer.
The authors conducted a study in Poland in which they determined selenium
levels in tissues taken at autopsy from 46 healthy individuals killed
in accidents and 75 corpses of victims of various diseases. Selenium
levels on a per-weight-unit basis ranged (in descending order) from
kidney at 469 to liver, spleen, pancreas, heart, brain, lung, bone,
and skeletal muscle at 51. Nevertheless, the highest proportion of
total body selenium was found in skeletal muscles (27.5 percent);
much less was found in bones (16 percent) and blood (10 percent).
Levels were much lower in tissues of corpses with cancer than in controls.
The lowest levels were found in the livers of alcoholics. The levels
of tissue selenium in the study subjects were significantly lower
than the levels reported in Japan, United States, Canada, and other
countries because of inadequate selenium levels in the soil in Poland.
Zachara BA, Pawluk H, Bloch-Boguslawska E, et
al. Tissue level, distribution, and total body selenium content in
healthy and diseased humans in Poland. Arch Environ Health.
2001;56:461-466.
Reprints: Dr. Bronislaw A. Zachara, Dept. of Biochemistry, Medical University,
85-092 Bydgoszcz, Poland; bronz@aci.amb.bydgoszcz.pl
Salmonella
epidemiology
Epidemiologic surveillance for Salmonella species in the United
States began in 1962 and is jointly conducted by the Council of State
and Territorial Epidemiologists, Association of Public Health Laboratories,
and the CDC. Its objectives are to define endemic patterns of salmonellosis,
identify trends in disease transmission, detect outbreaks, and monitor
control efforts. The authors reviewed trends in Salmonella
infections in the United States from 1987 through 1997. During this
time, 441,863 Salmonella isolates were reported, with the highest
age-specific rate among infants (159.5/100,000 infants at two months).
The isolation rates for the organism per annum decreased from 19/100,000
persons to 13/100,000 persons. The trends in these isolation rates,
however, varied by serotype of Salmonella. The isolation rate
of Salmonella serotype Enteritidis increased until 1996, whereas
serotypes Hadar and Heidelberg declined. The serotypes that increased
in frequency were significantly more likely than those that decreased
to be associated with contact with reptiles. Recent declines in food-associated
serotypes may reflect changes in the meat, poultry, and egg industries
that preceded or anticipated the 1996 implementation of the pathogen-reduction
programs. Additional educational measures should be taken to control
the emergence of reptile-associated salmonellosis.
Langlois MR, Martin ME, Boelaert JR, et al. The
haptoglobin 202 phenotype affects serum markers of iron status in
healthy males. Clin Chem. 2000;46:1619-1625.
Reprints: Dr. Sonja J. Olsen, Centers for Disease Control and Prevention,
Foodborne and Diarrheal Diseases Branch, 1600 Clifton Road, MS A-38, Atlanta,
GA 30333; sco2@cdc.gov
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